Search Results (119)

Acute kidney injury (AKI) is a frequent and severe complication in trauma patients, affecting up to 28% of intensive care unit (ICU) admissions and contributing significantly to morbidity, mortality, and long-term renal impairment. Trauma-related AKI (TRAKI) arises from diverse mechanisms, including hemorrhagic shock, ischemia–reperfusion injury, systemic inflammation, rhabdomyolysis, nephrotoxicity, and complex organ crosstalk involving the brain, lungs, and abdomen. Pathophysiologically, TRAKI involves early disruption of the glomerular filtration barrier, tubular epithelial injury, and renal microvascular dysfunction. Inflammatory cascades, oxidative stress, immune thrombosis, and maladaptive repair mechanisms mediate these injuries. Trauma-related rhabdomyolysis and exposure to contrast agents or nephrotoxic drugs further exacerbate renal stress, particularly in patients with pre-existing comorbidities. Traditional markers such as serum creatinine (sCr) are late indicators of kidney damage and lack specificity. Emerging structural and stress response biomarkers—such as neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule 1 (KIM-1), liver-type fatty acid-binding protein (L-FABP), interleukin-18 (IL-18), C-C motif chemokine ligand 14 (CCL14), Dickkopf-3 (DKK3), and the U.S. Food and Drug Administration (FDA)-approved tissue inhibitor of metalloproteinases-2 × insulin-like growth factor-binding protein 7 (TIMP-2 × IGFBP-7)—allow earlier detection of subclinical AKI and better predict progression and the need for renal replacement therapy. Together, functional indices like urinary sodium and fractional potassium excretion reflect early microcirculatory stress and add clinical value. In parallel, risk stratification tools, including the Renal Angina Index (RAI), the McMahon score, and the Haines model, enable the early identification of high-risk patients and help tailor nephroprotective strategies. Together, these biomarkers and risk models shift from passive AKI recognition to proactive, personalized management. A new paradigm that integrates biomarker-guided diagnostics and dynamic clinical scoring into trauma care promises to reduce AKI burden and improve renal outcomes in this critically ill population. Full article

Background: Physiologically based pharmacokinetic (PBPK) models utilize computer-based simulations to predict the pharmacokinetics of drugs. By using mathematical modeling techniques consisting of differential equations to simulate blood flow, tissue compositions, and organ properties, the pharmacokinetic properties of drugs can be better understood. Specifically, PBPK models can provide predictive information about drug absorption, distribution, metabolism, and excretion (ADME). The information gained from PBPK models can be useful in both drug discovery, development, and regulatory science. PBPK models can help to address some of the ethical dilemmas that arise during the drug development process, particularly when examining patient populations where testing a new drug may have significant ethical concerns. Patient populations where significant physiological change (i.e., pregnancy, pediatrics, geriatrics, organ impairment populations, etc.) and pathophysiological influences resulting in PK changes can also benefit from PBPK modeling. Additionally, PBPK models can be utilized to predict variations in drug metabolism resulting from genetic polymorphisms, age, and disease states. Methods: In this mini-review, we examine the various applications of PBPK models in drug metabolism. Current research articles related to drug metabolism in genetics, life-stages, and disease states were reviewed. Results: Several key factors in genetics, life-stage, and disease states that affect metabolism in PBPK models are identified. In genetics, the role of CYP enzymes, genetic polymorphisms, and ethnicity may influence metabolism. Metabolism generally changes over time from neonate, pediatric, adult, geriatric, and perinatal populations. Disease states such as renal and hepatic impairment, weight and other acute and chronic diseases also can also alter metabolism. Several examples of PBPK models applying these physiological changes have been published. Conclusions: The utilization and recognition of these specific areas in PBPK modeling can aid in personalized dosing strategy, clinical trial optimization, and regulatory submission. Full article

Hyperuricemia has been increasingly recognized as a modifiable contributor to chronic kidney disease (CKD) progression. Although the traditional classification of hyperuricemia distinguished between renal underexcretion and renal overload types, recent studies suggest that hyperuricemia in patients with CKD can result from heterogeneous excretory defects, including glomerular under-filtration and tubular over-reabsorption. These distinct phenotypes may drive divergent renal injury mechanisms. Experimental and clinical data reveal that monosodium urate crystals and soluble uric acid independently induce renal damage through oxidative stress, inflammasome activation, and endothelial dysfunction. Furthermore, clinical investigations showed inconsistent associations between serum uric acid levels and renal outcomes, suggesting that serum levels alone may not fully reflect urate-related renal risk. This has prompted increasing interest in uricosuric agents, particularly the selective urate reabsorption inhibitors (SURIs), which target tubular urate handling. Urate transporter 1 inhibitors have shown promise in enhancing urinary uric acid excretion and potentially preserving kidney function, especially in patients with CKD. In this review, we summarize the current evidence linking the emerging pathophysiological classification of hyperuricemia, mechanisms or urate-induced kidney injury, and therapeutic interventions. These insights may inform individualized approaches to urate-lowering therapy in CKD and support future research into phenotype-guided treatment strategies. Full article

Contemporary diabetes management is progressively moving away from a glucocentric approach, with growing expectations that novel antidiabetic agents offer benefits beyond glycaemic control. Sodium–glucose cotransporter 2 inhibitors (SGLT2i) have emerged as a cornerstone in the treatment of type 2 diabetes mellitus (T2DM). In addition to reducing blood glucose levels by promoting renal glucose excretion, these agents contribute significantly to cardio–renal–metabolic protection and are associated with improved cardiovascular outcomes and prolonged survival. Although SGLT2 inhibitors do not exhibit a class effect in all clinical aspects, growing evidence suggests their potential in a variety of additional therapeutic areas. We conducted an in-depth review of current scientific literature and clinical studies regarding this class of drugs. SGLT2 inhibitors demonstrate neuroprotective properties and may provide benefits in neurodegenerative disorders such as Alzheimer’s and Parkinson’s disease, potentially through the improvement of mitochondrial function and attenuation of inflammatory responses. Their anti-inflammatory and antioxidative effects are closely linked to reductions in cardiac and renal fibrosis. Other observed benefits include weight loss, improved insulin sensitivity, normalization of serum uric acid, and a reduction in hepatic steatosis—each with important metabolic implications. Furthermore, SGLT2 inhibitors have been shown to positively influence iron metabolism and improve erythrocyte indices. Emerging data also indicate beneficial effects in women with polycystic ovary syndrome. Another promising area of investigation involves the modulation of Klotho protein expression and support of vascular homeostasis. In oncology, SGLT2 inhibitors are gaining attention, with encouraging preclinical results observed in malignancies such as pancreatic, thyroid, breast, and lung cancers. Based on a comprehensive evaluation of the existing body of evidence, it is anticipated that the clinical indications for SGLT2 inhibitors will expand beyond the cardio–renal–metabolic axis in the near future. Full article

Although numerous studies have investigated gadolinium oxide (Gd₂O₃) nanoparticles (NPs) as positive (T₁) magnetic resonance imaging (MRI) contrast agents (CAs), comprehensive reviews on this topic remain scarce. Therefore, it is essential to evaluate their current status and outline prospects. Despite promising physicochemical properties such as considerably higher relaxivities compared to 3–5 s⁻¹mM⁻¹ of clinically approved Gd(III)-chelate contrast agents and encouraging results from in vivo animal studies such as highly improved contrast enhancements, drug loading, and tumor targeting, extensive in vivo toxicity assessments including long-term toxicity and formulation advancements suitable for renal excretion (d < ~3 nm) are still required for clinical translation. This review summarizes the synthesis, characterization, in vitro and in vivo toxicity, and in vivo MRI applications of surface-modified Gd₂O₃ NPs as T₁ MRI CAs. Finally, future perspectives on the development of surface-modified Gd₂O₃ NPs as potential next-generation T₁ MRI CAs are discussed. Full article

L-arginine and its derivatives L-homoarginine, asymmetric dimethylarginine (ADMA), and symmetric dimethylarginine (SDMA) show distinct (patho-) physiological properties as well as a differential renal handling. L-arginine and L-homoarginine have a lower renal clearance and are largely retained (i.e., reabsorbed) as compared to ADMA and SDMA, which are relatively enriched in the urine and excreted. To obtain a more complete picture of what is known regarding transport proteins involved in renal reabsorption and secretion of these substances, a comprehensive literature review and search of cell-specific gene expression databases were performed. Five transport proteins known to transport L-arginine and its derivatives were included, and the data available regarding their tubular expression pattern and their transport characteristics, as well as experimental and clinical data regarding their possible impact on the renal handling of L-arginine and its derivatives, are presented and discussed in a structured narrative review. Based on their transport properties and links to clinical phenotypes, b^0,+AT-rBAT and y⁺LAT1-4F2hc were identified as the most promising candidates to explain a significant part of the observed differential renal handling. This also makes them promising candidates for further investigations as mediators of possible adverse and beneficial drug effects involving L-arginine, L-homoarginine, ADMA, and SDMA. Full article

Background: Sodium–glucose cotransporter-2 inhibitors (SGLT2is), initially developed as antihyperglycemic agents, have emerged as multifunctional therapeutics with profound cardiorenal and metabolic benefits. Their unique insulin-independent mechanism, targeting renal glucose reabsorption, distinguishes them from conventional antidiabetic drugs. Mechanisms and Clinical Evidence: SGLT2is induce glycosuria, reduce hyperglycemia, and promote weight loss through increased caloric excretion. Beyond glycemic control, they modulate tubuloglomerular feedback, attenuate glomerular hyperfiltration, and exert systemic effects via natriuresis, ketone utilization, and anti-inflammatory pathways. Landmark trials (DAPA-HF, EMPEROR-Reduced, CREDENCE, DAPA-CKD) demonstrate robust reductions in heart failure (HF) hospitalizations, cardiovascular mortality, and chronic kidney disease (CKD) progression, irrespective of diabetes status. Adipose Tissue and Metabolic Effects: SGLT2is mitigate obesity-associated adiposopathy by shifting macrophage polarization (M1 to M2), reducing proinflammatory cytokines (TNF-α, IL-6), and enhancing adipose tissue browning (UCP1 upregulation) and mitochondrial biogenesis (via PGC-1α/PPARα). Modest weight loss (~2–4 kg) occurs, though compensatory hyperphagia may limit long-term effects. Emerging Applications: Potential roles in non-alcoholic fatty liver disease (NAFLD), polycystic ovary syndrome (PCOS), and neurodegenerative disorders are under investigation, driven by pleiotropic effects on metabolism and inflammation. Conclusions: SGLT2is represent a paradigm shift in managing T2DM, HF, and CKD, with expanding implications for metabolic syndrome. Future research should address interindividual variability, combination therapies, and non-glycemic indications to optimize their therapeutic potential. Full article

(1) Background: The urate-lowering effects of three iridoid glycosides, which are paederosidic acid, paederosidic acid methyl ester, and paederoside, isolated from Paederia foetida and the protection they provide against hyperuricemia-induced kidney injury were investigated in a rat model. (2) Methods: A hyperuricemia (HUA) rat model was established in Sprague-Dawley (SD) rats through intraperitoneal potassium oxonate (PO) and intragastrical adenine for 2 weeks. Subsequently, rats in the pharmaceutical intervention groups received corresponding drug treatments at a concentration of 40 mg/kg/day, maintained consistently for 7 days. (3) Results: The results showed that three compounds reduced serum urate (SU), creatinine (CRE), and blood urea nitrogen (BUN) levels and that the urinary excretion levels of uric acid, urine urea nitrogen, and creatinine increased. Furthermore, the administration of three iridoid glycosides enhanced renal filtration capacity, as demonstrated by the elevated 24 h creatinine clearance rate (CCR) and 24 h uric acid clearance rate (CUA); improved the fraction excretion of uric acid (FEUA); and attenuated renal damage. Finally, three iridoid glycosides promoted uric acid excretion in HUA rats by downregulating URAT1 and GLUT9 and upregulating ABCG2, OAT1, and OAT3. Moreover, the molecular docking results further corroborated the finding that the three compounds can bind to multiple sites of the uric acid transporter via hydrogen, P-π, and hydrophobic bonds. (4) Conclusions: The three iridoid glycosides were found to lower SU levels by increasing uric acid excretion. They are promising natural products for the prevention of HUA and HUA-induced kidney injury. Full article

Hepato-renal crosstalk is a complex biological communication between liver and kidneys mediated by various factors, including cellular, endocrine, and paracrine molecules. This interaction highlights the functional consequences that damage in one organ can have on the other. In particular, the liver and kidney play a pivotal role in maintaining body homeostasis, as they are both involved in the excretion of toxic bioproducts and drugs. The overlap of liver and kidney disease has both therapeutic and prognostic implications. Therefore, a better understanding of the mechanisms involved in the pathogenesis of this bidirectional crosstalk is essential for improving the management of these clinical conditions and patient outcomes. Specifically, a multidisciplinary approach involving hepatologists and nephrologists is crucial to reduce the long-term burden of these clinical settings. This review focuses on the hepato-renal crosstalk in the context of liver and kidney disease, with particular attention to acute kidney injury associated with liver injury, hepatorenal syndrome and, chronic kidney disease in the context of liver fibrosis. Full article

Gout, a metabolic and autoinflammatory disease, is the most common form of inflammatory arthritis worldwide. Hyperuricemia may result in monosodium urate (MSU) crystals forming and depositing in joints and surrounding tissues, triggering an autoinflammatory response. Effective urate-lowering therapies, as well as anti-inflammatory medications, are used to treat gout. Over the past few decades, new antihyperglycemic drug classes with different modes of action have been added to treat hyperglycemia in type 2 diabetes mellitus (T2DM). Two of these drug classes, sodium–glucose co-transporter-2 (SGLT2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists (RAs), have reduced cardiovascular and renal events and mortality. Several clinical studies have demonstrated that SGLT2 inhibitors possess urate-lowering properties, which may be beneficial for treating gout patients, particularly those with comorbid T2DM. Regarding SGLT2 inhibitors, some researchers have suggested that their benefits are partly explained by their ability to reduce serum urate (SU) levels, probably through increased urinary uric acid excretion. The effect of GLP-1 RA on SU levels and urinary excretion of uric acid in humans is unclear. This paper reviews the mechanisms of action of SGLT2 inhibitors and GLP-1RA, both approved and in development. Additionally, it examines what is known about their structure–activity relationships, uricosuric effects, pharmacokinetic profiles, and adverse effects. Full article

Chronic kidney disease (CKD) is associated with the systemic accumulation of uremic toxins (UTs) due to impaired renal elimination. Among these, indoxyl sulfate (IS) and p-cresyl sulfate (PCS) are particularly challenging because of their high protein binding and limited removal by dialysis. In addition to renal excretion, the transport of IS and PCS, and their microbiota-derived precursors, indole and p-cresol, across key physiological barriers—the intestinal barrier, blood–brain barrier, and renal proximal tubule—critically influences their distribution and elimination. This review provides an overview of transporter-mediated mechanisms involved in the disposition of IS, PCS, and their microbial precursors, indole and p-cresol. It also examines how these UTs may interact with commonly prescribed drugs in CKD, particularly those that share transporter pathways as substrates or inhibitors. These drug–toxin interactions may influence the pharmacokinetics and toxicity of IS and PCS, but remain poorly characterized and largely overlooked in clinical settings. A better understanding of these processes may guide future efforts to optimize pharmacotherapy and support more informed management of CKD patients, particularly in the context of polypharmacy. Full article

Background/Objectives: As a monocyclic β-lactam antibiotic, aztreonam has regained attention recently because combining it with β-lactamase inhibitors helps fight drug-resistant bacteria. This study aimed to systematically characterize the plasma and tissue concentration-time profiles of aztreonam in rats, mice, dogs, monkeys, and humans by developing a multi-species, physiologically based pharmacokinetic (PBPK) model. Methods: A rat PBPK model was optimized and validated using plasma concentration-time curves determined by liquid chromatography–tandem mass spectrometry (LC-MS/MS) following intravenous administration, with reliability confirmed through another dose experiment. The rat model characteristics, modeling experience, ADMET Predictor (11.0) software prediction results, and allometric scaling were used to extrapolate to mouse, human, dog, and monkey models. The tissue-to-plasma partition coefficients (K_p values) were predicted using GastroPlus (9.0) software, and the sensitivity analyses of key parameters were evaluated. Finally, the cross-species validation was performed using the average fold error (AFE) and absolute relative error (ARE). Results: The cross-species validation showed that the model predictions were highly consistent with the experimental data (AFE < 2, ARE < 30%), but the deviation of the volume of distribution (V_ss) in dogs and monkeys suggested the need to supplement the species-specific parameters to optimize the prediction accuracy. The K_p values revealed a high distribution of aztreonam in the kidneys (K_p = 2.0–3.0), which was consistent with its clearance mechanism dominated by renal excretion. Conclusions: The PBPK model developed in this study can be used to predict aztreonam pharmacokinetics across species, elucidating its renal-targeted distribution and providing key theoretical support for the clinical dose optimization of aztreonam, the assessment of target tissue exposure in drug-resistant bacterial infections, and the development of combination therapy strategies. Full article

Background: Pharmacokinetic drug–drug interactions (DDIs) can be caused by the effect of a pharmaceutical compound on the activity of one or more subtypes of the Cytochrome P450 (CYP) family, UDP-glucuronosyltransferases (UGTs), and/or transporters. As the number of therapeutic areas with polypharmacy has increased, interest has grown in assessing the risk of DDIs during the early phases of drug development. Various lines of research have led to improved mathematical models to predict DDIs, culminating in the Food and Drug Administration’s (FDA) guidelines on evaluating pharmacokinetic DDI risks. However, the recommended static models are highly conservative and often result in false positive predictions. The current research aims to improve the workflow for assessing CYP-mediated DDI risk using Boehringer Ingelheim (BI) proprietary compounds. Methods: The Drug–drug Interaction Risk Calculator (PharmaPendium) was used to evaluate the mechanistic static model, and predictions were correlated with human pharmacokinetic studies from Phase I clinical trials. Results: The results demonstrated that the FDA formula performed well in predicting DDIs for BI proprietary compounds. Furthermore, the integration of either human renal excretion or preclinical species total excretion data into the mechanistic static model enhanced the predictive performance for candidate drugs as victims in DDIs. Conclusions: The basic static models (BSMs) for drug interactions should be used in early drug discovery to “rule out” DDI risks because of the minimal inputs required and the low rate of false negative predictions. Mechanistic static models (MSMs) can then be implemented for compounds that require additional evaluation. Full article

Fentanyl is a synthetic opioid widely used for its potent analgesic effects in chronic pain management and intraoperative anesthesia. However, its high potency, low cost, and accessibility have also made it a significant drug of abuse, contributing to the global opioid epidemic. This review aims to provide an in-depth analysis of fentanyl’s medical applications, pharmacokinetics, metabolism, and pharmacogenetics while examining its adverse effects and forensic implications. Special attention is given to its misuse, polydrug interactions, and the challenges in determining the cause of death in fentanyl-related fatalities. Fentanyl misuse has escalated dramatically, driven by its substitution for heroin and its availability through online platforms, including the dark web. Polydrug use, where fentanyl is combined with substances like xylazine, alcohol, benzodiazepines, or cocaine, exacerbates its toxicity and increases the risk of fatal outcomes. Fentanyl undergoes rapid distribution, metabolism by CYP3A4 into inactive metabolites, and renal excretion. Genetic polymorphisms in CYP3A4, OPRM1, and ABCB1 significantly influence individual responses to fentanyl, affecting its efficacy and potential for toxicity. Fentanyl’s side effects include respiratory depression, cardiac arrhythmias, gastrointestinal dysfunction, and neurocognitive impairments. Chronic misuse disrupts brain function, contributes to mental health disorders, and poses risks for younger and older populations alike. Fentanyl-related deaths require comprehensive forensic investigations, including judicial inspections, autopsies, and toxicological analyses. Additionally, the co-administration of xylazine presents distinct challenges for the scientific community. Histological and immunohistochemical studies are essential for understanding organ-specific damage, while pharmacogenetic testing can identify individual susceptibilities. The growing prevalence of fentanyl abuse highlights the need for robust forensic protocols, advanced research into its pharmacogenetic variability, and strategies to mitigate its misuse. International collaboration, public education, and harm reduction measures are critical for addressing the fentanyl crisis effectively. Full article

Albumin, the most abundant protein, contributes significantly to various physiological processes, indicating its multifunctional properties. It has drawn the attention of scientists and physicians because of its primary role in maintaining osmotic pressure and involvement in transporting numerous small molecules, including hormones, fatty acids, and drugs. A growing body of evidence has recently illustrated an additional aspect of albumin’s antioxidant properties. Therefore, based on recent research findings, this review article delves into the molecular and biochemical aspects of albumin’s antioxidative capabilities. We highlight the multifaceted significance of proteins in oxidative stress and their relation to pathologies in obstetrics and gynecology. In particular, we focused on preeclampsia, in which oxidative stress is closely involved in the pathogenesis, and renal dysfunction leads to increased albumin excretion into the urine, resulting in hypoalbuminemia. In addition, we discussed the role of albumin in preeclampsia pathogenesis, diagnosis, and patient prognosis. Understanding the antioxidant properties of albumin opens new avenues for therapeutic intervention and sheds light on novel strategies for combating preeclampsia associated with oxidative damage. In this study, we employed the PubMed database to search for articles that assessed the antioxidant properties of albumin, with a specific focus on obstetric diseases, particularly preeclampsia. The last update of the search was conducted in November 2024. Full article