Renal Tubular Reabsorption Research Articles

Nonatherosclerotic Renovascular Hypertension.

Renovascular hypertension (RVH) is a secondary form of high blood pressure resulting from impaired blood flow to the kidneys with subsequent activation of the renin-angiotensin-aldosterone system. Often, this occurs due to abnormally small, narrowed, or blocked blood vessels supplying one or both kidneys (ie: renal artery occlusive disease) and is correctable. Juxtaglomerular cells release renin in response to decreased pressure, which in turn catalyzes the cleavage of circulating angiotensinogen synthesized by the liver to the decapeptide angiotensin I. Angiotensin-converting enzyme then cleaves angiotensin I to form the octapeptide angiotensin II, a potent vasopressor and the primary effector of renin-induced hypertension. The effects of angiotensin II are mediated by signaling downstream of its receptors. Angiotensin receptor type 1 is a G-protein-coupled receptor that activates vasoconstrictor and mitogenic signaling pathways resulting in peripheral arteriolar vasoconstriction and increased renal tubular reabsorption of sodium and water which promotes intravascular volume expansion. Angiotensin II stimulates the adrenal cortical release of aldosterone, which promotes renal tubular sodium reabsorption, resulting in volume expansion. Angiotensin II acts on glial cells and regions of the brain responsible for blood pressure regulation increasing renal sympathetic activation. Angiotensin II simulates the release of vasopressin from the pituitary which stimulates thirst and water reabsorption from the kidney to expand the intravascular volume and cause peripheral vasoconstriction (increased sympathetic tone). All of these mechanisms coalesce to increase arterial pressure by way of arteriolar constriction, enhanced cardiac output, and the retention of sodium and water.

Uncertainty in measurement and the renal tubular reabsorption of phosphate.

The ratio of tubular maximum reabsorption of phosphate to glomerular filtration rate (TmP/GFR) is used toevaluate renal phosphate transport. TmP/GFR is most probably calculated using the formula described by Kenny and Glen or obtained from the nomogram described by Walton and Bijvoet. Even though the calculation itself is well described, no attention has been given to its measurement uncertainty (MU). The aim of this study is to provide a procedure for evaluating the MU of the Kenny and Glen formula; a procedure which is based on the Evaluation of measurement data- Guide to the expression of uncertainty in measurement (GUM). TmP/GFR is a quantity value calculated from the input of measured values for serum (plasma) phosphate and creatinine, plus measured values of urine phosphate and creatinine. Given the measurement uncertainty associated with these input quantities, the GUM describes the mathematical procedures required to determine the uncertainty ofthe calculated TmP/GFR. From a medical laboratory perspective, these input uncertainties are the standard deviations of the respective internal quality control estimates for serum and urine phosphate, plus serum and urine creatinine. Based on representative measurements for the input quantities and their associated standard uncertainties, the expanded relative uncertainty for a calculated TmP/GFR is approximately 3.0-4.5 %. With the continued relevance of the TmP/GFR procedure and the use of creatinine clearance as an estimate of GFR, the addition of an uncertainty estimate is important as an adjunct to this diagnostic procedure.

Occipital bone and tumor-induced osteomalacia: a rare tumor site for an uncommon paraneoplastic syndrome

IntroductionTumor-induced osteomalacia (TIO) is an uncommon paraneoplastic syndrome due to the overproduction of fibroblast growth factor 23 (FGF23). It is predominantly caused by mesenchymal tumors and cured upon their complete removal. Non-surgical treatment is an alternative option but limited to specific clinical conditions.MethodsWe report a challenging case of TIO caused by a tumor involving the occipital bone. We also performed a literature review of TIO caused by tumors localized at this site, focusing on clinical findings, treatment, and outcomes.ResultsThe patient, a 62-year-old male, presented with a long-lasting history of progressive weakness. Biochemical evaluation revealed severe hypophosphatemia due to low renal tubular reabsorption of phosphate with raised intact FGF23 values. A 68 Ga-DOTATATE PET/TC imaging showed a suspicious lesion located in the left occipital bone that MRI and selective venous catheterization confirmed to be the cause of TIO. Stereotactic gamma knife radiosurgery was carried out, but unfortunately, the patient died of acute respiratory failure.To date, only seven additional cases of TIO have been associated to tumors located in the occipital bone. Furthermore, the tumor involved the left side of the occipital bone in all these patients.ConclusionThe occipital region is a difficult area to access so a multidisciplinary approach for their treatment is required. If anatomical differences could be the basis for the predilection of the left side of the occipital bone, it remains to be clarified.

9-LB: PDZK1 Inhibits Fatty Acid Uptake in Renal Tubular Epithelial Cell through FATP2 to Ameliorate Diabetic Kidney Disease

Background: Renal tubular injury is the driving force of diabetic kidney disease (DKD) and their targeting may be an effective means for prevention. PDZK1 is a scaffold protein that is highly expressed in proximal renal tubules and participates in renal tubular reabsorption. However, the role of PDZK1 in DKD with disorder of glucose and lipid metabolism is unclear. Methods: We generated mice lacking the Pdzk1 gene specifically in renal tubular epithelial cells by crossing Pdzk1 floxed mice with Pax8-Cre mice. We observed renal tubular injury and renal fibrosis in Pdzk1 Pax8-cre+ and Pdzk1 Pax8-cre- mice induced by high fat diet and streptozotin. In vitro, we elucidated that PDZK1 regulates fatty acid uptake and renal tubular injury. Results: In this study, proteomic analysis found that compared with the control, the expression of PDZK1 in kidney of DKD mice was significantly reduced. Compared with non-DKD patients, PDZK1 was also lower in renal tissue samples of patients with DKD. Pdzk1 Pax8-cre+ mice significantly increased lipid deposition of renal tubules, renal tubular injury and renal fibrosis compared with Pdzk1 Pax8-cre- mice induced by high fat diet and streptozotin. Knocked down PDZK1 increased intracellular lipid deposition in renal tubular epithelial cells stimulated with high glucose and palmitic acid. Knockdown PDZK1 could promote fatty acid uptake in renal tubular epithelial cells. PDZK1 interacted with fatty acid transporter 2 (FATP2) and inhibited the expression and localization of FATP2 on cell membrane. Conclusion: Diabetes stimulates the decreased expression of PDZK1 in renal tubular epithelial cells. The decrease of PDZK1 attenuates the inhibition of FATP2 localization on cell membrane, promoting ectopic lipid deposition and renal tubular injury, leading to DKD. This study will reveal the new regulatory mechanism of renal tubular injury and provide a new target for the treatment of DKD. Disclosure L. Yang: None. Y. Wang: None. Y. Xu: None. J. Ke: None. D. Zhao: None. Funding National Natural Science Foundation of China (82170454)

#4205 ESTIMATED PROXIMAL TUBULE FLUID PHOSPHATE (EPTFP) CONCENTRATION: AN EARLY MARKER OF CHRONIC KIDNEY DISEASE-MINERAL AND BONE DISORDER (CKD-MBD)?

Abstract Background and Aims MBD develops early in CKD and is associated with kidney damage progression, but CKD-MBD markers, of initial CKD-MBD like FGF23 and α-Klotho are not available in clinical practice. Recently ePTFp has been proposed as a new early marker of MBD. In fact, the progressive reduction of nephron number, with the proportional FGF23 increments, reduce renal tubular phosphate reabsorption to maintain phosphate balance. As a consequence, PTFp concentration per single nephron progressively increases, leading to progression of kidney tubular damage. For this reason, PTFp could represent an innovative early marker of CKD-MBD. We evaluated the relationship of ePTFp with FGF23, α-Klotho and kidney damage progression. Method In CKD stage G2-4, we assayed serum FGF23, α-Klotho and ePTFp [ePTFp = (Phosphaturia / creati-ninuria) x creatininemia x 3,33]. The progression of CKD was evaluated during 5 years and the patients were splitted in two groups according to the basal ePTFp median value. 30 healthy subject pro-vided the normal value of ePTFp. Results In 68 CKD patients (age 58,9 ± 15.6 y.o. eGFR 45 ± 21 mL/min), ePTFp averaged 2.4±1.3 mg/mg which was higher than the control group (ePTFp = 1.2±0.5; p<.01). ePTFp increased progressively along with the increasing CKD stages with values higher than the control group since stage 2 (Table 1). ePTFp showed a positive correlation with FGF23 (r: 0.69; p<.001) and a negative correlation with α-Klotho (r:-237; p<.05) and eGFR (r:-647; p<.001). Follow-up was available in 30 patients (Table 2) and showed a greater reduction of eGFR in the 15 patient with higher ePTFp (threshold 2 mg/dl) (Fig. 1). Conclusion Our data show early and progressive increments of ePTFp in CKD along with increments of FGF23 and PTH and reduction of α-Klotho, as per reciprocal pathophysiologic dependence. ePTFp values > than 2 mg/dl identified patients at highest risk of CKD progression. Accordingly, ePTFp, a surrogate of renal tubular cells phosphate overload, could represent a novel marker of CKD-MBD development and of increased risk of kidney damage potentially helpful to make therapeutic choice.

Endoplasmic reticulum stress in diabetic kidney disease: adaptation and apoptosis after three UPR pathways.

Diabetes kidney disease (DKD) is one of the common chronic microvascular complications of diabetes, which has become the most important cause of modern chronic kidney disease beyond chronic glomerulonephritis. The endoplasmic reticulum is one of the largest organelles, and endoplasmic reticulum stress (ERS) is the basic mechanism of metabolic disorder in all organs and tissues. Under the stimulation of stress-induced factors, the endoplasmic reticulum, as a trophic receptor, regulates adaptive and apoptotic ERS through molecular chaperones and three unfolded protein reaction (UPR) pathways, thereby regulating diabetic renal damage. Therefore, three pathway factors have different expressions in different sections of renal tissues. This study deeply discussed the specific reagents, animals, cells, and clinical models related to ERS in DKD, and reviewed ERS-related three pathways on DKD with glomerular filtration membrane, renal tubular reabsorption, and other pathological lesions of different renal tissues, as well as the molecular biological mechanisms related to the balance of adaption and apoptosis by searching and sorting out MeSH subject words from PubMed database.

Self-oriented ferritin nanocages mitigate iron overload-induced oxidative stress for acute kidney injury

Iron overload-induced oxidative injury of renal tubular epithelial cells plays crucial roles in the pathogenesis of ischemia–reperfusion acute kidney injury (IR-AKI). Curcumin is a polyphenolic compound that can effectively scavenge free radicals, but its poor water solubility and renal distribution restrict its application. Although nanotechnology helps to improve this situation by enabling solubility and renal accumulation, the headstream of oxidative injury, iron overload, has not been reverted. Ferritin (Fer) is a well-known iron storage protein with a favorable particle size for renal filtration that can potently transport excess iron into its core to prevent further oxidative damage. In this regard, ferritin nanocages loaded with curcumin (FNC/Cur) were prepared. It is worth noting that ferritin nanocage-based proteins showed a significant self-orientation capability into injured kidneys at 4 h. After kidney aggregation, glomerular filtration and renal tubular reabsorption, FNC/Cur finally internalized by the target cells (renal tubular epithelial cells) under the mediation of transferrin receptor-1 (TfR1). Once internalized, FNC/Cur released curcumin to reduce excess reactive oxygen species (ROS) with the help of lysosomal acidic environment and protease-rich environment. At the same time, the dissembled FNC or their released heavy chain are able to bind lysosomal redox-active iron for a period of time, thereby temporarily protect against iron-mediated oxidation. As a result, FNC/Cur represents a potential kidney-targeted nanoplatform for synergistic treatment of IR-AKI.

The physiology of growth hormone (GH) in adults: translational journey to GH replacement therapy.

The fact that growth hormone (GH) plays an important role in health after the cessation of growth requiring replacement therapy in adult life has only been recognised in the last three decades. This has only been made possible by recombinant technology providing GH supplies required to undertake investigations in the physiology of GH action and the benefits of replacement therapy in patients identified by rigorously validated diagnostic tests for GH deficiency (GHD). Human studies have revealed important regulatory roles in substrate metabolism, sodium homeostasis, body composition, and physical function. GH-induced anabolism is achieved by stimulating amino acid incorporation into protein while reducing oxidative loss simultaneously enhancing lipid utilisation by stimulating fatty acid oxidation and reducing lipid storage. Sodium and fluid retention are enhanced by activating the renin-angiotensin system and distal renal tubular reabsorption. GH stimulates the aerobic and anaerobic energy systems that underpin muscle and cardiovascular function. These pleiotropic actions explain the clinical picture of increased adiposity, reduced lean mass, and impaired physical and psychological function in the GHD adult, all of which are reversed when GH is replaced. Women require a greater replacement dose of GH than men. This is because androgens enhance while oestrogens attenuate GH action. The oestrogen effect is route-dependent, occurring with oral delivery blunting the liver-mediated actions of GH by directly inhibiting GH receptor signalling, global experience spanning over 30 years has attested to the safety, efficacy, and benefits of replacement therapy for adults with GHD.

Effects of burosumab treatment on mineral metabolism in children and adolescents with X-linked hypophosphatemia.

Burosumab has been approved for the treatment of children and adults with X-linked hypophosphatemia (XLH). Real-world data and evidence for its efficacy in adolescents is lacking. To assess the effects of 12 months burosumab treatment on mineral metabolism in children (aged < 12 years) and adolescents (aged 12-18 years) with XLH. Prospective national registry. Hospital clinics. 93 XLH patients (65 children, 28 adolescents). Z-scores for serum phosphate, alkaline phosphatase (ALP), and renal tubular reabsorption of phosphate per glomerular filtration rate (TmP/GFR) at 12 months. At baseline, patients showed hypophosphatemia (-4.4 SD), reduced TmP/GFR (-6.5 SD) and elevated ALP (2.7 SD, each p < 0.001 versus healthy children) irrespective of age, suggesting active rickets despite prior therapy with oral phosphate and active vitamin D in 88% of patients. Burosumab treatment resulted in comparable increases in serum phosphate and TmP/GFR in children and adolescents with XLH, and a steady decline in serum ALP (each p < 0.001 versus baseline). At 12 months, serum phosphate, TmP/GFR, and ALP levels were within the age-related normal range in approximately 42%, 27% and 80% of patients in both groups, respectively, with a lower, weight-based final burosumab dose in adolescents compared to children (0.72 versus 1.06 mg/kg, p < 0.01). In this real-world setting, 12 months of burosumab treatment was equally effective in normalizing serum ALP in adolescents and children, despite persistent mild hypophosphatemia in half of patients, suggesting that complete normalization of serum phosphate is not mandatory for substantial improvement of rickets in these patients. Adolescents appear to require lower weight-based burosumab dosage than children.

Anti-Diabetic Therapy and Heart Failure: Recent Advances in Clinical Evidence and Molecular Mechanism.

Diabetic patients have a two- to four-fold increase in the risk of heart failure (HF), and the co-existence of diabetes and HF is associated with poor prognosis. In randomized clinical trials (RCTs), compelling evidence has demonstrated the beneficial effects of sodium-glucose co-transporter-2 inhibitors on HF. The mechanism includes increased glucosuria, restored tubular glomerular feedback with attenuated renin-angiotensin II-aldosterone activation, improved energy utilization, decreased sympathetic tone, improved mitochondria calcium homeostasis, enhanced autophagy, and reduced cardiac inflammation, oxidative stress, and fibrosis. The RCTs demonstrated a neutral effect of the glucagon-like peptide receptor agonist on HF despite its weight-reducing effect, probably due to it possibly increasing the heart rate via increasing cyclic adenosine monophosphate (cAMP). Observational studies supported the markedly beneficial effects of bariatric and metabolic surgery on HF despite no current supporting evidence from RCTs. Bromocriptine can be used to treat peripartum cardiomyopathy by reducing the harmful cleaved prolactin fragments during late pregnancy. Preclinical studies suggest the possible beneficial effect of imeglimin on HF through improving mitochondrial function, but further clinical evidence is needed. Although abundant preclinical and observational studies support the beneficial effects of metformin on HF, there is limited evidence from RCTs. Thiazolidinediones increase the risk of hospitalized HF through increasing renal tubular sodium reabsorption mediated via both the genomic and non-genomic action of PPARγ. RCTs suggest that dipeptidyl peptidase-4 inhibitors, including saxagliptin and possibly alogliptin, may increase the risk of hospitalized HF, probably owing to increased circulating vasoactive peptides, which impair endothelial function, activate sympathetic tones, and cause cardiac remodeling. Observational studies and RCTs have demonstrated the neutral effects of insulin, sulfonylureas, an alpha-glucosidase inhibitor, and lifestyle interventions on HF in diabetic patients.

Novel Calcium-Sensing Receptor (CASR) Mutation in a Family with Autosomal Dominant Hypocalcemia Type 1 (ADH1): Genetic Study over Three Generations and Clinical Characteristics

Introduction: Activating mutation of the calcium-sensing receptor gene (CASR) reduces parathyroid hormone secretion and renal tubular reabsorption of calcium, defined as autosomal dominant hypocalcemia type 1 (ADH1). Patients with ADH1 may present with hypocalcemia-induced seizures. Calcitriol and calcium supplementation in symptomatic patients may exacerbate hypercalciuria, leading to nephrocalcinosis, nephrolithiasis, and compromised renal function. Methods: We report on a family with seven members over three generations with ADH1 due to a novel heterozygous mutation in exon 4 of CASR: c.416T>C. Results: This mutation leads to substitution of isoleucine with threonine in the ligand-binding domain of CASR. HEK293T cells transfected with wild type or mutant cDNAs demonstrated that p.Ile139Thr substitution led to increased sensitivity of the CASR to activation by extracellular calcium relative to the wild-type CASR (EC50 of 0.88 ± 0.02 mM vs. 1.1 ± 0.23 mM, respectively, p < 0.005). Clinical characteristics included seizures (2 patients), nephrocalcinosis and nephrolithiasis (3 patients), and early lens opacity (2 patients). In 3 of the patients, serum calcium and urinary calcium-to-creatinine ratio levels obtained simultaneously over 49 patient-years were highly correlated. Using the age-specific maximal-normal levels of calcium-to-creatinine ratio in the correlation equation, we obtained age-adjusted serum calcium levels that are high enough to reduce hypocalcemia-induced seizures and low enough to reduce hypercalciuria. Conclusion: We report on a novel CASR mutation in a three-generation kindred. Comprehensive clinical data enabled us to suggest age-specific upper limit of serum calcium levels, considering the association between serum calcium and renal calcium excretion.

Serum sodium as a diabetes risk factor?

Electrolytes play a key role in controlling fluid status, muscle contraction, neurological function, coagulation, and acid base status, as well as multiple enzymatic reactions. Diabetes is associated with multiple significant electrolyte disorders, predominantly affecting serum sodium (Na), potassium, and magnesium.1 In healthy individuals, serum Na levels range between 135–146 mmol/L. Hyponatremia is defined as a serum Na < 135 mmol/L, typically accompanied by a low serum osmolality (<275 mosm/L). It is the most frequently seen electrolyte disorder, present in about 5% of adults and 35% of hospitalized patients.2, 3 In a New York health system analysis of 10 385 patients hospitalized with COVID-19 in 2020, hyponatremia was present in 37.5% of patients.4 Low serum Na may activate the renin-angiotensin-aldosterone system, may cause increased sympathetic nervous system tone, and may be associated with oxidative stress. Insulin, either administered therapeutically or in the setting of hyperinsulinemia from insulin resistance, increases renal tubular water reabsorption via a presumed vasopressin effect and can result in hyponatremia. Chronic kidney disease and diuretic use in hypertension further increase the risk of hyponatremia as well as other electrolyte imbalances such as hypokalemia and hypomagnesemia.7 Serum Na simply may represent the state of hydration. Might some of these mechanisms contribute to effects of even small deviations in serum Na from normal? Should we look more carefully at Na as a biomarker of outcome? Further analysis of large clinical data sets may give answers to these questions.

Global guidance for the recognition, diagnosis, and management of tumor-induced osteomalacia.

Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome caused by mesenchymal tumors that secrete fibroblast growth factor 23 (FGF23). Patients present with progressive bone pain, muscle weakness, and fragility fractures. TIO is characterized by hypophosphatemia, excess renal phosphate excretion, and low/inappropriately normal 1,25-dihydroxyvitamin D (1,25(OH)2 D) levels. Rarity and enigmatic clinical presentation of TIO contribute to limited awareness among the medical community. Accordingly, appropriate diagnostic tests may not be requested, leading to delayed diagnosis and poorer patient outcomes. We have developed a global guidance document to improve the knowledge of TIO in the medical community, enabling the recognition of patients with TIO and appropriate referral. We provide recommendations aiding diagnosis, referral, and treatment, helping promote a global standard of patient management. We reviewed the literature and conducted a three-round Delphi survey of TIO experts. Statements were drafted based on published evidence and expert opinions (≥70% consensus required for final recommendations). Serum phosphate should be measured in patients presenting with chronic muscle pain or weakness, fragility fractures, or bone pain. Physical examination should establish features of myopathy and identify masses that could be causative tumors. Priority laboratory evaluations should include urine/serum phosphate and creatinine to assess renal tubular reabsorption of phosphate and TmP/GFR, alkaline phosphatase, parathyroid hormone, 25-hydroxyvitamin D, 1,25(OH)2 D, and FGF23. Patients with the clinical/biochemical suspicion of TIO should be referred to a specialist for diagnosis confirmation, and functional imaging should be used to localize causative tumor(s). Recommended treatment is tumor resection or, with unresectable/unidentifiable tumors, phosphate salts plus active vitamin D, or burosumab.

Loss of Pten in Renal Tubular Cells Leads to Water Retention by Upregulating AQP2

Introduction: Phosphatase and tensin (PTEN) is a multifunctional gene associated with the normal development and physiological function of various tissues including the kidney. However, its role in renal tubular reabsorption function has not been well elucidated. Methods: We generated a renal tubule-specific Pten knockout mouse model by crossing Pten^fl/fl mice with Ksp-Cre transgenic mice, evaluated the effect of Pten loss on renal tubular function, and investigated the underlying mechanisms. Results: Pten loss resulted in abnormal renal structure and function and water retention in multiple organs. Our results also demonstrated that aquaporin-2 (AQP2), an important water channel protein, was upregulated and concentrated on the apical plasma membrane of collecting duct cells, which could be responsible for the impaired water balance in Pten loss mice. The regulation of Pten loss on AQP2 was mediated by protein kinase B (AKT) activation. Conclusions: Our results reveal a connection between PTEN gene inactivation and water retention, suggesting the importance of PTEN in normal kidney development and function.

Abstract #1316800: Acute Pancreatitis as a Rare Side Effect of Using Empagliflozin

Acute pancreatitis is a rapid onset inflammatory process of the pancreas. The most common causes are gallstones and alcohol use. Other causes include drug-induced, hypertriglyceridemia, trauma, infectious. Sodium-glucose cotransporter-2 (SGLT2) inhibitors are a class of oral hypoglycemic agents which is approved by the FDA for treating diabetes and heart failure. SGLT2 inhibitors function through a novel mechanism of reducing renal tubular glucose reabsorption, producing a reduction in blood glucose without stimulating insulin release.

Abstract 14073: Hypercalcemia Induced Reversible LBBB

Background: Parathyroid hormone (PTH) and calcitriol are the two hormones responsible for calcium and phosphate homeostasis. PTH exerts its effect on the renal tubular calcium reabsorption and bone resorption. PTH secretion is modulated by calcium acting on the sensitive calcium-sensing receptor on the parathyroid cells. Primary hyperparathyroidism has been linked to hypertension and valvular calcification. Structural changes are also seen including elevated left ventricular mass, diastolic dysfunction and myocardial calcification. Case presentation: A 61-year old female with hyperlipidemia and osteoporosis presented with polyarticular joint pain and diffuse myalgia noted to have elevated PTH of 90 pg/ml and elevated Ca of 10.1 mg/dl. Her calcium levels has ranged from 10.1 to 11.2 mg/dl and her PTH ranged from 90 to 113 pg/ml. She had a negative sestamibi scan, and thyroid ultrasound showed fusiform&amp;nbsp;lesion measuring&amp;nbsp;0.82 x 0.36 in the right posterior neck&amp;nbsp;suspicious for a parathyroid adenoma with the plan made for resection. The diagnosis at this time was primary hyperparathyroidism induced hypercalcemia. She developed exertional dizziness and was found to have a new LBBB and reduced ejection fraction of 40-45% with a small fixed defect in the septal area which was attributed to the LBBB. She was initiated on metoprolol succinate 25 mg, irbesartan 75 mg, atorvastatin 40 mg and aspirin 81 mg because of the reduced systolic function. SPECT was negative for ischemia with a fixed decreased uptake of the septum. She underwent right lower parathyroid excision on 11/2021 with normalization of calcium to 9.4 mg/dl and PTH to 9 pg/ml with resolution of the LBBB and systolic function in 2/2021 improving to 48%. Discussion: Calcium plays a key role in cardiac excitation, depolarization, repolarization, and also coupling of these signals to mechanical contraction via calcium induced calcium release and myofibril cross linking. In this case, calcium was only mildly elevated to cause a partial conduction defect. Literature is lacking on whether there is a threshold level for calcium that predisposes to varying degrees of conduction disease. This case also highlights the temporal nature of symptom resolution following parathyroid surgery with resolution of the LBBB.

LBSUN289 Ketonuria — A Possible Early Indicator Of Impending Euglycemic DKA In Setting Of Recent SGLT-2 Inhibitor Use And Acute Stress

Abstract Introduction - Euglycemic DKA is a notorious entity; previously thought to be primarily afflicting type 1 diabetics and rarely type 2 diabetics in a state of relative insulin deficiency, it has now become a major cause of concern and lead to the issuance of FDA warning in 2015 with regards to its link with SGLT-2 inhibitors. Although DKA is characterized by hyperglycemia, metabolic acidosis and ketogenesis, euglycemic DKA poses a diagnostic challenge as it remains disguised under the cover of euglycemia. Moreover, in the setting of recent SGLT-2 inhibitor use, this definition becomes even more of a paradox as SGLT-2 inhibitors, by the virtue of their action, promote ketogenesis thereby further adding to this enigma. Case presentation - A 67 year old male with hypertension and diabetes mellitus type 2 (on Metformin and Empagliflozin) presented to the emergency room with dizziness. He woke up to go to the bathroom that day and felt weak, dizzy and like he was going to fall. He endorsed nausea and vomiting but denied headache, fever, chills, chest pain, shortness of breath, abdominal pain, and problems with urination/bowel movements. He was afebrile and hemodynamically stable. On examination, left sided dysmetria, loss of coordination, and axial imbalance were noted. No motor/sensory deficits. Labs were significant for WBC count 10 k/mm cu (4 - 11), Creatinine 0.78 mg/dL (0.7 - 1.3), Glucose 279 mg/dL (70 - 99), Bicarbonate 21 mmol/L (21 -31), Anion gap 19 mmol/L (6 - 14), and Lactate 3.2 mmol/L (0.7 - 2). Urinalysis showed glucosuria (glucose &amp;gt;500 mg/dL) and ketonuria (ketones 20 mg/dl). CT head was negative but MRI brain showed left inferior cerebellar peduncle acute ischemic infarct. Stroke protocol was initiated and he transferred to telemetry. The next day, labs showed Glucose 166, Bicarbonate 13, Anion gap 21, and Ketones 5.6 mmol/L (&amp;lt;0.6). Since blood glucose levels remained less than 250 mg/dl with concurrent anion gap metabolic acidosis in the setting of recent Empagliflozin use, he was transferred to ICU for insulin infusion for management of euglycemic diabetic ketoacidosis. Subsequently, he was transitioned to a basal-bolus insulin regimen and transferred to the floors. Discussion - SGLT-2 inhibitors reduce renal tubular glucose reabsorption, causing glycosuria, and promote ketonemia directly by enhancing ketogenesis via glucagon secretion from the pancreatic alpha cells and indirectly by decreasing the renal clearance of ketone bodies. In the setting of acute stress, such as stroke in our patient, and recent SGLT-2 inhibitor use, the presence of ketonuria should be recognized as an early ominous warning sign for euglycemic DKA. A targeted approach detailing diagnostic and therapeutic interventions should be designed to halt its progression in its track before it transforms into the dreaded euglycemic DKA. Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.

Beta-Hydroxybutyric Acid Inhibits Renal Tubular Reabsorption via the AKT/DAB2/Megalin Signalling Pathway.

Patients with diabetic ketosis often exhibit albuminuria. We previously found that acute hyperglycaemia can cause nephrotoxic injury. Here, we explored whether an excessive ketone body level causes kidney injury and the potential underlying mechanism. Fifty-six type 2 diabetes without ketosis (NDK group), 81 type 2 diabetes with ketosis (DK group), and 38 healthy controls (NC group) were enrolled. Clinical data were collected before and after controlling diabetic ketosis. Beta-hydroxybutyric acid (BOHB), an AKT activator, an AKT inhibitor, or plasmids encoding DAB2 were transformed into human renal proximal tubule epithelial cells (HK-2 cells). The urinary albumin-to-creatinine ratio (ACR), transferrin (TF), immunoglobulin G (IgG), Beta2-microglobulin (β2-MG), retinol-binding protein (RBP), N-acetyl-beta-glucosaminidase (NAG), and Beta-galactosidase (GAL) were higher in the DK than NC and NDK groups. The proportion of patients with an increased urinary level of TF, IgG, β2-MG, RBP, NAG, or GAL was higher in the DK group too. After controlling ketosis, urinary microalbumin, TF, IgG, β2-MG, and RBP decreased significantly. In HK-2 cells, albumin endocytosis and megalin expression decreased with increasing BOHB concentration. Compared with BOHB treatment, BOHB with AKT activator significantly increased the DAB2, megalin levels and albumin endocytosis; the AKT inhibitor treatment exhibited the opposite effects. Compared with BOHB treatment, megalin expression and albumin endocytosis were significantly increased after BOHB with DAB2 overexpression treatment. Patients with diabetic ketosis may suffer from glomerular and tubular injuries that recover after ketosis control. High concentrations of BOHB downregulate megalin expression by inhibiting the AKT/DAB2/megalin signalling pathway and albumin endocytosis in proximal renal tubules.

Difelikefalin, a peripherally restricted KOR (kappa opioid receptor) agonist, produces diuresis through a central KOR pathway

Difelikefalin is a peripherally restricted kappa opioid receptor (KOR) agonist that was recently approved by the FDA to treat pruritis in dialysis patients. Here, we investigated the cardiovascular and renal responses to difelikefalin, and using the KOR antagonist norbinaltorphimine (norBNI), examined whether any difelikefalin-induced changes in the renal excretion of water and/or electrolytes were mediated through a central or peripheral KOR pathway. The effects of norBNI pretreatment on nalfurafine, a KOR agonist that crosses the blood-brain barrier, were also examined. We hypothesized that difelikefalin would alter urine output differently than nalfurafine, given that KOR agonists produce diuresis via activating central KORs to inhibit vasopressin release. Following catheterization, conscious Sprague-Dawley rats were infused i.v. with isotonic saline and pretreated with norBNI centrally via an intracerebroventricular (ICV) cannula or peripherally via an intravenous catheter. After stabilization, difelikefalin or nalfurafine was administered i.v. and urine output, heart rate and mean arterial pressure (MAP) were recorded for 90 min. Difelikefalin produced a significant increase in urine output, and significant decrease in urinary sodium and potassium excretion, urine osmolality, and MAP. ICV norBNI pretreatment markedly attenuated the increase in urine output caused by difelikefalin and nalfurafine but did not inhibit the electrolyte effects. However, IV norBNI pretreatment prevented all responses to difelikefalin and nalfurafine. Together, these findings demonstrate that difelikefalin and nalfurafine utilize central KOR pathways to elicit diuresis and a decrease in MAP but enhance renal tubular electrolyte reabsorption through a peripheral KOR pathway, providing important insight into two clinically useful KOR agonists.

A comparative study on obese and non-obese for evaluating the risk of hypertension

Obesity-associated arterial hypertension is characterized by stimulation of the sympathetic nervous system, activation of the renin-angiotensin system (RAS) and sodium retention, among other abnormalities. Stimulation of the sympathetic nervous system has been considered to have an important function in the pathogenesis of obesity-related hypertension. During the early phases of obesity, primary sodium retention exists as a result of increase in renal tubular reabsorption. Plasma renin activity, angiotensinogen, angiotensin II and aldosterone values display significant increase during obesity. Leptin and other neuropeptides are possible links between obesity and the development of hypertension. Obesity should be considered as a chronic medical condition, which is likely to require long-term treatment. Understanding of the mechanisms associated with obesity-related hypertension is essential for successful treatment strategies.