Renal Excretion Research Articles

Clinical and biochemical associations of urinary metabolites: quantitative epidemiological approach on renal-cardiometabolic biomarkers.

Urinary metabolomics has demonstrated considerable potential to assess kidney function and its metabolic corollaries in health and disease. However, applications in epidemiology remain sparse due to technical challenges. We added 17 metabolites to an open-access urinary nuclear magnetic resonance metabolomics platform, extending the panel to 61 metabolites (n = 994). We also introduced automated quantification for 11 metabolites, extending the panel to 12 metabolites (+creatinine). Epidemiological associations between these 12 metabolites and 49 clinical measures were studied in three independent cohorts (up to 5989 participants). Detailed regression analyses with various confounding factors are presented for body mass index (BMI) and smoking. Sex-specific population reference concentrations and distributions are provided for 61 urinary metabolites (419 men and 575 women), together with methodological intra-assay metabolite variations as well as the biological intra-individual and epidemiological population variations. For the 12 metabolites, 362 associations were found. These are mostly novel and reflect potential molecular proxies to estimate kidney function, as the associations cannot be simply explained by estimated glomerular filtration rate. Unspecific renal excretion results in leakage of amino acids (and glucose) to urine in all individuals. Seven urinary metabolites associated with smoking, providing questionnaire-independent proxy measures of smoking status in epidemiological studies. Common confounders did not affect metabolite associations with smoking, but insulin had a clear effect on most associations with BMI, including strong effects on 2-hydroxyisobutyrate, valine, alanine, trigonelline and hippurate. Urinary metabolomics provides new insight on kidney function and related biomarkers on the renal-cardiometabolic system, supporting large-scale applications in epidemiology.

Stroke and Bleeding in Patients with Atrial Fibrillation and End-Stage Renal Disease Treated with Apixaban Versus Warfarin

Introduction: Treating patients with atrial fibrillation (AF) in patients with advanced chronic kidney disease (CKD) can be particularly challenging as CKD is associated with higher risk of both thrombotic and bleeding events. Direct oral anticoagulants (DOACs) are partially eliminated through the kidneys to varying extents and initial trials validating their effectiveness excluded individuals with advanced kidney disease (creatinine clearance <25). Among the DOACs, apixaban undergoes the least renal excretion, making it a preferred choice for numerous physicians when it comes to stroke prevention in dialysis patients with AF who are either unable or unwilling to take warfarin for any reason. Hence, in this study, we aim to describe the clinical outcomes and safety of apixaban therapy compared to warfarin among patients with end-stage renal disease (ESRD) and AF. Methods: We conducted a retrospective cohort study through population data collected and analyzed through the multicentric platform TriNetX, across 75 health care organizations (HCOs). Using International Classification of Diseases, tenth revision (ICD-10) codes, we identified patients diagnosed with ESRD (N18.6 and Z99.2) and AF (I48.0, I48.1, I48.91) after the year 2000. Over the period of 5 years, the incidence of ischemic embolic stroke, nontraumatic intracranial bleeding, gastrointestinal (GI) bleeding, and hemorrhage were compared among patients treated with warfarin versus those treated with apixaban. Results: Our search yielded 23447 patients that had been started on warfarin and 21466 that had been started on apixaban. After propensity score matching of demographics, 10037 patients remained in each group. The average age in our population was 69 years-old with a standard deviation of 12 years, 62% males and 38% females: 62% white, 22% black, 13% unknown, and 2% Asian. Compared with patients who were treated with warfarin over a 5-year period, patients with ESRD and AF treated with apixaban had a decreased risk of nontraumatic intracranial bleeding (161 events vs 205 events, risk ratio 0.777, confidence interval 0.633 to 0.953, p<0.05) and a decreased risk of hemorrhage (212 events vs 293 events, risk ratio 0.711, confidence interval 0.597 to 0.847, p<0.01). No significant difference was observed in the risk of ischemic embolic stroke (57 events vs 56 events, risk ratio 1.01, confidence interval 0.699 to 1.459, p=0.9567) or in the risk of GI bleed (705 events vs 723 events, risk ratio 0.935, confidence interval 0.847 to 1.033, p=0.1846). Conclusions: Patients with ESRD are at an increased risk of bleeding and thrombotic events. In patients with ESRD and AF, the use of apixaban was associated with a slight reduction in the risk of intracranial bleeding and hemorrhage. Meanwhile, no significant difference was observed in the risk of ischemic stroke or GI bleed. Notably, bleeding events were far more common compared to stroke events in our study. However, the evidence comparing the safety profiles of these two anticoagulants remains limited, particularly concerning randomized double-blind prospective data. Recent studies, such as the RENAL-AF trial showed similar rates of bleeding and strokes in both drugs, however, the study stopped prematurely because of enrollment challenges in the End-stage renal disease (ESRD) population. These findings warrant further investigation in a controlled prospective trial.

Single Ascending Doses of REGN7999, a Monoclonal Antibody Inhibitor of TMPRSS6, Increase Serum Hepcidin and Cause Deep, Sustained Reductions in Serum Iron in Healthy Human Volunteers

Background: Iron overload (IOL) develops in dyserythropoieses such as beta-thalassemia and myelodysplastic syndromes due both to red blood cell transfusions as well as inappropriate regulation of the hormone hepcidin, a key regulator of iron homeostasis. Hepcidin, produced in the liver, sequesters iron mainly in enterocytes and macrophages. In the setting of hepcidin down-regulation, toxic levels of labile iron can accumulate in organs such as the heart, liver, bone marrow, pancreas, and pituitary gland. The current standard-of-care for the treatment of IOL is iron chelation. Chelation solubilizes iron for renal excretion, but is associated with toxicities and limited patient satisfaction, severely limiting adoption and efficacy in certain disorders of IOL. There is a high unmet need for novel therapies which can safely reduce, and even prevent, toxic iron accumulation in organs in patients with IOL. Transmembrane serine protease 6 (TMPRSS6) is a membrane-bound serine protease whose expression is highly restricted to hepatocytes, where its only known role is inhibiting hepcidin transcription by cleaving the hemojuvelin co-receptor and thus reducing the bone morphogenetic protein (BMP) signaling pathway driving hepcidin production. Aims: REGN7999, an investigational monoclonal antibody targeting TMPRSS6, is being developed for the treatment of IOL. We have conducted a phase 1, first-in-human, placebo-controlled, single ascending dose study in healthy volunteers (NCT05481333) to explore the safety, tolerability, pharmacokinetics, and pharmacologic effects associated with REGN7999 administration. Methods: Healthy participants at a single center were randomized 6:2 to receive R7999 or placebo in 5 ascending IV and 3 ascending SC cohorts. Key inclusion criteria included hemoglobin, hematocrit, serum iron, and transferrin saturation at or above the lower limit of normal for age and sex. Female participants were required to be non-menstruating. The primary objective of the study was to identify the safety and tolerability of single doses of REGN7999. Key secondary and exploratory objectives included characterizing the drug concentration profile of REGN7999, and evaluating the effects of REGN7999 on serum biomarkers of iron homeostasis. Data reported uses the cutoff date of June 13, 2023. Results: In all cohorts, a total of 64 subjects were exposed. REGN7999 was well-tolerated, with no serious adverse events reported, and no participants developed anemia. Single doses of REGN7999 (ranging from 10 to 900 mg) resulted in acute 2-fold to 12-fold increases in serum hepcidin among all the REGN7999 dose cohorts, as well as acute 50-70% reductions from baseline in serum iron with the longest sustained effects (up to 7 weeks) in the highest IV and SC dose cohorts. Conclusion: Single doses of REGN7999 are well tolerated by healthy volunteers and lead to sustained reductions in serum iron with no associated safety concerns. These findings support continued development of REGN7999 for the treatment of IOL.

Synthesis and preclinical evaluation of novel 18F-labeled fibroblast activation protein tracers for positron emission tomography imaging of cancer-associated fibroblasts

Fibroblast activation protein (FAP) is overexpressed in cancer-associated fibroblasts in more than 90% of epithelial tumors. Several radiotracers targeting FAPs have been used in clinical settings in recent years. However, the number of 18F-labeled FAP tracers is still limited. Herein, we aimed to develop 18F-labeled FAP tracers with optimized pharmacokinetics. Labeling precursors (NOTA-DD-FAPI and NOTA-PD-FAPI) were synthesized and labeled with fluorine‐18. The precursors NOTA-DD-FAPI (IC50 = 0.21 ± 0.06 nM) and NOTA -PD-FAPI (IC50 = 0.13 ± 0.07 nM) showed a higher affinity for FAP compared to NOTA-FAPI-42 (IC50 = 0.66 ± 0.19 nM). Novel 18F-labeled FAP tracers showed a specific uptake, high internalized fraction, and low cellular efflux in vitro. Compared to the clinically used tracer [18F]AlF-FAPI-42, both the novel 18F-labeled FAP tracers, and especially the [18F]AlF-PD-FAPI tracer with a higher tumor-to-background ratio demonstrated rapid renal excretion and higher tumor uptake during preclinical evaluation, resulting in images with higher contrast. Thus, [18F]AlF-PD-FAPI shows promise for use as a FAP-targeting tracer for clinical translation.

Pseudovicarious Renal Contrast Excretion in a Postoperative Tracheo-Esophageal Fistula patient: Contrast in Pleural Space can be the cause. A Case Report

BACKGROUND: Iodinated contrast is normally not introduced into the intrapleural space except for detecting diaphragmatic injury in stable patients on Computerized Tomography scans, and these studies are limited. Thus, the literature on pleural absorption of contrast is non-existent. We report a novel case with images of renal excretion of contrast after pleural absorption. CASE PRESENTATION: In this case there was inadvertent leakage of contrast into pleural space with subsequent systemic absorption of contrast with renal excretion in a child with a remote history of tracheo-esophageal fistula repair and recent esophageal resection and anastomosis for esophageal stenosis. The child developed a right pleural effusion after the second surgery, proven to be due to anastomotic site leakage. An esophagogram was performed using iodinated contrast, showing the leak and communication with the pleural space. Four hours later, a confusing abdominal radiograph showed excretion of contrast in the kidneys confusing the radiologist reader. CONCLUSION: This imaging finding was due to the systemic absorption of iodinated contrast that had leaked from the anastomotic site into the pleural cavity.

Asperulosidic Acid Ameliorates Renal Interstitial Fibrosis via Removing Indoxyl Sulfate by Up-Regulating Organic Anion Transporters in a Unilateral Ureteral Obstruction Mice Model

Asperulosidic acid is a bioactive iridoid isolated from Hedyotis diffusa Willd. with anti-inflammatory and renal protective effects. However, its mechanism on renal interstitial fibrosis has not been elucidated yet. The present study aims to explore whether asperulosidic acid could retard renal fibrosis by reducing the circulating indoxyl sulfate (IS), which is a uremic toxin and accelerates chronic kidney disease progression by inducing renal fibrosis. In this paper, a unilateral ureteral obstruction (UUO) model of Balb/C mice was established. After the mice were orally administered with asperulosidic acid (14 and 28 mg/kg) for two weeks, blood, liver and kidney were collected for biochemical, histological, qPCR and Western blot analyses. Asperulosidic acid administration markedly reduced the serum IS level and significantly alleviated the histological changes in glomerular sclerosis and renal interstitial fibrosis. It is noteworthy that the mRNA and protein levels of the organic anion transporter 1 (OAT1), OAT3 and hepatocyte nuclear factor 1α (HNF1α) in the kidney were significantly increased, while the mRNA expressions of cytochrome P450 2e1 (Cyp2e1) and sulfotransferase 1a1 (Sult1a1) in the liver were not altered after asperulosidic acid administration. These results reveal that asperulosidic acid could accelerate the renal excretion of IS by up-regulating OATs via HNF1α in UUO mice, thereby alleviating renal fibrosis, but did not significantly affect its production in the liver, which might provide important information for the development of asperulosidic acid.

The Cardiorenal Effects of Piper amalago Are Mediated by the Nitric Oxide/Cyclic Guanosine Monophosphate Pathway and the Voltage-Dependent Potassium Channels.

Piper amalago L. is used in Brazilian traditional medicine to treat inflammation, chest pain, and anxiety. This study aimed to investigate the safety and the renal and cardiovascular effects of the volatile oil (VO) and the aqueous (AE) and hydroalcoholic (HE) extracts from P. amalago. The gas chromatography-mass spectrometry analyses identified 47 compounds in the VO, with β-cyclogermacrene, spathulenol, β-phellandrene, and α-pinene standing out. Among the 47 compounds also found in AE and HE by liquid chromatography-mass spectrometry, glycosylated flavones, organic acids, amino acids, and amides were highlighted. Some examples of these compounds are methoxy-methylenedioxy cis-cinnamoyl pyrrolidine, methoxy-methylenedioxy trans-cinnamoyl pyrrolidine, and cyclobutene-2,4-bis-(1,3-benzodioxol-5-methoxy-6-yl)-1,3-dicarboxapyrrolidide. The acute toxicity experiments were conducted on female rats (n = 5). The cardiorenal assays (n = 8) and evaluations of vasodilatory effects on the mesenteric vascular bed (n = 5) were conducted on male rats. In either extract or VO, there were no mortality or changes in relative weights or histopathological analysis of the organs. Urinary volume and renal electrolyte excretion were elevated significantly during repeated dose 7-day treatment with different preparations from P. amalago. None of the preparations induced hypotension or changes in cardiac electrical activity. Only HE promoted significant vasodilatory effects in rats' isolated mesenteric vascular beds. These effects were completely abolished in the presence of L-NAME plus 4-aminopyridine. Therefore, P. amalago leaves are safe and present diuretic activity after acute and repeated dose administration over 7 days. Moreover, the HE induced significant vasodilator response in rats' mesenteric vascular beds by NO/cGMP pathway and voltage-dependent K+ channels activation.

Serum Titanium Levels Remain Elevated But Urine Titanium is Undetectable in Children With Early Onset Scoliosis Undergoing Growth-Friendly Surgical Treatment: A Prospective Study

Background: Elevated serum titanium levels have been found in patients with early onset scoliosis (EOS) treated with traditional growing rods (TGR), magnetically controlled growing rods (MCGR), and vertical expandable prosthetic titanium rib (VEPTR). No studies have investigated whether serum titanium remains persistently elevated and if titanium is excreted. Our purpose was to compare serum titanium levels in patients with EOS with growth-friendly instrumentation to age-matched controls and evaluate urine titanium and serial serum titanium levels in patients with EOS. Methods: This was a prospective case-control study. Patients with EOS with TGR, MCGR, or VEPTR underwent urine titanium and serial serum titanium collection at a minimum 6-month interval. Control patients did not have a history of metal implant insertion and underwent serum titanium collection before fracture fixation. Results: Twenty patients with EOS (6 TGR, 8 MCGR, and 6 VEPTR) and 12 controls were analyzed. The control group had no detectable serum titanium (0 ng/mL), whereas the patients with EOS had a median serum titanium of 4.0 ng/mL (P < 0.001). Analysis of variance showed significantly higher median serum titanium levels in the MCGR and VEPTR groups than the TGR group at time point 1 (5.5 vs 6.0 vs 2.0 ng/mL, P = 0.01) and time point 2 (6.5 vs 7.5 vs 2.0 ng/mL, P < 0.001). Binary comparisons showed a significant difference in serum titanium level between TGR and MCGR (time point 1: P = 0.026, time point 2: P = 0.011) and TGR and VEPTR (time point 1: P = 0.035, time point 2: P = 0.003). However, there was no difference between MCGR and VEPTR (time point 1: P = 0.399, time point 2: P = 0.492) even though the VEPTR group had a longer duration of follow-up (P = 0.001) and a greater number of lengthenings per patient at the first serum collection (P = 0.016). No patients with EOS had detectable urine titanium. Conclusions: Patients with EOS treated with titanium alloy growth-friendly instrumentation had elevated serum titanium levels compared with age-matched controls that persisted over time with no evidence of renal excretion. Additional studies are necessary to assess for local and systemic accumulation of titanium and the significance of long-term exposure to titanium in growing children. Level of Evidence: Level III, therapeutic.

Study Models of Drug-Drug Interactions Involving P-Glycoprotein: The Potential Benefit of P-Glycoprotein Modulation at the Kidney and Intestinal Levels.

P-glycoprotein (P-gp) is a crucial membrane transporter situated on the cell's apical surface, being responsible for eliminating xenobiotics and endobiotics. P-gp modulators are compounds that can directly or indirectly affect this protein, leading to changes in its expression and function. These modulators can act as inhibitors, inducers, or activators, potentially causing drug-drug interactions (DDIs). This comprehensive review explores diverse models and techniques used to assess drug-induced P-gp modulation. We cover several approaches, including in silico, in vitro, ex vivo, and in vivo methods, with their respective strengths and limitations. Additionally, we explore the therapeutic implications of DDIs involving P-gp, with a special focus on the renal and intestinal elimination of P-gp substrates. This involves enhancing the removal of toxic substances from proximal tubular epithelial cells into the urine or increasing the transport of compounds from enterocytes into the intestinal lumen, thereby facilitating their excretion in the feces. A better understanding of these interactions, and of the distinct techniques applied for their study, will be of utmost importance for optimizing drug therapy, consequently minimizing drug-induced adverse and toxic effects.

Calcitriol reverses age-related hypertension via downregulating renal AP1/AT1R pathway through regulating mitochondrial function

ABSTRACT Background The vitamin D level in the blood is associated with the incidence of hypertension. The present study investigated whether or not calcitriol, an active form of vitamin D, reverses age-related hypertension. Methods Young (3-month-old) and aged (12-month-old) C57BL/6 male mice were administered with or without calcitriol at 150 ng/kg per day by oral gavage for 8 weeks. Blood pressure was measured by tail-cuff plethysmography and telemetry, and superoxide production in renal tissue was assessed by fluorescence imaging, and the protein expression of AP1/AT1R signaling pathway was examined by Western blot. Results We showed that 24-hour renal sodium excretion was impaired and blood pressure was increased in aged mice, which was related to the enhancement of renal AT1R expression and function. In addition, the expression of transcription factor AP1 (a dimer of c-Fos and c-Jun) and the binding of AP1 to the AT1R promoter region was significantly enhanced, accompanied by decreased nuclear translocation of Nrf2, abnormal mitochondrial function including decreased ATP production, NAD+/NADH ratio and mtDNA copy numbers, and increased reactive oxygen species. Calcitriol increased 24-hour urinary sodium excretion and reduced blood pressure in aged mice. Mechanically, calcitriol increased the nuclear translocation of Nrf2, improved mitochondrial function, reduced AP1 binding ability to AT1R promoter, which reversed enhanced AT1R expression and function, and lowered blood pressure in aged mice. Conclusions Our findings indicated that calcitriol reversed age-related hypertension via downregulating renal AP1/AT1R pathway through regulating mitochondrial function. Thus, calcitriol may be a valuable therapeutic strategy for age-related hypertension.

Abstract 15242: The Flipside of Flecainide: A Case of Flecainide Induced Loss of Capture

Introduction: Flecainide is a class 1c anti-arrhythmic agent that slows phase 0 of the fast inward sodium (Na) channels in a rate-dependent fashion leading to decreased conduction velocity in the His-Purkinje and ventricular myocardium. Its high affinity and slow unbinding prolong QRS duration on electrocardiogram (EKG). Partial renal excretion and a narrow therapeutic index of 0.2-1mcg/mL can cause drug toxicity. Case: A 72-year-old woman presented with palpitations and weakness. She had a history of non-ischemic cardiomyopathy, biventricular (BiV) implantable cardioverter defibrillator, frequent premature ventricular contractions on flecainide 100 mg twice a day, and chronic kidney disease. She was hypotensive and with acute kidney injury. EKG showed wide complex ventricular rhythm, QRS duration of 305 ms and intermittent ventricular pacing (Fig.1A), changed since EKG 6 months ago (Fig.1B). Device interrogation revealed normal sensing and impedances but failure to capture from all 3 leads. She had stable lead parameters and appropriate BiV pacing 6 months ago. Chest X ray showed stable lead positions. Flecainide toxicity was suspected, and Na bicarbonate infusion was started. Flecainide level was 2.4mcg/mL (normal <1mcg/mL). She went into an idioventricular rhythm which terminated spontaneously (Fig.1C). After 48 hours of Na bicarbonate infusion, lead capture was noted with narrower QRS (198 ms) (Fig.1D) and on day 6, EKG was back to effective BiV pacing with QRS duration 127 ms (Fig.1E). Discussion: This case highlights the EKG manifestations of flecainide toxicity including QRS widening, sine-wave pattern and loss of pacing capture due to prolonged ventricular refractoriness. It also underscores the reversibility of this condition with prompt treatment using Na bicarbonate. Conclusion: Early recognition and rapid treatment of the cardiac effects of flecainide toxicity is critical in managing a life threatening but reversible medical condition.

Tubular dysfunction impairs renal excretion of pseudouridine in diabetic kidney disease.

Plasma nucleosides-pseudouridine (PU) and N2N2-dimethyl guanosine (DMG) predict the progression of type 2 diabetic kidney disease (DKD) to end-stage renal disease, but the mechanisms underlying this relationship are not well understood. We used a well-characterized model of type 2 diabetes (db/db mice) and control nondiabetic mice (db/m mice) to characterize the production and excretion of PU and DMG levels using liquid chromatography-mass spectrometry. The fractional excretion of PU and DMG was decreased in db/db mice compared with control mice at 24 wk before any changes to renal function. We then examined the dynamic changes in nucleoside metabolism using in vivo metabolic flux analysis with the injection of labeled nucleoside precursors. Metabolic flux analysis revealed significant decreases in the ratio of urine-to-plasma labeling of PU and DMG in db/db mice compared with db/m mice, indicating significant tubular dysfunction in diabetic kidney disease. We observed that the gene and protein expression of the renal tubular transporters involved with nucleoside transport in diabetic kidneys in mice and humans was reduced. In conclusion, this study strongly suggests that tubular handling of nucleosides is altered in early DKD, in part explaining the association of PU and DMG with human DKD progression observed in previous studies.NEW & NOTEWORTHY Tubular dysfunction explains the association between the nucleosides pseudouridine and N2N2-dimethyl guanosine and diabetic kidney disease.

Preparation, Radiolabeling with 68Ga/177Lu and Preclinical Evaluation of Novel Angiotensin Peptide Analog: A New Class of Peptides for Breast Cancer Targeting.

Angiotensin II (AngII) is known to play a significant part in the development of breast cancer by triggering cell propagation of breast cancer, tumor angiogenesis, and regulating tumor invasion and cell migration. AngII arbitrates its action via two G-protein-coupled receptors, AngII type 1 receptor (AT1) and AngII type 2 receptor (AT2). Overexpression of the AT1 receptor in breast cancer cells seems to promote tumor growth and angiogenesis, thus targeting the AT1 receptor using AngII peptide would facilitate the detection of breast carcinoma. We developed an AngII peptide intending to assess whether the peptide of the renin-angiotensin system holds the ability to target AT1 receptor-overexpressing breast cancer in vivo. DOTA-coupled AngII peptide was synthesized by conventional solid-phase peptide synthesis according to Fmoc/HATU chemistry. 68Ga/177Lu labeled AngII peptide was evaluated for its binding with TNBC MDA-MB-231 and ER+ MCF7 cell lines. Pharmacokinetics was studied in healthy balb/c mice and in vivo tumor targeting in nude mice with MDA-MB-231 tumors xenografts. DOTA-AngII peptide was labeled efficiently with 68Ga/177Lu with high labeling efficiency (≥90%). The stability of the radiopeptide in human plasma was found to be high. The AngII peptide analog showed nanomolar (<40 nM) AT1 receptor-specific binding affinity. The radioactivity internalized into MDA-MBA-231 and MCF7 cells were 14.97% and 11.75%, respectively. In vivo, biodistribution in balb/c mice exhibited efficient clearance of 68Ga/177Lu-DOTA-AngII peptide from the blood and elimination predominantly by the renal system due to its hydrophilic nature. A low amount of radioactivity was seen in the major organs including lungs, liver, stomach, spleen, and intestines (<3% ID/g) except the kidneys. A high renal-urinary excretion was observed for the radiotracer. In the TNBC MDA-MB-231 xenografts model, radiolabeled AngII peptide exhibited specific and effective AT1-based targeting in vivo. A rapid and efficient tumor targeting (2.18% ID/g at 45 min p.i.) together with fast renal excretion (~67% ID) highlights the tumor-targeting potential of the radiotracer. The AT1 receptor specificity of the radiotracer was validated by blocking assays. Furthermore, PET imaging provided sufficient visualization of MDA-MB-231 tumors in nude mice. Our findings suggest that 68Ga/177Lu-DOTA-AngII peptide can be useful for the theranostic application of breast carcinomas. This study suggests the potential of this innovative class of peptides for rapid and efficient targeting of tumors and warrants further evaluation.

Adaptable polymerization platform for therapeutics with tunable biodegradability.

Biodegradable polymer-based therapeutics have recently become essential drug delivery biomaterials for various bioactive compounds. Biodegradable and biocompatible polymer-based biomaterials fulfill the requirements of these therapeutics because they enable to obtain polymer biomaterials with optimized blood circulation, pharmacokinetics, biodegradability, and renal excretion. Herein, we describe an adaptable polymerization platform employed for the synthesis of long-circulating, stimulus-sensitive and biodegradable biomaterials, therapeutics, or theranostics. Four chain transfer agents (CTA) were designed and successfully synthesized for the reversible addition-fragmentation chain transfer polymerization, allowing the straightforward synthesis of hydrolytically biodegradable structures of block copolymers-based biomaterials. The controlled polymerization using the CTAs enables controlling the half-life of the hydrolytic degradation of polymer precursors in a wide range from 5h to 21 days. Moreover, the antitumor drug pirarubicin (THP) was successfully conjugated to the polymer biomaterials via a pH-sensitive hydrazone bond for in vitro and in vivo experiments. Polymer conjugates demonstrated superior antitumor efficacy compared to basic linear polymer-based conjugates. Notably, the biodegradable systems, even though those with degradation in the order of hours were selected, increased the half-life of THP in the bloodstream almost two-fold. Indeed, the presented platform design enables the main chain-end specific attachment of targeting ligands or diagnostic molecules. The adaptable polymerization platform design allows tuning of the biodegradability rate, stimuli-sensitive drug bonding, and optimized pharmacokinetics to increase the therapy outcome and system targeting, thus allowing the preparation of targeted or theranostic polymer conjugates. STATEMENT OF SIGNIFICANCE: Biodegradable and biocompatible polymer-based biomaterials are recognized as potential future bioactive nanomedicines. To advance the development of such biomaterials, we developed polymerization platforms utilizing tailored chain transfer agents allowing the straightforward synthesis of hydrolytically degradable polymer biomaterials with tuned biodegradability from hours to several days. The platform allows for the synthesis of long-circulating, stimulus-sensitive and biodegradable biomaterial serving as drug carriers or theranostics. The therapeutic potential was validated by preparation of polymer biomaterials containing pirarubicin, anticancer drug, bound via pH sensitive bond and by showing prolonged blood circulation and increased antitumor activity while keeping the drug side effects low. This work paves the way for future development of biodegradable polymer biomaterials with advanced properties in drug delivery.

Investigation of the effects of oral dapoxetine on kidney function and histopathologic changes in male rats; an animal study and future perspectives

Introduction: Dapoxetine is a novel therapeutic agent employed in treating specific diseases. However, its potential impact on renal excretion processes has yet to be thoroughly investigated, necessitating further exploration in this study. Objectives: This research aimed to assess the effects of dapoxetine on renal function and explore any potential disturbances in kidney excretion processes. Materials and Methods: In this study, 32 male Albino rats weighing between 200-250 g were utilized. The rats were randomly divided into four groups. Group one served as the control and received a normal diet, while groups two to four were administered dapoxetine through gavage at doses of 1 mg/kg, 2 mg/kg, and 4 mg/kg, respectively. The study evaluated blood urea nitrogen (BUN), and serum creatinine levels and examined renal pathological changes in the rats. Results: The results demonstrated a significant increase in average BUN levels in group four compared to other groups (P&lt;0.001). For creatinine, group three displayed higher levels compared to other groups. However, the difference was not statistically significant (P&gt;0.05). Importantly, no indications of apoptosis, necrosis, edema, hydropic degeneration, or glomerular changes were observed in any of the renal cells from the rat groups. Conclusion: Dapoxetine administration led to changes in BUN and creatinine levels; however, it did not adversely affect the renal cells’ pathological outcomes. These results suggest that dapoxetine could be considered for use in the future treatment of certain diseases, considering its minimal impact on renal function. Further investigations and clinical trials are warranted to corroborate these findings and inform medical decision-making.

Personalized application of antimicrobial drugs in pediatric patients with augmented renal clearance: a review of literature.

ARC impacts antimicrobial drugs in pediatric patients. • ARC is inextricably linked to the failure of antimicrobial therapy, recurrence of infection, and subtherapeutic concentrations of drugs. • This study provides an updated overview of the influence of ARC on medication use and clinical outcomes in pediatric patients. • In this context, there are several recommendations for using antibiotics in pediatric patients with ARC: 1) increase the dose administered; 2) prolonged or continuous infusion administration; 3) use of TDM; and 4) use alternative drugs that do not undergo renal elimination.

Effect of probenecid on blood levels and renal elimination of furosemide and endogenous compounds in rats: Discovery of putative organic anion transporter biomarkers

Transporter-mediated drug-drug interactions (DDIs) are assessed using probe drugs and in vitro and in vivo models during drug development. The utility of endogenous metabolites as transporter biomarkers is emerging for prediction of DDIs during early phases of clinical trials. Endogenous metabolites such as pyridoxic acid and kynurenic acid have shown potential to predict DDIs mediated by organic anion transporters (OAT1 and OAT3). However, these metabolites have not been assessed in rats as potential transporter biomarkers. We carried out a rat pharmacokinetic DDI study using probenecid and furosemide as OAT inhibitor and substrate, respectively. Probenecid administration led to a 3.8-fold increase in the blood concentrations and a 3-fold decrease in renal clearance of furosemide. High inter-individual and intra-day variability in pyridoxic acid and kynurenic acid, and no or moderate effect of probenecid administration on these metabolites suggest their limited utility for prediction of Oat-mediated DDI in rats. Therefore, rat blood and urine samples were further analysed using untargeted metabolomics. Twenty-one m/z features (out of >8000 detected features) were identified as putative biomarkers of rat Oat1 and Oat3 using a robust biomarker qualification approach. These m/z features belong to metabolic pathways such as fatty acid analogues, peptides, prostaglandin analogues, bile acid derivatives, flavonoids, phytoconstituents, and steroids, and can be used as a panel to decrease variability caused by processes other than Oats. When validated, these putative biomarkers will be useful in predicting DDIs caused by Oats in rats.

TrisOxine abiotic siderophores for technetium complexation: radiolabeling and biodistribution studies

BackgroundDespite the development of positron emission tomography (PET), single photon emission computed tomography (SPECT) still accounts for around 80% of all examinations performed in nuclear medicine departments. The search for new radiotracers or chelating agents for Technetium-99m is therefore still ongoing. O-TRENSOX and O-TRENOX two synthetic siderophores would be good candidates for this purpose as they are hexadentate ligands based on the very versatile and efficient 8-hydroxyquinoline chelating subunit. First, the radiolabeling of O-TRENOX and O-TRENSOX with 99mTc was investigated. Different parameters such as the quantity of chelating agent, type of reducing agent, pH and temperature of the reaction mixture were adjusted in order to find the best radiolabeling conditions. Then an assessment of the partition coefficient by measuring the distribution of each radiosynthesized complex between octanol and phosphate-buffered saline was realized. The complex’s charge was evaluated on three different celluloses (neutral, negatively charged P81 and positively charged DE81), and finally in vivo studies with biodistribution and SPECT imaging of [99mTc]Tc-O-TRENOX and [99mTc]Tc-O-TRENSOX were performed.ResultsThe radiolabeling studies showed a rapid and efficient complexation of 99mTc with both chelating agents. Using tin pyrophosphate as the reducing agent and a minimum of 100 nmol of ligand, we obtained the [99mTc]Tc-O-TRENOX complex with a radiochemical purity of more than 98% and the [99mTc]Tc-O-TRENSOX complex with one above 97% at room temperature within 5 min. [99mTc]Tc-O-TRENOX complex was lipophilic and neutral, leading to a hepatobiliary elimination in mice. On the contrary, the [99mTc]Tc-O-TRENSOX complex was found to be hydrophilic and negatively charged. This was confirmed by a predominantly renal elimination in mice.ConclusionsThese encouraging results allow us to consider the O-TRENOX/99mTc and O-TRENSOX/99mTc complexes as serious candidates for SPECT imaging chelators. This study should be continued by conjugating these tris-oxine ligands to peptides or antibodies and comparing them with the other bifunctional agents used with Tc.

Molecular mechanisms regulating uric acid metabolism in the human intestine, systematic literature review

This review presents recent data on direct and indirect pathogenetic relationships between metabolism of purine compounds and biochemical processes in cells of the digestive system. A comprehensive analysis of available modern publications for the period from 2000 to 2022 in the Scopus, PubMed, eLIIBRARY, and Google Scholar databases was performed. The hypothesis linking the pathogenesis of hyperuricemia to “renal overload” suggests that the disease may develop due to impaired renal excretion with insufficient excretion of uric acid (UA) via the intestine. Some of the UA transport systems work actively in hepatocytes and enterocytes, which determines their formation and excretion. UA transporter proteins are divided into two categories: urate reabsorption transporters and urate excretion transporters; their expression is regulated by transcription factors, hormones, and metabolites of the intestinal microflora. The influence of intestinal microbiota on UA metabolism is associated with its involvement in purine metabolism, degradation and excretion of UA together with metabolites of intestinal flora, and suppression of gout inflammation, and is evaluated as a new therapeutic potential for gout and hyperuricemia to prevent renal damage and urolithiasis.

Hyperuricaemia-associated all-cause mortality risk effect is increased by non-impaired kidney function – Is renal hyperuricaemia less dangerous?

BackgroundBoth hyperuricaemia and chronic kidney disease are known mortality risk factors. This study examined the modifying effect of renal function on hyperuricaemia-associated mortality risk, which is an issue that has not been studied before. MethodsData on levels of serum uric acid (SUA), creatinine, cystatin C and other variables of persons aged 52–76 years were collected. Persons with SUA >410 μmol/L (75th percentile) were classified as clearly hyperuricaemic and persons with eGFR of ≤67 ml/min (25th percentile) as having reduced kidney function. ResultsReduced kidney function was associated with higher mortality in both SUA groups. When compared to individuals with SUA ≤410 μmol/L and eGFR >67 ml/min the hazard ratio (HR) for all-cause mortality was 1.53 (95 % CI: 1.26–1.84) in clearly hyperuricaemic persons with reduced kidney function, 1.26 (95 % CI: 1.02–1.55) in clearly hyperuricaemic persons with eGFR of >67 ml/min and 1.15 (95 % CI: 0.96–1.39) in persons with SUA ≤410 μmol/L and reduced kidney function. The HR for hyperuricaemia-related premature death was lowest in individuals with reduced eGFR, and it rose strikingly as the eGFR increased above 90 ml/min. ConclusionsReduced kidney function is a risk factor for mortality both in individuals with normal and elevated SUA. The hyperuricaemia-associated mortality risk is remarkably higher in individuals with normal kidney function than in individuals with reduced kidney function. Presumably overproduction of uric acid (metabolic hyperuricaemia) is a separate and more deleterious entity than hyperuricaemia resulting from reduced renal excretion of uric acid (renal hyperuricaemia).