Gadolinium [Gd (III)] released from gadolinium-based contrast agents, commonly used in magnetic resonance imaging, may accumulate in organs, altering metal homeostasis. We aimed to clarify Gd (III), iron and other metal accumulation in the kidney and brain, in the short (2 days) and long term (20 weeks), following exposure to gadoteric acid (Gd-DOTA) or free Gd (III). Wistar rats received one dose of Gd (III), Gd-DOTA, or saline. Gd (III) and metal levels in the blood (whole blood, and serum in the case of iron), kidney, and brain, and iron metabolism biomarkers, were assessed. Gd (III) was detectable in the blood, kidney, and brain, at both time points, for both Gd (III) and Gd-DOTA-treated groups. Exposure to free Gd (III) showed a significant Gd (III) accumulation in the kidney, brain and blood in the short term and long term; Gd-DOTA presented significant accumulation only in the short term. Gd-DOTA appears to have faster elimination and minimal brain deposition. Exposure to free Gd (III), but not to Gd-DOTA, led to disturbances in metal homeostasis and in iron metabolism markers (serum ferritin and transferrin saturation), but did not alter tissue iron levels. In summary, the kidney appears as the primary site of accumulation and retention. Despite the safer profile shown by Gd-DOTA in the long term, our data highlight the importance of clarifying the pathophysiological implications of Gd (III) retention and/or accumulation, particularly in vulnerable conditions and repeated exposures.

The increasing prevalence of silver nanoparticles (AgNP) in various applications has sparked concerns about their potential adverse effects on human health. Hence, it is crucial to devise strategies to minimize their detrimental effects. Quercetin, a naturally occurring flavonoid present in human diet is known for its broad biological effects, including anti-inflammatory properties. Considering this, quercetin could serve as a promising strategy to protect the body against the harmful effects of AgNP. Thus, this study aimed to evaluate the potential protective role of quercetin against the deleterious effects induced by 5 nm polyvinylpyrrolidone (PVP)-AgNP in C57BL/6J mice. Using a novel administration technology (HaPILLness), mice were given a daily oral dose of AgNP at 1 mg/kg body weight (bw) or 10 mg/kg bw for 14 days, combined with daily IP injections of quercetin at 1 mg/kg bw. Our findings demonstrate that quercetin effectively attenuated the AgNP-induced intestinal inflammatory response, as demonstrated by reduced histological vascular and cellular alterations, along with a notable decrease in cytokine production, attributed to the inhibition of the nuclear factor (NF)-& kcy;B inflammatory pathway. Quercetin's protective effects extended to the liver and lungs, by reversing changes in the inflammatory and antioxidant markers cluster of differentiation (CD)4, superoxide dismutase 1 (SOD1) and catalase.

Non-communicable diseases, such as obesity, type 2 diabetes mellitus (T2DM), cardiovascular diseases, allergies, and cancer are escalating global health concerns [...]

Background:Lifestyle modifications, particularly the adoption of healthy dietary patterns such as the Mediterranean Diet (MedDiet), are foundational in any treatment plan, including for patients prescribed first-line statin therapy for hypercholesterolemia. However, the rising popularity of MedDiet-associated foods and nutraceuticals among health-conscious consumers has raised concerns about their potential interactions with statins, potentially leading to adverse effects. One notable example involves polyphenol supplements, a class of anti-dyslipidemic phytochemicals known to influence statins' pharmacokinetics. Still, whether chronic polyphenol exposure achieves plasma concentrations sufficient to alter statin pharmacokinetics in clinical settings is controverse. Moreover, it remains unclear which key biological targets are shared by both classes of molecules and how they mediate potential pharmacokinetic and pharmacodynamic interactions. This study aims to systematically map reported statin-polyphenol interactions and identify the principal biological targets involved, elucidating their impact on statin pharmacokinetics, efficacy, and toxicity. Methods:A scoping review was conducted using the PubMed/Medline, Scopus, and Web of Science databases. This work was designed in accordance with PRISMA-ScR. The review protocol was registered in the Open Science Framework. Results:Statin-polyphenol interactions were reported in 83.9% of the studies analyzed. The biological targets mediating these interactions play chief roles in statins' cellular uptake (OATP/P-glycoprotein), metabolism (CYP450/intestinal esterases), and core mechanisms underlying statin action, namely, HMG-CoA reductase inhibition. Polyphenols significantly influenced statin pharmacokinetics, altering total drug exposure (AUC) and extent (Cmax), either by enhancement or inhibition, with apparently less impact on statins' absorption rate (Tmax). At the clinical level, only five studies addressed statin-polyphenol interactions, yielding conflicting results on the potential enhancement of therapeutic efficacy and adverse effects. Discussion:This work presents an integrated perspective on the cellular and molecular mechanisms underlying statin-polyphenol interactions. It highlights substantial inter-individual variability linked to conflicting evidence, from synergistic effects enabling lower statin doses and reduced adverse events to potential exacerbation of side effects. These findings underscore the need for controlled studies to clarify the clinical relevance of polyphenol-induced alterations in statin pharmacokinetics and pharmacodynamics. Such data are essential to develop evidence-based guidelines that may optimize statin therapy and support individualized treatment strategies. Systematic review registration:identifier 10.17605/OSF.IO/DJW5G.

Regarding the safety of gadolinium (Gd (III))-based contrast agents, we aimed to evaluate the short- and long-term effects following a single exposure to gadoteric acid (DOTA) or to free Gd (III) using animal models. Biomarkers of kidney injury, inflammation, iron metabolism, dyslipidemia, hepatic and hematologic disturbances and kidney histopathological and differential gene expression (DGE) analyses were evaluated. In the short-term study, compared to the controls, exposure to Gd (III) was associated with higher inflammation; changes in lipid, iron and hepatic metabolisms; hematological alterations; and kidney damage. Exposure to DOTA revealed changes in hematological, lipid and hepatic biomarkers. In the long-term study, compared to the controls, exposure to Gd (III) or to DOTA showed much fewer changes than the short-term exposure. Comparing the kidney gene expression of Gd (III) or DOTA exposure versus the control, we found clearly different DGE patterns and a lower number of differently expressed genes in the long-term study, for both compounds. Our data show that a single-dose exposure to these compounds induces several short-term changes which over time return to normal or are sustained, although with less severity, especially in the case of DOTA.

The influence of gut microbiota in the onset and development of several metabolic diseases has gained attention over the last few years. Diet plays an essential role in gut microbiota modulation. Western diet (WD), characterized by high-sugar and high-fat consumption, alters gut microbiome composition, diversity index, microbial relative levels, and functional pathways. Despite the promising health effects demonstrated by polyunsaturated fatty acids, their impact on gut microbiota is still overlooked. The effect of Fish oil (omega-3 source) and Pomegranate oil (punicic acid source), and a mixture of both oils in gut microbiota modulation were determined by subjecting the oil samples to in vitro fecal fermentations. Cecal samples from rats from two different dietary groups: a control diet (CD) and a high-fat high-sugar diet (WD), were used as fecal inoculum. 16S amplicon metagenomics sequencing showed that Fish oil + Pomegranate oil from the WD group increased alpha-diversity. This sample can also increase the relative abundance of the Firmicutes and Bacteroidetes phylum as well as Akkermansia and Blautia, which were affected by the WD consumption. All samples were able to increase butyrate and acetate concentration in the WD group. Moreover, tyrosine concentrations, a precursor for dopamine and norepinephrine, increase in the Fish oil + Pomegranate oil WD sample. GABA, an important neurotransmitter, was also increased in WD samples. These results suggest a potential positive impact of these oils' mixture on gut-brain axis modulation. It was demonstrated, for the first time, the great potential of using a mixture of both Fish and Pomegranate oil to restore the gut microbiota changes associated with WD consumption.

Abstract Background and Aims Concerns regarding the safety of gadolinium-based contrast agents (GBCA), which are often employed in medical imaging, have been raised in light of reports of free gadolinium's [Gd (III)] cytotoxicity. It appears that GBCAs having macrocyclic structures, like gadoteric acid (Gd-DOTA), are more stable and less toxic. Previous work from our group found that Gd (III) promotes inflammation and fibrosis in proximal tubular cells cultures. A disturbance of lipid metabolism was also reported, accompanied by the build-up of lipid droplets, lipid peroxidation and the overexpression of genes linked to lipogenesis and lipolysis. The aim of this study was to evaluate the short-term effects of Gd (III) and of Gd-DOTA on renal function and lipid metabolism biomarkers, using an animal model. Method Male Wistar rats were exposed to a single dose of Gd (III) or Gd-DOTA (groups A and B, respectively); a control group was also included (C). Blood was collected after 48h of exposure to compounds. We evaluated circulating levels of renal function biomarkers—creatinine and cystatin—using a routine automated assay and ELISA, respectively. The lipid profile was also determined including triglycerides (TG), total cholesterol, HDL-cholesterol, LDL-cholesterol, and oxidized LDL (oxLDL) levels. Results Gd (III) group (A) presented significantly higher circulating cholesterol (P=0.006) and LDL-cholesterol (P<0.001) and lower TG (P<0.001) levels than the control group (C); a non-significant increment in cystatin was also observed for group A. The Gd-DOTA group (B) only presented lower TG levels (P=0.002) compared to the control group (C), being similar to those presented by group A. Both exposed groups (A and B) presented non-significantly higher oxLDL levels compared to the control group. Conclusion Single exposition to free Gd (III) induced prompt changes in lipid profile, with little short-term influence in traditional kidney biomarkers. The exposition to Gd-DOTA was associated with lower disturbance in lipids and lipoproteins (only lower TG levels) and imperceptible renal changes. Despite the significantly safer profile for Gd-DOTA, further studies are necessary, testing different biomarkers, to clarify the short-term, and even the long-term impacts, of these molecules. Acknowledgements This work was financed by FCT through the project 2022.08400.PTDC; FCT, in the scope of the project UIDP/04378/2020 and UIDB/04378/2020 of the Research Unit on Applied Molecular Biosciences—UCIBIO and the project LA/P/0140/2020 of the Associate Laboratory Institute for Health and Bioeconomy—i4HB.

Blueberries, red fruits enriched in polyphenols and fibers, are envisaged as a promising nutraceutical intervention in a plethora of metabolic diseases. Prediabetes, an intermediate state between normal glucose tolerance and type 2 diabetes, fuels the development of complications, including hepatic steatosis. In previous work, we have demonstrated that blueberry juice (BJ) supplementation benefits glycemic control and lipid profile, which was accompanied by an amelioration of hepatic mitochondrial bioenergetics. The purpose of this study is to clarify the impact of long-term BJ nutraceutical intervention on cellular mechanisms that govern hepatic lipid homeostasis, namely autophagy and endoplasmic reticulum (ER) stress, in a rat model of prediabetes. Two groups of male Wistar rats, 8-weeks old, were fed a prediabetes-inducing high-fat diet (HFD) and one group was fed a control diet (CD). From the timepoint where the prediabetic phenotype was achieved (week 16) until the end of the study (week 24), one of the HFD-fed groups was daily orally supplemented with 25 g/kg body weight (BW) of BJ (HFD + BJ). BW, caloric intake, glucose tolerance and insulin sensitivity were monitored throughout the study. The serum and hepatic lipid contents were quantified. Liver and interscapular brown and epidydimal white adipose tissue depots (iBAT and eWAT) were collected for histological analysis and to assess thermogenesis, ER stress and autophagy markers. The gut microbiota composition and the short-chain fatty acids (SCFAs) content were determined in colon fecal samples. BJ supplementation positively impacted glycemic control but was unable to prevent obesity and adiposity. BJ-treated animals presented a reduction in fecal SCFAs, increased markers of arrested iBAT thermogenesis and energy expenditure, together with an aggravation of HFD-induced lipotoxicity and hepatic steatosis, which were accompanied by the inhibition of autophagy and ER stress responses in the liver. In conclusion, despite the improvement of glucose tolerance, BJ supplementation promoted a major impact on lipid management mechanisms at liver and AT levels in prediabetic animals, which might affect disease course.

Objective Obesity is linked to perturbations in energy balance mechanisms, including ghrelin and leptin actions at the hypothalamic circuitry of neuropeptide Y (NPY) and melanocortin. However, information about the regulation of this system in the periphery is still scarce. Our objective was to study the regulation of the NPY/melanocortin system in the adipose tissue (AT) and evaluate its therapeutic potential for obesity and type 2 diabetes. Methods The expression of the NPY/melanocortin receptors’ levels was assessed in the visceral AT of individuals with obesity and altered metabolism. Protein levels of these receptors were evaluated in cultured adipocytes incubated with ghrelin (30 and 100 ng/mL) and leptin (1 and 10 nM) and in the AT of an animal model with a mutation in the leptin receptor (ZSF1 rat), to understand their regulation by leptin and ghrelin. The vertical sleeve gastrectomy animal model was used to evaluate the putative therapeutic potential of the NPY/melanocortin system. Results In this study, we unravelled that leptin (1 nM and 10 nM) selectively reduced the levels of NPY5R and MC3R but no other NPYR/MCRs in cultured adipocytes. In turn, acylated ghrelin (100ng/mL) significantly increased NPY1R, but the inhibition of its receptor also abrogates MC3R levels. However, in the Lepr-deficient ZSF1 rat, both NPY5R and MC3R levels were reduced, along with other NPYRs and MCRs, suggesting that leptin resistance negatively affects NPY and melanocortin signalling. In human adipose tissue, we found a downregulation of genes encoding the NPY and melanocortin receptors in the visceral AT of individuals with obesity and insulin resistance, being correlated with genes regulating metabolic activity. Additionally, diabetic obese rats submitted to vertical sleeve gastrectomy showed increased levels of NPY, melanocortin, ghrelin, and leptin receptors in the AT, including MC3R, suggesting it may constitute a therapeutic target in obesity. Conclusions Our results suggest that the AT NPY/melanocortin system, particularly the MC3R, may be involved in the neuroendocrine regulation of adipocyte metabolism. Altogether, our work shows MC3R is under the control of the ghrelin/leptin duo, is reduced in patients with obesity and prediabetes, and may constitute a therapeutic target in obesity.

Vaccine adjuvants are important for enhancing vaccine efficacy, and although aluminium salts (Alum) are the most used, their limited ability to induce specific immune responses has spurred the search for new adjuvants. However, many adjuvants fail during product development due to manufacturability, supply, stability, or safety concerns. This work hypothesizes that protein-free yeast glucans can be used as vaccine adjuvants due to their known immunostimulatory activity and high abundancy. Thus, high molecular weight glucans with over 99% purity, comprising 64-70% beta-glucans and 29-35% alpha-glucans, were extracted from a wild-type yeast and an engineered yeast to produce a steviol glycoside. These glucans underwent carboxymethylation to enhance solubility. Both water-dispersible and particulate glucans were evaluated as adjuvants, either alone or in combination with Alum or squalene stable emulsion (SE), for a SARS-CoV-2 vaccine. The study demonstrated that glucans triggered a robust immune response and enhanced the effects of Alum and SE when used in combination, both in vitro and in vivo. Water-dispersible glucans combined with Alum, and particulate glucans combined with SE, increased the production of specific antibodies against SARS-CoV-2 spike protein and enhanced serum neutralization titers against SARS-CoV-2 pseudovirus. Furthermore, the results indicated that larger molecular weight glucans from engineered yeast exhibited stronger immunogenic activity in comparison to wild-type yeast glucans. In conclusion, appropriately formulated glucans have the potential to be scalable, low-cost vaccine adjuvants, potentially overcoming the limitations of current adjuvants.

Biological therapies have transformed high-burden treatments. As the patent and exclusivity period for biological medicines draws to a close, there is a possibility for the development and authorization of biosimilars. These products boast comparable levels of safety, quality, and effectiveness to their precursor reference products. Biosimilars, although similar to reference products, are not identical copies and should not be considered generic substitutes for the original. Their development and evaluation involve a rigorous step-by-step process that includes analytical, functional, and nonclinical evaluations and clinical trials. Clinical studies conducted for biosimilars aim to establish similar efficacy, safety, and immunogenicity, rather than demonstrating a clinical benefit, as with the reference product. However, although the current knowledge regarding biosimilars has significantly increased, several controversies and misconceptions still exist regarding their immunogenicity, extrapolation, interchangeability, substitution, and nomenclature. The development of biosimilars stimulates market competition, contributes toward healthcare sustainability, and allows for greater patient access. However, maximizing the benefits of biosimilars requires cooperation between regulators and developers to ensure that patients can benefit quickly from access to these new therapeutic alternatives while maintaining high standards of quality, safety, and efficacy. Recognizing the inherent complexities of comprehending biosimilars fully, it is essential to focus on realistic approaches, such as fostering open communication between healthcare providers and patients, encouraging informed decision-making, and minimizing risks. This review addresses the regulatory and manufacturing requirements for biosimilars and provides clinicians with relevant insights for informed prescribing.

Abstract Background and Aims The nephrotoxicity of free gadolinium [Gd (III)] has been reported, raising concerns about the safety of gadolinium-based contrast agents (GBCA), widely used in magnetic resonance imaging. The GBCA with macrocyclic structure, such as gadoteric acid (Gd-DOTA), appear as more stable. Using human proximal tubular cells cultures, we found that free Gd (III) triggers death by apoptosis and necrosis, and increases the expression of modulators of inflammation, hypoxia and fibrosis, which are known as major risk factors for the development and worsening of kidney disease. Our aim was, using animal models, to evaluate the short-term effects of Gd (III) and of gadoteric acid on inflammatory biomarkers, at blood and renal tissue levels. Method Wistar rats were exposed to a single dose of Gd (III) or Gd-DOTA (groups A and B, respectively); a control group was also included (C). After 48h, blood and kidney samples were collected. The plasma levels of interleukin (IL)6 and transforming growth factor (TGF) beta 1 were assessed by ELISA; the kidney gene expression of IL6 (il6), TGF beta 1 (tgbf1) and nuclear factor-kappa B (nfkb1) was determined through qPCR. Results Gd (III) group (A) presented higher circulating IL6 levels (P = 0.001) and increased kidney gene expression of il6 (P = 0.013), tgbf1 (P = 0.006) and nfkb1 (P = 0.011) than the control group (C); compared to Gd-DOTA group (B), the IL6 plasma concentration (P = 0.005) and tgbf1 mRNA levels were also higher (P = 0.004). The Gd-DOTA group (B) presented increased gene expression of il6 (P = 0.006) than the control group (C). Conclusion Short-term exposition to free Gd (III) induced an inflammatory response, shown by the increase in circulating IL6, and in kidney gene expression of il6, tgbf1 and nfkb1. The exposition to Gd-DOTA was associated with a lower inflammatory response, showing only increased kidney gene expression of il6. Despite the much safer profile for Gd-DOTA, further studies are warranted, evaluating other biomarkers, to clarify the short-term, and even the long-term effects, of these compounds. Acknowledgements This work was financed by FCT through the project 2022.08400.PTDC; FCT, in the scope of the project UIDP/04378/2020 and UIDB/04378/2020 of the Research Unit on Applied Molecular Biosciences—UCIBIO and the project LA/P/0140/2020 of the Associate Laboratory Institute for Health and Bioeconomy—i4HB.

Mounting evidence progressively appreciates the vital interplay between immunity and metabolism in a wide array of immunometabolic chronic disorders, both autoimmune and non-autoimmune mediated. The immune system regulates the functioning of cellular metabolism within organs like the brain, pancreas and/or adipose tissue by sensing and adapting to fluctuations in the microenvironment’s nutrients, thereby reshaping metabolic pathways that greatly impact a pro- or anti-inflammatory immunophenotype. While it is agreed that the immune system relies on an adequate nutritional status to function properly, we are only just starting to understand how the supply of single or combined nutrients, all of them termed immunonutrients, can steer immune cells towards a less inflamed, tolerogenic immunophenotype. Polyphenols, a class of secondary metabolites abundant in Mediterranean foods, are pharmacologically active natural products with outstanding immunomodulatory actions. Upon binding to a range of receptors highly expressed in immune cells (e.g. AhR, RAR, RLR), they act in immunometabolic pathways through a mitochondria-centered multi-modal approach. First, polyphenols activate nutrient sensing via stress-response pathways, essential for immune responses. Second, they regulate mammalian target of rapamycin (mTOR)/AMP-activated protein kinase (AMPK) balance in immune cells and are well-tolerated caloric restriction mimetics. Third, polyphenols interfere with the assembly of NLR family pyrin domain containing 3 (NLRP3) in endoplasmic reticulum-mitochondria contact sites, inhibiting its activation while improving mitochondrial biogenesis and autophagosome-lysosome fusion. Finally, polyphenols impact chromatin remodeling and coordinates both epigenetic and metabolic reprogramming. This work moves beyond the well-documented antioxidant properties of polyphenols, offering new insights into the multifaceted nature of these compounds. It proposes a mechanistical appraisal on the regulatory pathways through which polyphenols modulate the immune response, thereby alleviating chronic low-grade inflammation. Furthermore, it draws parallels between pharmacological interventions and polyphenol-based immunonutrition in their modes of immunomodulation across a wide spectrum of socioeconomically impactful immunometabolic diseases such as Multiple Sclerosis, Diabetes (type 1 and 2) or even Alzheimer’s disease. Lastly, it discusses the existing challenges that thwart the translation of polyphenols-based immunonutritional interventions into long-term clinical studies. Overcoming these limitations will undoubtedly pave the way for improving precision nutrition protocols and provide personalized guidance on tailored polyphenol-based immunonutrition plans.

Adipose tissue dysfunction is more related to insulin resistance than body mass index itself and an alteration in adipose tissue function is thought to underlie the shift from metabolically healthy to unhealthy obesity. Herein, we performed a clustering analysis that revealed distinct visceral adipose tissue gene expression patterns in patients with obesity at distinct stages of metabolic dysregulation. We have built a cross-sectional cohort that aims at reflecting the evolution of the metabolic sequelae of obesity with the main objective to map the sequential events that play a role in adipose tissue dysfunction from the metabolically healthy (insulin-sensitive) state to several incremental degrees of metabolic dysregulation, encompassing insulin resistance establishment, pre-diabetes, and type 2 diabetes. We found that insulin resistance is mainly marked by the downregulation of adipose tissue vasculature remodeling-associated gene expression, suggesting that processes like angiogenesis and adaptative expansion/retraction ability suffer early dysregulation. Prediabetes was characterized by compensatory growth factor-dependent signaling and increased response to hypoxia, while type 2 diabetes was associated with loss of cellular response to insulin and hypoxia and concomitant upregulation of inflammatory markers. Our findings suggest a putative sequence of dysregulation of biological processes that is not linear and has multiple distinct phases across the metabolic dysregulation process, ultimately culminating in the climax of adipose tissue dysfunction in type 2 diabetes. Several studies have addressed the transcriptomic changes in adipose tissue of patients with obesity. However, to the best of our knowledge, this is the first study unraveling the potential molecular mechanisms associated with the multi-step evolution of adipose tissue dysfunction along the metabolic sequelae of obesity.

Silver nanoparticles (AgNP) are among the most widely commercialized nanomaterials globally, with applications in medicine and the food industry. Consequently, the increased use of AgNP in the food industry has led to an unavoidable rise in human exposure to these nanoparticles. Their widespread use raises concerns about potential hazards to human health, specifically their intestinal pro-inflammatory effects. Thus, the main objective of this study was to evaluate the biological effects of two subacute doses of 5 nm polyvinylpyrrolidone (PVP)-AgNP in C57BL/6J mice. One mg/kg body weight or 10 mg/kg bw was provided once a day for 14 days, using a new technology (HaPILLness) that allows voluntary, stress-free, and accurate oral dosing. It was observed that after oral ingestion, while AgNP is biodistributed throughout the entire organism, most of the ingested dose is excreted in the feces. The passage and accumulation of AgNP throughout the intestine instigated a prominent inflammatory response, marked by significant histological, vascular, and cellular transformations. This response was driven by the activation of the nuclear factor-кB (NF-кB) inflammatory pathway, ultimately leading to the generation of multiple cytokines and chemokines.

Abstract Background and Aims Beta trace protein (BTP) is a low molecular weight protein that has been proposed as an earlier biomarker of decreased glomerular filtration rate (GFR) and renal damage, than the traditional biomarkers, particularly in the creatinine blind range. Early biomarkers of renal (dys)function are needed to allow, in due time, the detection and treatment, to prevent worsening of the disease. To the authors’ knowledge, neither urine nor serum BTP has been assessed in animals with kidney disease. In the present study, we aimed to concomitantly evaluate BTP and creatinine circulating levels, to compare their value as early biomarkers of renal dysfunction, by performing the studies in rat models of mild and moderate chronic renal failure (CRF) induced by nephrectomy. Method Male Wistar rats, 12 weeks old, were randomly divided in three groups: Sham (n = 8, subjected to surgical process without kidney mass reduction), Mild CRF (n = 8, subjected to 1/2 nephrectomy), and Moderate CRF (n = 7, subjected to 5/6 nephrectomy). After five weeks, rats were sacrificed, blood and kidneys were collected. We analysed the circulating levels of BTP and creatinine and studied the association of BTP concentration with the glomerular and tubulointerstitial lesions, and with the traditional biomarkers of renal (dys)function, eGFR and creatinine. Results The serum levels of BTP were correlated with serum levels of creatinine (r = 0.575, p = 0.004) and also with eGFR (r = -0.453, p = 0.030); additionally, we found positive correlations with the total score of mild and advanced tubular lesions (r = 0.610, p = 0.02 and r = 0.517, p = 0.011, respectively), observed in kidney sections. The circulating levels of BTP increased with disease severity; Mild CRF showed a higher value of BTP than Sham group, although without statistical significance that was reached in Moderate CRF group, as observed for serum creatinine. The combined use of BTP and creatinine did not improve the discriminatory power in early disease detection. Though, the combination showed stronger correlations with the total score of tubular lesions (r = 0.849, p < 0.001 for mild tubular lesions and r = 0.774, p < 0.01 for advanced tubular lesions). Conclusion In rat models of mild and moderate CRF induced by nephrectomy, serum BTP levels increased with kidney function worsening, and correlated with disease severity, assessed by GFR and the degree of histopathological alterations. However, the earlier diagnostic value of BTP does not outperform serum creatinine in this model.