Impaired distal renal potassium handling in streptozotocin-induced diabetic mice.

Diabetes is closely associated with K+ disturbances during disease progression and treatment. However, it remains unclear whether K+ imbalance occurs in diabetes with normal kidney function. In this study, we examined the effects of dietary K+ intake on systemic K+ balance and renal K+ handling in streptozotocin (STZ)-induced diabetic mice. The control and STZ mice were fed low or high K+ diet for 7 days to investigate the role of dietary K+ intake in renal K+ excretion and K+ homeostasis and to explore the underlying mechanism by evaluating K+ secretion-related transport proteins in distal nephrons. K+-deficient diet caused excessive urinary K+ loss, decreased daily K+ balance, and led to severe hypokalemia in STZ mice compared with control mice. In contrast, STZ mice showed an increased daily K+ balance and elevated plasma K+ level under K+-loading conditions. Dysregulation of the NaCl cotransporter (NCC), epithelial Na+ channel (ENaC), and renal outer medullary K+ channel (ROMK) was observed in diabetic mice fed either low or high K+ diet. Moreover, amiloride treatment reduced urinary K+ excretion and corrected hypokalemia in K+-restricted STZ mice. On the other hand, inhibition of SGLT2 by dapagliflozin promoted urinary K+ excretion and normalized plasma K+ levels in K+-supplemented STZ mice, at least partly by increasing ENaC activity. We conclude that STZ mice exhibited abnormal K+ balance and impaired renal K+ handling under either low or high K+ diet, which could be primarily attributed to the dysfunction of ENaC-dependent renal K+ excretion pathway, despite the possible role of NCC.NEW & NOTEWORTHY Neither low dietary K+ intake nor high dietary K+ intake effectively modulates renal K+ excretion and K+ homeostasis in STZ mice, which is closely related to the abnormality of ENaC expression and activity. SGLT2 inhibitor increases urinary K+ excretion and reduces plasma K+ level in STZ mice under high dietary K+ intake, an effect that may be partly due to the upregulation of ENaC activity.

Metabolic study of trimetazidine using ultra-high performance liquid chromatography-tandem mass spectrometry

Abstract In the present study, the application of ultra-high performance liquid chromatography-tandem mass spectrometry allowed us to study of known-as well as hitherto unknown-trimetazidine (TMZ) metabolites in human urine and to propose their renal excretion profiles. Urine samples from a healthy volunteer were analyzed at baseline and at 0-4 h, 4-8 h, 8-12 h, and 12-24 h after a single dose of TMZ. A dilute-and-shoot procedure was used as sample treatment before separation. Full-scan spectra of possible metabolites were acquired. Additionally, product ion scan spectra of precursor ions of interest were also acquired at two collision energies. Intact TMZ was a major excretion product, with a maximum concentration at 4-8 h after administration. Moreover, five minor metabolites were observed, namely trimetazidine-N-oxide (M1), N-formyl trimetazidine (M2), desmethyl-trimetazidine O-sulfate (M3), desmethyl-trimetazidine O-glucuronide (M4), and desmethyl-trimetazidine-N-oxide-O-glucuronide (M5). Metabolite M5 has not previously been reported. Excretion curves were constructed based on the chromatographic peak areas of specific mass transitions (precursor ion > product ion) related to each of the detected metabolites

High baseline ROMK activity in the mouse late distal convoluted and early connecting tubule probably contributes to aldosterone-independent K+ secretion.

The renal outer medullary K+ channel (ROMK) is colocalized with the epithelial Na+ channel (ENaC) in the late distal convoluted tubule (DCT2), connecting tubule (CNT), and cortical collecting duct (CCD). ENaC-mediated Na+ absorption generates the electrical driving force for ROMK-mediated tubular K+ secretion, which is critically important for maintaining renal K+ homeostasis. ENaC activity is aldosterone dependent in the late CNT and early CCD (CNT/CCD) but aldosterone independent in the DCT2 and early CNT (DCT2/CNT). This suggests that under baseline conditions with low plasma aldosterone, ROMK-mediated K+ secretion mainly occurs in the DCT2/CNT. Therefore, we hypothesized that baseline ROMK activity is higher in the DCT2/CNT than in the CNT/CCD. To test this hypothesis, patch-clamp experiments were performed in the DCT2/CNT and CNT/CCD microdissected from mice maintained on a standard diet. In single-channel recordings from outside-out patches, we detected typical ROMK channel activity in both the DCT2/CNT and CNT/CCD and confirmed that ROMK is the predominant K+ channel in the apical membrane. Amiloride-sensitive and tertiapin-sensitive whole-cell currents were determined to assess ENaC and ROMK activity, respectively. As expected, baseline amiloride-sensitive current was high in the DCT2/CNT (∼370 pA) but low in the CNT/CCD (∼60 pA). Importantly, tertiapin-sensitive current was significantly higher in the DCT2/CNT than in the CNT/CCD (∼810 vs. ∼350 pA). We conclude that high ROMK activity in the DCT2/CNT is critical for aldosterone-independent renal K+ secretion under baseline conditions. A low-K+ diet significantly reduced ENaC but not ROMK activity in the DCT2/CNT. This suggests that modifying ENaC activity in the DCT2/CNT plays a key regulatory role in adjusting renal K+ excretion to dietary K+ intake.NEW & NOTEWORTHY ROMK-mediated renal K+ secretion is essential for maintaining K+ balance and requires a lumen negative transepithelial potential critically dependent on ENaC activity. Using microdissected distal mouse tubules, we demonstrated that baseline apical ROMK activity is high in the DCT2/CNT. Aldosterone-independent baseline ENaC activity is also high in the DCT2/CNT and downregulated by a low-K+ diet, which highlights the important role of the DCT2/CNT in regulating K+ secretion in an aldosterone-independent manner.

Effect of high-dose intravenous ascorbic acid on cancer patients following ketogenic diet.

BACKGROUND: The role of ascorbic acid in cancer therapy is mainly due to its structural similarity with glucose. When supplemented intravenously in high dose, ascorbic acid can get into the cancer cells and induce apoptosis by causing mitochondrial damage. AIM: The aim was to study the efficacy of high-dose intravenous (IV) ascorbic acid as monotherapy in cancer patients following ketogenic diet and its role in improving the quality of life. RESULTS: C-reactive protein (CRP) and erythrocyte sedimentation rates (ESRs) were considered as parameters to determine the efficacy of the treatment, and substantial decrease in both the levels was observed within 1-week treatment. CRP levels declined from 3.1946 ± 3.2508 mg/L to 1.0606 ± 0.6706 mg/L (P = 2.27E-10), whereas ESR levels declined from 64.1333 ± 38.8253 mm/h to 31.6 ± 16.5520 mm/h (P = 0.0041). A decline in these parameters shows the association of ascorbic acid in reducing the inflammatory response in cancer. The renal effect of ascorbic acid was also studied by analyzing the creatinine level pre- and postascorbic acid treatment sessions, and it raised from 0.8526 ± 0.22904 to 1.1666 ± 0.2894 mg/dL (P = 1.18E-14). This showed the renal impact of ascorbic acid. CONCLUSION: The study highlighted the clinical benefit of IV ascorbic acid in the reduction of inflammatory response in cancer patients. The renal adverse events associated with ascorbic acid alarm the use with caution and therapeutic drug monitoring for ascorbic acid.

Dapagliflozin Reduces Urinary Albumin Excretion by Downregulating the Expression of cAMP, MAPK, and cGMP-PKG Signaling Pathways Associated Genes.

Objective: Diabetic nephropathy (DN), the most severe complication of diabetes mellitus, is characterized by albuminuria and progressive loss of kidney function. Dapagliflozin (DAP), a sodium-glucose cotransporter inhibitor, is an oral medication that improves blood glucose control in diabetic patients. However, the effects and mechanisms of DAP on DN remain unclear. Materials and Methods: The effect of DAP was based on a retrospective cohort study of patients who underwent 2-year surveillance, and the concentration of urine albumin-to-creatinine ratio, glomerular filtration rate, and serum creatinine were collected after treatment with DAP. To investigate the underlying mechanisms through which DAP reduces urinary albumin excretion, we used RNA-sequencing (RNA-seq) to analyze gene expression in human kidney 2 (HK-2) cells treated with DAP. Results: The retrospective cohort analysis indicated that DAP could reduce the excretion rate of urinary albumin in patients with type 2 diabetes and renal impairment. The results of the RNA-seq experiments showed 349 differentially expressed genes between DAP-treated HK-2 cells and control cells. Gene ontology annotation enrichment analysis showed that DAP mainly affected the expression of integral component of membrane- and cell junction-related genes, while the Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis showed that DAP primarily downregulated the expression of gene clusters associated with cyclic adenosine monophosphate, mitogen-activated protein kinase, and cyclic guanosine monophosphate-protein kinase G signaling pathways, which play critical roles in the progression of DN. Conclusion: Our results shed light on the mechanism by which DAP controls DN progression and provide a theoretical basis for the clinical treatment of DN.

Pharmacokinetics and ADME Characterization of Intravenous and Oral [14C]-Linerixibat in Healthy Male Volunteers.

Linerixibat, an oral small-molecule ileal bile acid transporter inhibitor under development for cholestatic pruritus in primary biliary cholangitis, was designed for minimal absorption from the intestine (site of pharmacological action). This study characterized the pharmacokinetics, absorption, metabolism, and excretion of [14C]-linerixibat in humans after an intravenous microtracer concomitant with unlabeled oral tablets and [14C]-linerixibat oral solution. Linerixibat exhibited absorption-limited flip-flop kinetics: longer oral versus intravenous half-life (6-7 hours vs. 0.8 hours). The short intravenous half-life was consistent with high systemic clearance (61.9 l/h) and low volume of distribution (16.3 l). In vitro studies predicted rapid hepatic clearance via cytochrome P450 3A4 metabolism, which predicted human hepatic clearance within 1.5-fold. However, linerixibat was minimally metabolized in humans after intravenous administration: ∼80% elimination via biliary/fecal excretion (>90%-97% as unchanged parent) and ∼20% renal elimination by glomerular filtration (>97% as unchanged parent). Absolute oral bioavailability of linerixibat was exceedingly low (0.05%), primarily because of a very low fraction absorbed (0.167%; fraction escaping first-pass gut metabolism (fg) ∼100%), with high hepatic extraction ratio (77.0%) acting as a secondary barrier to systemic exposure. Oral linerixibat was almost entirely excreted (>99% recovered radioactivity) in feces as unchanged and unabsorbed linerixibat. Consistent with the low oral fraction absorbed and ∼20% renal recovery of intravenous [14C]-linerixibat, urinary elimination of orally administered radioactivity was negligible (<0.04% of dose). Linerixibat unequivocally exhibited minimal gastrointestinal absorption and oral systemic exposure. Linerixibat represents a unique example of high CYP3A4 clearance in vitro but nearly complete excretion as unchanged parent drug via the biliary/fecal route. SIGNIFICANCE STATEMENT: This study conclusively established minimal absorption and systemic exposure to orally administered linerixibat in humans. The small amount of linerixibat absorbed was eliminated efficiently as unchanged parent drug via the biliary/fecal route. The hepatic clearance mechanism was mispredicted to be mediated via cytochrome P450 3A4 metabolism in vitro rather than biliary excretion of unchanged linerixibat in vivo.

Effects of systemic and renal intramedullary endothelin-1 receptor blockade on tissue NO and intrarenal hemodynamics in normotensive and hypertensive rats.

Endothelin 1 (ET-1) seems essential in salt-dependent hypertension, and activation of ETA receptors causes renal vasoconstriction. However, the response in the renal medulla and the role of tissue NO availability has never been adequately explored in vivo. We examined effects of ETA and ETB receptor blockade (atrasentan and BQ788) on blood pressure (MAP), medullary blood flow (MBF) and medullary tissue NO. Effects of systemic and intramedullary blocker application were compared in anesthetized normotensive ET-1-pretreated Sprague-Dawley rats (S-D), in salt-dependent hypertension (HS/UNX) and in spontaneously hypertensive rats (SHR). Total renal blood flow (RBF) was measured using a Transonic renal artery probe, MBF as laser-Doppler flux, and tissue NO signal using selective electrodes. In normotensive rats ET-1 significantly increased MAP, decreased RBF (-20%) and renal medullary NO. In HS/UNX rats atrasentan decreased MAP and increased medullary NO, earlier and more profoundly with intravenous infusion. In SHR atrasentan decreased MAP, more effectively with intravenous infusion; the increase in tissue NO (∼10%) was similar with both routes; however, only intramedullary atrasentan increased MBF. No consistent responses to BQ788 were seen. We confirmed dominant role of ETA receptors in regulation of blood pressure and renal hemodynamics in normotensive and hypertensive rats and provided novel evidence for the role of ETA in control of intrarenal NO bioavailability in salt-dependent and spontaneous hypertension. Under conditions of activation of the endothelin system ETB stimulation preserved medullary perfusion.

SGLT2 inhibitor ipragliflozin exerts antihyperglycemic effects via the blood glucose-dependent increase in urinary glucose excretion in type 2 diabetic mice.

This study investigated the antihyperglycemic effects of the sodium-glucose cotransporter 2 (SGLT2) inhibitor ipragliflozin via the blood glucose-dependent increase in urinary glucose excretion in KK/Ay type 2 diabetic mice. In oral glucose tolerance tests (glucose load: 1, 2, or 4 g/kg) in 24-h-fasted mice, blood glucose levels increased in a glucose-loading dose-dependent manner. Oral administration of ipragliflozin (1 mg/kg) significantly inhibited the increase in blood glucose concomitant with urinary glucose excretion. To investigate the effects of ipragliflozin under low blood glucose conditions, blood glucose level and urinary glucose excretion were examined under fasting conditions in diabetic mice that had prefasted for 0, 6, 12, 18, or 24 h. Ipragliflozin significantly lowered blood glucose levels in mice that had prefasted for 0, 6, or 12 h, but not 18 h or more. Blood glucose level was well correlated with ipragliflozin-induced antihyperglycemic and urinary glucose excretion effects, suggesting that these effects occur in a blood glucose-dependent manner. Thus, in a hyperglycemic state, ipragliflozin exerts a potent antihyperglycemic effect and marked increases in urinary glucose excretion; however, in a non-hyperglycemic or hypoglycemic state, the hypoglycemic effect is weak. Ipragliflozin may therefore be a useful antidiabetic agent for normalizing daily blood glucose fluctuations in type 2 diabetes.

Inhibition of UDP-Glucuronosyltransferase Enzymes by Major Cannabinoids and Their Metabolites.

The UDP-glucuronosyltransferase (UGT) family of enzymes play a central role in the metabolism and detoxification of a wide range of endogenous and exogenous compounds. UGTs exhibit a high degree of structural similarity and display overlapping substrate specificity, often making estimations of potential drug-drug interactions difficult to fully elucidate. One such interaction yet to be examined may be occurring between UGTs and cannabinoids, as the legalization of recreational and medicinal cannabis and subsequent co-usage of cannabis and therapeutic drugs increases in the United States and internationally. In the present study, the inhibition potential of the major cannabinoids Δ9-tetrahydrocannabinol (THC), cannabidiol (CBD), and cannabinol (CBN), as well as their major metabolites, was determined in microsomes isolated from HEK293 cells overexpressing individual recombinant UGTs and in microsomes from human liver and kidney specimens. The highest inhibition was seen by CBD against the glucuronidation activity of UGTs 1A9, 2B4, 1A6, and 2B7, with binding-corrected IC50 values of 0.12 ± 0.020 µM, 0.22 ± 0.045 µM, 0.40 ± 0.10 µM, and 0.82 ± 0.15 µM, respectively. Strong inhibition of UGT1A9 was also demonstrated by THC and CBN, with binding-corrected IC50 values of 0.45 ± 0.12 µM and 0.51 ± 0.063 µM, respectively. Strong inhibition of UGT2B7 was also observed for THC and CBN; no or weak inhibition was observed with cannabinoid metabolites. This inhibition of UGT activity suggests that in addition to playing an important role in drug-drug interactions, cannabinoid exposure may have important implications in patients with impaired hepatic or kidney function. SIGNIFICANCE STATEMENT: Major cannabinoids found in the plasma of cannabis users inhibit several UDP-glucuronosyltransferase (UGT) enzymes, including UGT1A6, UGT1A9, UGT2B4, and UGT2B7. This study is the first to show the potential of cannabinoids and their metabolites to inhibit all the major kidney UGTs as well as the two most abundant UGTs present in liver. This study suggests that as all three major kidney UGTs are inhibited by cannabinoids, greater drug-drug interaction effects might be observed from co-use of cannabinods and therapeutics that are cleared renally.

Minimal Change Disease Following the Pfizer-BioNTech COVID-19 Vaccine.

We report on the development of minimal change disease (MCD) with nephrotic syndrome and acute kidney injury (AKI), shortly after first injection of the BNT162b2 COVID-19 vaccine (Pfizer-BioNTech). A 50-year-old previously healthy man was admitted to our hospital following the appearance of peripheral edema. Ten days earlier, he had received the first injection of the vaccine. Four days after injection, he developed lower leg edema, which rapidly progressed to anasarca. On admission, serum creatinine was 2.31 mg/dL and 24-hour urinary protein excretion was 6.9 grams. As kidney function continued to decline over the next days, empirical treatment was initiated with prednisone 80 mg/d. A kidney biopsy was performed and the findings were consistent with MCD. Ten days later, kidney function began to improve, gradually returning to normal. The clinical triad of MCD, nephrotic syndrome, and AKI has been previously described under a variety of circumstances, but not following the Pfizer-BioNTech COVID-19 vaccine. The association between the vaccination and MCD is at this time temporal and by exclusion, and by no means firmly established. We await further reports of similar cases to evaluate the true incidence of this possible vaccine side effect.

Severe Inflammation, Acute Kidney Injury, and Drug-Drug Interaction: Triple Penalty for Prolonged Elimination of Apixaban in Patients With Coronavirus Disease 2019: A Grand Round.

ABSTRACT: In this article, we present a case of apixaban elimination prolonged by 450% in a patient with coronavirus disease 2019 because of multiple conditions, including drug-drug interaction, severe inflammation, and acute kidney injury. Therapeutic drug monitoring was used to explain unusual routine coagulation assays. This grand round highlights the importance of dialog between the clinician and a therapeutic drug monitoring consultant for optimal patient care.

Sex and Gender Differences in Clinical Pharmacology: Implications for Transgender Medicine.

The transgender adult population is growing globally, but clinical pharmacology has lagged behind other areas of transgender medicine. Medical care for transgender adults may include long-term testosterone or estrogen treatment to align secondary sex characteristics with gender identity. Clinicians often use drug-drug interaction data from the general adult population to predict medication disposition or safety among transgender adults. However, this approach does not address the complex pharmacodynamic effects of hormone therapy in transgender adults. In this review, we critically examine sex-related and gender-related differences in clinical pharmacology and apply these data to discuss current gaps in transgender medicine.

Glycine suppresses kidney calcium oxalate crystal depositions via regulating urinary excretions of oxalate and citrate.

An abnormal urine composition is a key reason for kidney stone formation, but little is known about the roles of small metabolites in the urine during kidney stone formation. Here, we found urine glycine in patients with kidney calcium oxalate (CaOx) stone was significantly lower than that in healthy people via 1 H NMR spectra detection, and investigated the role and underlying mechanism of glycine in the regulation of CaOx stone formation. Our results showed that glycine could significantly attenuate ethylene glycol-induced CaOx crystal depositions in rat kidney via decreasing urine oxalate and increasing urine citrate. Mechanism studies revealed that glycine could decrease urine oxalate through downregulating Slc26a6 expression, whereas increase urine citrate via inhibiting Nadc1 expression. Moreover, glycine decreased the protein expression of both Slc26a6 and Nadc1 via increasing the expression of miRNA-411-3p, which directly bound to the 3'-untranslated regions of Slc26a6 and Nadc1 messenger RNAs, in vitro and in vivo. Together, our results revealed a novel role of glycine in the regulation of kidney CaOx crystal formation and provided a potential target for the treatment of kidney CaOx stone.

Effect of sodium-glucose cotransporter-2 inhibitors on renal handling of electrolytes.

Sodium-glucose cotransporter-2 inhibitors (SGLT2i) are the latest introduction into the armamentarium of diabetes care in the present decade. By virtue of their beneficial effects, such as blood pressure-lowering, bodyweight reduction and significant renal and cardioprotective effects which extends beyond their glycaemic control effects, SGLT2i have become one of the most preferred oral antihyperglycaemic agents of recent times. However, they can influence tubular handling of electrolytes that can result in some electrolyte disturbances such as alteration in the serum levels of magnesium, potassium and phosphate levels. Some of these changes are mild or transient and may not have significant clinical implications. The underlying putative mechanism(s) responsible for disturbances of electrolytes are yet to be deciphered. In this review, we aim to describe electrolytes and acid-base abnormalities due to SGLT2i as well as to elucidate the underlying mechanism.

Benzamil-mediated urine alkalization is caused by the inhibition of H+-K+-ATPases.

Epithelial Na+ channel (ENaC) blockers elicit acute and substantial increases of urinary pH. The underlying mechanism remains to be understood. Here, we evaluated if benzamil-induced urine alkalization is mediated by an acute reduction in H+ secretion via renal H+-K+-ATPases (HKAs). Experiments were performed in vivo on HKA double-knockout and wild-type mice. Alterations in dietary K+ intake were used to change renal HKA and ENaC activity. The acute effects of benzamil (0.2 µg/g body wt, sufficient to block ENaC) on urine flow rate and urinary electrolyte and acid excretion were monitored in anesthetized, bladder-catheterized animals. We observed that benzamil acutely increased urinary pH (ΔpH: 0.33 ± 0.07) and reduced NH4+ and titratable acid excretion and that these effects were distinctly enhanced in animals fed a low-K+ diet (ΔpH: 0.74 ± 0.12), a condition when ENaC activity is low. In contrast, benzamil did not affect urine acid excretion in animals kept on a high-K+ diet (i.e., during high ENaC activity). Thus, urine alkalization appeared completely uncoupled from ENaC function. The absence of benzamil-induced urinary alkalization in HKA double-knockout mice confirmed the direct involvement of these enzymes. The inhibitory effect of benzamil was also shown in vitro for the pig α1-isoform of HKA. These results suggest a revised explanation of the benzamil effect on renal acid-base excretion. Considering the conditions used here, we suggest that it is caused by a direct inhibition of HKAs in the collecting duct and not by inhibition of the ENaC function.NEW & NOTEWORTHY Bolus application of epithelial Na+ channel (EnaC) blockers causes marked and acute increases of urine pH. Here, we provide evidence that the underlying mechanism involves direct inhibition of the H+-K+ pump in the collecting duct. This could provide a fundamental revision of the previously assumed mechanism that suggested a key role of ENaC inhibition in this response.

Clinical Investigation of Metabolic and Renal Clearance Pathways Contributing to the Elimination of Fevipiprant Using Probenecid as Perpetrator.

Fevipiprant, an oral, nonsteroidal, highly selective, reversible, and competitive prostaglandin D2 receptor 2 antagonist, is eliminated by glucuronidation and by direct renal excretion predominantly via organic anion transporter (OAT) 3. This study aimed to assess the effect of simultaneous UDP-glucuronosyltransferase (UGT) and OAT3 inhibition by probenecid on the pharmacokinetics of fevipiprant and its acyl glucuronide (AG) metabolite to support the dosing recommendation of fevipiprant in the presence of drugs inhibiting these pathways; however, phase III clinical trial results did not support its submission. This was a single-center, open-label, single-sequence, two-period crossover study in healthy subjects. Liquid chromatography with tandem mass spectrometry was used to measure concentrations of fevipiprant and its AG metabolite in plasma and urine. In the presence of probenecid, the mean maximum concentrations of fevipiprant increased approximately 1.7-fold, and the area under the concentration-time curve in plasma increased approximately 2.5-fold, whereas the mean apparent volume of distribution and the AG metabolite:fevipiprant ratio decreased. The apparent systemic clearance decreased by approximately 60% and the renal clearance decreased by approximately 88% in the presence of probenecid. Using these data and those from previous studies, the relative contribution of OAT and UGT inhibition to the overall effect of probenecid was estimated. Furthermore, a general disposition scheme for fevipiprant was developed, showing how a perpetrator drug such as probenecid, which interferes with two key elimination pathways of fevipiprant, causes only a moderate increase in exposure and allows estimation of the drug-drug inhibition when only one of the two pathways is inhibited. SIGNIFICANCE STATEMENT: In this drug-drug interaction (DDI) study, probenecid was used as a tool to inhibit both glucuronidation and active renal secretion of fevipiprant. The combination of plasma and urine pharmacokinetic data from this study with available data allowed the development of a quantitative scheme to describe the fate of fevipiprant in the body, illustrating why the DDI effect on fevipiprant is weak-to-moderate even if a perpetrator drug inhibits several elimination pathways.

Glucocorticoids dexamethasone and prednisolone suppress fibroblast growth factor 23 (FGF23).

Fibroblast growth factor 23 (FGF23) is a hormone mainly secreted by bone cells. Its most prominent effects are the regulation of renal phosphate reabsorption and calcitriol (active vitamin D, 1,25(OH)2D3) formation, effects dependent on its co-receptor αKlotho. Besides these actions, further paracrine and endocrine effects exist. The production of FGF23 is regulated by 1,25(OH)2D3, parathyroid hormone, dietary phosphate intake, iron status, as well as inflammation. Glucocorticoids are hormones with anti-inflammatory properties and are, therefore, widely used for acute and chronic inflammatory diseases, autoimmune disorders, and malignancies. The present study explored whether glucocorticoids influence the production of FGF23 in vitro as well as in mice. Fgf23 transcription was analyzed by semi-quantitative real-time PCR. Serum concentrations of FGF23 and 1,25(OH)2D3 were measured by ELISA. Urinary phosphate and Ca2+ excretion were determined in metabolic cages. As a result, in UMR106 rat osteoblast-like cells and in MC3T3-E1 cells, both, dexamethasone and prednisolone, downregulated Fgf23 transcription and FGF23 protein synthesis. Dexamethasone increased Dmp1 and Phex (encoding FGF23-regulating genes) as well as Nfkbia (encoding NFκB inhibitor IκBα) transcription in UMR106 cells. In mice, a single injection of dexamethasone or prednisolone was followed by a significant decrease of serum C-terminal and intact FGF23 concentration and bone Fgf23 mRNA expression within 12 h. These effects were paralleled by increased renal phosphate excretion and enhanced 1,25(OH)2D3 formation. We conclude that a single glucocorticoid treatment strongly downregulates the FGF23 plasma concentration. KEY MESSAGES: Glucocorticoids dexamethasone and prednisolone suppress the formation of bone-derived hormone fibroblast growth factor 23 (FGF23) in vitro. The effect is accompanied by an upregulation of Dmp1, Phex, and IκBα, negative regulators of FGF23, in UMR106 osteoblast-like cells. Glucocorticoid receptor antagonist RU-486 attenuates the effect of dexamethasone on FGF23, Dmp1, and Phex. In mice, a single glucocorticoid dose suppresses FGF23 and enhances 1,25(OH)2D3 (active vitamin D).

A real or apparent decrease in glomerular filtration rate in patients using olaparib?

PURPOSE: Olaparib is a poly (ADP-ribose) polymerase (PARP) inhibitor indicated for ovarian and metastatic breast cancer. Increased serum creatinine levels have been observed in patients taking olaparib, but the underlying mechanism is unknown. This study aimed to investigate if patients receiving olaparib have increased creatinine levels during olaparib treatment and whether this actually relates to a declined glomerular filtration rate (GFR). METHODS: We retrospectively identified patients using olaparib at the Netherlands Cancer Institute - Antoni van Leeuwenhoek (NKI-AVL) from 2012 until 2020. Patients with at least one plasma or serum sample available at baseline/off treatment and during olaparib treatment were included. Cystatin C levels were measured, creatinine levels were available and renal function was determined by calculating the estimated glomerular filtration rate (eGFR) using the Creatinine Equation (CKD-EPI 2009) and the Cystatin C Equation (CKD-EPI 2012). RESULTS: In total, 66 patients were included. Olaparib treatment was associated with a 14% increase in median creatinine from 72 (inter quartile range (IQR): 22) µmol/L before/off treatment to 82 (IQR: 20) µmol/L during treatment (p < 0.001) and a 13% decrease in median creatinine-derived eGFR from 86 (IQR: 26) mL/min/1.73 m2 before/off treatment to 75 (IQR: 29) mL/min/1.73 m2 during treatment (p < 0.001). Olaparib treatment had no significant effect on median cystatin C levels (p = 0.520) and the median cystatin C-derived eGFR (p = 0.918). CONCLUSIONS: This study demonstrates that olaparib likely causes inhibition of renal transporters leading to a reversible and dose-dependent increase in creatinine and does not affect GFR, since the median cystatin C-derived eGFR was comparable before/off treatment and during treatment of olaparib. Using the creatinine-derived eGFR can give an underestimation of GFR in patients taking olaparib. Therefore, an alternative renal marker such as cystatin C should be used to accurately calculate eGFR in patients taking olaparib.

Does fludrocortisone treatment cause hypomagnesemia in children with primary adrenal insufficiency?

Background/aim: Aldosterone is a mineralocorticoid that secreted from adrenal glands and a known factor to increase magnesium excretion by direct and indirect effects on renal tubular cells. Although the frequency of hypomagnesemia was found to be approximately 5% in adult studies, there is no study in the literature investigating the frequency of hypomagnesemia in children by using fludrocortisone, which has a mineralocorticoid activity. Materials and methods: A multi-center retrospective study was conducted, including children who were under fludrocortisone treatment for primary adrenal insufficiency and applied to participant pediatric endocrinology outpatient clinics. Results: Forty-three patients (58.1% male, 41.9% prepubertal) included in the study, whose median age was 9.18 (0.61-19) years, and the most common diagnosis among the patients was a salt-wasting form of congenital adrenal hyperplasia (67.4%). Mean serum magnesium level was 2.05 (±0.13) mg/dL, and hypomagnesemia was not observed in any of the patients treated with fludrocortisone. None of the patients had increased urinary excretion of magnesium. Conclusion: Unlike the studies performed in adults, we could not find any evidence of magnesium wasting effect of fludrocortisone treatment with normal or even high doses in children and adolescents.

Combination treatment with tenapanor and sevelamer synergistically reduces urinary phosphorus excretion in rats.

The majority of patients with chronic kidney disease (CKD) receiving dialysis do not achieve target serum phosphorus concentrations, despite treatment with phosphate binders. Tenapanor is a nonbinder, sodium/hydrogen exchanger isoform 3 (NHE3) inhibitor that reduces paracellular intestinal phosphate absorption. This preclinical study evaluated the effect of tenapanor and varying doses of sevelamer carbonate on urinary phosphorus excretion, a direct reflection of intestinal phosphate absorption. We measured 24-h urinary phosphorus excretion in male rats assigned to groups dosed orally with vehicle or tenapanor (0.3 mg/kg/day) and provided a diet containing varying amounts of sevelamer [0-3% (wt/wt)]. We also evaluated the effect of the addition of tenapanor or vehicle on 24-h urinary phosphorus excretion to rats on a stable dose of sevelamer [1.5% (wt/wt)]. When administered together, tenapanor and sevelamer decreased urinary phosphorus excretion significantly more than either tenapanor or sevelamer alone across all sevelamer dose levels. The Bliss statistical model of independence indicated that the combination was synergistic. A stable sevelamer dose [1.5% (wt/wt)] reduced mean ± SE urinary phosphorus excretion by 42 ± 3% compared with vehicle; together, tenapanor and sevelamer reduced residual urinary phosphorus excretion by an additional 37 ± 6% (P < 0.05). Although both tenapanor and sevelamer reduce intestinal phosphate absorption individually, administration of tenapanor and sevelamer together results in more pronounced reductions in intestinal phosphate absorption than if either agent is administered alone. Further evaluation of combination tenapanor plus phosphate binder treatment in patients receiving dialysis with hyperphosphatemia is warranted.