Potential impact of underlying diseases influencing ADME in nonclinical safety assessment.

Nonclinical studies involve in vitro, in silico, and in vivo experiments to assess the toxicokinetics, toxicology, and safety pharmacology of drugs according to regulatory requirements by a national or international authority. In this review, we summarize the potential effects of various underlying diseases governing the absorption, distribution, metabolism, and excretion (ADME) of drugs to consider the use of animal models of diseases in nonclinical trials. Obesity models showed alterations in hepatic metabolizing enzymes, transporters, and renal pathophysiology, which increase the risk of drug-induced toxicity. Diabetes models displayed changes in hepatic metabolizing enzymes, transporters, and glomerular filtration rates (GFR), leading to variability in drug responses and susceptibility to toxicity. Animal models of advanced age exhibited impairment of drug metabolism and kidney function, thereby reducing the drug-metabolizing capacity and clearance. Along with changes in hepatic metabolic enzymes, animal models of metabolic syndrome-related hypertension showed renal dysfunction, resulting in a reduced GFR and urinary excretion of drugs. Taken together, underlying diseases can induce dysfunction of organs involved in the ADME of drugs, ultimately affecting toxicity. Therefore, the use of animal models of representative underlying diseases in nonclinical toxicity studies can be considered to improve the predictability of drug side effects before clinical trials.

Kidney Renin-Angiotensin System: Lost in a RAS Cascade.

Renin was discovered more than a century ago. Since then, the functions of the renin-angiotensin system in the kidney have been the focus of intensive research revealing its importance in regulation of renal physiology and in the pathogenesis of heart, vascular, and kidney diseases. Inhibitors of renin-angiotensin system components are now foundational therapies for a range of kidney and cardiovascular diseases from hypertension to heart failure to diabetic nephropathy. Despite years of voluminous research, emerging studies continue to reveal new complexities of the regulation of the renin-angiotensin system within the kidney and identification of nonclassical components of the system like the prorenin receptor (PRR) and ACE2 (angiotensin-converting enzyme 2), with powerful renal effects that ultimately impact the broader cardiovascular system. With the emergence of a range of novel therapies for cardiovascular and kidney diseases, the importance of a detailed understanding of the renin-angiotensin system in the kidney will allow for the development of informed complementary approaches for combinations of treatments that will optimally promote health and longevity over the century ahead.

Renal-specific loss of ferroportin disrupts iron homeostasis and attenuates recovery from acute kidney injury.

Chronic kidney disease is increasing at an alarming rate and correlates with the increase in diabetes, obesity, and hypertension that disproportionately impact socioeconomically disadvantaged communities. Iron plays essential roles in many biological processes including oxygen transport, mitochondrial function, cell proliferation, and regeneration. However, excess iron induces the generation and propagation of reactive oxygen species, which lead to oxidative stress, cellular damage, and ferroptosis. Iron homeostasis is regulated in part by the kidney through iron resorption from the glomerular filtrate and exports into the plasma by ferroportin (FPN). Yet, the impact of iron overload in the kidney has not been addressed. To test more directly whether excess iron accumulation is toxic to kidneys, we generated a kidney proximal tubule-specific knockout of FPN. Despite significant intracellular iron accumulation in FPN mutant tubules, basal kidney function was not measurably different from wild type kidneys. However, upon induction of acute kidney injury (AKI), FPN mutant kidneys exhibited significantly more damage and failed recovery, evidence for ferroptosis, and increased fibrosis. Thus, disruption of iron export in proximal tubules, leading to iron overload, can significantly impair recovery from AKI and can contribute to progressive renal damage indicative of chronic kidney disease. Understanding the mechanisms that regulate iron homeostasis in the kidney may provide new therapeutic strategies for progressive kidney disease and other ferroptosis-associated disorders.NEW & NOTEWORTHY Physiological iron homeostasis depends in part on renal resorption and export into the plasma. We show that specific deletion of iron exporters in the proximal tubules sensitizes cells to injury and inhibits recovery. This can promote a chronic kidney disease phenotype. Our paper demonstrates the need for iron balance in the proximal tubules to maintain and promote healthy recovery after acute kidney injury.

Assessment of the impact of glyphosate and 2,4-D herbicides on the kidney injury and transcriptome changes in obese mice fed a Western diet.

The development of chronic kidney disease has been associated with comorbidities resulting from the consumption of Westernized dietary (WD) patterns, including obesity and other metabolic dysfunctions. Kidneys also have a crucial role in the metabolism and excretion of xenobiotics, including herbicides. There is limited knowledge regarding the simultaneous exposure to WD and glyphosate (glypho) and 2,4-D, the most used herbicides globally. Thus, this study examined whether exposure to glypho and/or 2,4-D, either individually or in mixed, could impact the early effects of WD intake on kidney histology and gene expression in a rodent model. Male C57BL6J mice were fed a WD containing 20% lard, 0.2% cholesterol, 20% sucrose, and high sugar solution with 23.1 and 18.9 g/L of D-fructose and D-glucose for six months. During this period, the mice also received glypho (0.05 or 5 mg/kg/day), 2,4-D (0.02 or 2 mg/kg/day), or a mixture of both (0.05 +0.02, 5 +2 mg/kg/day) via intragastric administration five times per week. The doses were within or below the established regulatory limits. While single or mixed exposures did not alter WD-induced obesity, tubular lipid vacuolation, or increased serum creatinine levels; the exposure to higher doses of the mixture (5 +2) reduced the mesangial matrix area and tubular cell proliferation, while increasing the density of F4/80 macrophages in the renal interstitium. In terms of transcriptomic analysis, the herbicide mixture altered the expression of 415 genes in the kidney, which were found to be associated with immune response processes, particularly those related to phagocyte activity. While discrete, findings indicate that herbicide mixtures, rather than single exposures, might induce minor deleterious effects on the kidneys of obese mice under WD intake.

Assessment of Kidney Mitochondrial Function by High-Resolution Respirometry, Transmission Electron Microscopy, and Histological Techniques.

Proper kidney function depends highly on mitochondria homeostasis. This organelle is the primary source of ATP production in the kidney and regulates other cellular processes such as redox and calcium homeostasis. Although the mitochondria's primary recognized function is cellular energy production, through the function of the Krebs cycle, electron transport system (ETS), as well as oxygen and electrochemical gradient consumption, this function is interconnected with multiple signaling and metabolic pathways, making bioenergetics a central hub in renal metabolism. Furthermore, mitochondrial biogenesis, dynamics, and mass are also strongly related to bioenergetics. This central role is not surprising given that mitochondrial impairment, including functional and structural alterations, has been recently reported in several kidney diseases. Here, we describe assessment of mitochondrial mass, structure, and bioenergetics in kidney tissue and renal-derived cell lines. These methods allow investigation of mitochondrial alterations in kidney tissue and renal cells under different experimental conditions.

Assessment of focal renal ischemia-reperfusion injury in a porcine model using hyperpolarized [1-13 C]pyruvate MRI.

PURPOSE: Ischemic injury in the kidney is a common pathophysiological event associated with both acute kidney injury and chronic kidney disease; however, regional ischemia-reperfusion as seen in thromboembolic renal disease is often undetectable and thus subclinical. Here, we assessed the metabolic alterations following subclinical focal ischemia-reperfusion injury with hyperpolarized [1-13 C]pyruvate MRI in a porcine model. METHODS: Five pigs were subjected to 60 min of focal kidney ischemia. After 90 min of reperfusion, a multiparametric proton MRI protocol was performed on a clinical 3T scanner system. Metabolism was evaluated using 13 C MRI following infusion of hyperpolarized [1-13 C]pyruvate. Ratios of pyruvate to its detectable metabolites (lactate, bicarbonate, and alanine) were used to quantify metabolism. RESULTS: The focal ischemia-reperfusion injury resulted in injured areas with a mean size of 0.971 cm3 (±1.019). Compared with the contralateral kidney, the injured areas demonstrated restricted diffusion (1269 ± 83.59 × 10-6 mm2 /s vs. 1530 ± 52.73 × 10-6 mm2 /s; p = 0.006) and decreased perfusion (158.8 ± 29.4 mL/100 mL/min vs. 274 ± 63.1 mL/100 mL/min; p = 0.014). In the metabolic assessment, the injured areas displayed increased lactate/pyruvate ratios compared with the entire ipsilateral and the contralateral kidney (0.35 ± 0.13 vs. 0.27 ± 0.1 vs. 0.25 ± 0.1; p = 0.0086). Alanine/pyruvate ratio was unaltered, and we were unable to quantify bicarbonate due to low signal. CONCLUSION: MRI with hyperpolarized [1-13 C]pyruvate in a clinical setup is capable of detecting the acute, subtle, focal metabolic changes following ischemia. This may prove to be a valuable future addition to the renal MRI suite.

FTIR Analysis of Renal Tissue for the Assessment of Hypertensive Organ Damage and proANP31-67 Treatment.

The kidneys are one of the main end organs targeted by hypertensive disease. Although the central role of the kidneys in the regulation of high blood pressure has been long recognized, the detailed mechanisms behind the pathophysiology of renal damage in hypertension remain a matter of investigation. Early renal biochemical alterations due to salt-induced hypertension in Dahl/salt-sensitive rats were monitored by Fourier-Transform Infrared (FTIR) micro-imaging. Furthermore, FTIR was used to investigate the effects of proANP31-67, a linear fragment of pro-atrial natriuretic peptide, on the renal tissue of hypertensive rats. Different hypertension-induced alterations were detected in the renal parenchyma and blood vessels by the combination of FTIR imaging and principal component analysis on specific spectral regions. Changes in amino acids and protein contents observed in renal blood vessels were independent of altered lipid, carbohydrate, and glycoprotein contents in the renal parenchyma. FTIR micro-imaging was found to be a reliable tool for monitoring the remarkable heterogeneity of kidney tissue and its hypertension-induced alterations. In addition, FTIR detected a significant reduction in these hypertension-induced alterations in the kidneys of proANP31-67-treated rats, further indicating the high sensitivity of this cutting-edge imaging modality and the beneficial effects of this novel medication on the kidneys.

Assessment of microvascular involvement in lupus nephritis patients by retinal OCT-angiography and kidney biopsies.

OBJECTIVES: Ocular and renal microvascular damage in lupus nephritis (LN) share similar physiopathological pathways that have investigated using traditional fundus examination and high-resolution colour electroretinography. Optical coherence tomography angiography (OCTA) is a recent, non-invasive technique for imaging the microvasculature of retina and choroid. Aim of the study was to investigate through OCTA analysis the relationship between retinal microvascular alterations and renal functional and histologic features. METHODS: Systemic lupus erythematosus (SLE) patients with LN, SLE without renal involvement and healthy controls were recruited and accomplished an ophthalmological evaluation, including OCTA. SLE-LN patients underwent a rheumatological evaluation, including disease-related clinical and laboratory features collection and kidney biopsy examination. RESULTS: This cross-sectional study enrolled forty-six eyes of 23 LN patients, thirty-two eyes of 16 SLE patients and forty-two eyes of 21 controls. Thirteen SLE-LN patients (56.5%) displayed lupus retinopathy, 10 at moderate (77%) and 3 at severe stage (23%) by fundus oculi examination. Analysis of OCTA data showed with high/moderate accuracy a reduction of retinal capillary vessel density in both SLE and SLE-LN patients compared to controls in superficial and deep plexi. A reduction in fovea thickness and an increase in foveal avascular zone were also detected. OCTA data of LN patients correlated with LN duration, disease activity, kidney function and the presence of LN-vascular lesions at kidney biopsy. CONCLUSIONS: Our results suggest the role of OCTA in early detection of systemic vascular involvement in SLE-LN patients and related kidney functional-histological impairment.

Examination of the emerging role of transporters in the assessment of nephrotoxicity.

INTRODUCTION: The kidney is vulnerable to various injuries based on its function in the elimination of many xenobiotics, endogenous substances and metabolites. Since transporters are critical for the renal elimination of those substances, it is urgent to understand the emerging role of transporters in nephrotoxicity. AREAS COVERED: This review summarizes the contribution of major renal transporters to nephrotoxicity induced by some drugs or toxins; addresses the role of transporter-mediated endogenous metabolic disturbances in nephrotoxicity; and discusses the advantages and disadvantages of in vitro models based on transporter expression and function. EXPERT OPINION: Due to the crucial role of transporters in the renal disposition of xenobiotics and endogenous substances, it is necessary to further elucidate their renal transport mechanisms and pay more attention to the underlying relationship between the transport of endogenous substances and nephrotoxicity. Considering the species differences in the expression and function of transporters, and the low expression of transporters in general cell models, in vitro humanized models, such as humanized 3D organoids, shows significant promise in nephrotoxicity prediction and mechanism study.

The Effect of Mild Renal Dysfunction on the Assessment of Plasma Amino Acid Concentration and Insulin Resistance in Patients with Type 2 Diabetes Mellitus.

Background: An increase in the levels of branched-chain amino acids (BCAAs) and certain aromatic amino acids, such as alanine, in plasma is correlated with insulin resistance (IR) in type 2 diabetes mellitus (T2DM). T2DM is a leading risk factor for chronic kidney disease. Meanwhile, renal dysfunction causes changes in plasma amino acid levels. To date, no study has examined how mild renal dysfunction and IR interact with plasma amino acid levels. This study examines the effects of IR and renal dysfunction on plasma amino acid concentrations in T2DM. Methods: Data were collected from healthy male participants (controls) and male patients with T2DM between May 2018 and February 2022. Blood samples were collected after overnight fasting. IR and renal function were evaluated using the homeostasis model assessment of IR (HOMA-IR) and serum cystatin C (CysC), respectively. Results: A total of 49 and 93 participants were included in the control and T2DM groups, respectively. In the T2DM group, eight amino acids (alanine, glutamic acid, glutamine, glycine, isoleucine, leucine, tyrosine, and valine) and total BCAA showed a significant correlation with HOMA-IR (p < 0.01), whereas six amino acids (γ-aminobutyric acid, citrulline, cysteine, glycine, methionine, and valine) and total BCAA showed a significant correlation with 1/CysC (p < 0.02). However, only alanine, glutamic acid, and each BCAA showed significant differences between the control group and the IR T2DM subgroup. Increases in the BCAA levels with T2DM were canceled by renal dysfunction (CysC ≥ 0.93) in patients with intermediate IR. Conclusion: To use plasma BCAA concentration as a marker of IR, renal function must be considered, even in mild renal dysfunction. Increased alanine and glutamic acid levels indicate IR, regardless of mild renal dysfunction.

Assessment of Mitochondrial Function and Oxygen Consumption Measured During Ex Vivo Normothermic Machine Perfusion of Injured Pig Kidneys Helps to Monitor Organ Viability.

Donor kidney assessment may improve organ utilisation. Normothermic Machine Perfusion (NMP) has the potential to facilitate this advance. The mechanism of action is not yet determined and we aimed to assess mitochondrial function during NMP. Anaesthetised pigs (n = 6) had one kidney clamped for 60 min. The healthy contralateral kidney was removed and underwent NMP for 8 h (healthy control (HC), n = 6). Following 60 min warm ischaemia the injured kidney underwent HMP for 24 h, followed by NMP for 8 h (n = 6). Mitochondria were extracted from fresh tissue for analysis. Injured kidneys were analysed as two separate groups (IMa, n = 3 and IMb, n = 3). Renal resistance was higher (0.39ï, ± 0.29 vs. 1.65ï, ± 0.85; p = 0.01) and flow was lower (55ï, ± 28 vs. 7ï, ± 4; p = 0.03) during HMP in IMb than IMa. NMP blood flow was higher in IMa versus IMb (2-way ANOVA; p < 0.001) After 60 min NMP, O2 consumption was significantly lower in IMb versus IMa (p ≤ 0.002). State-3 respiration was significantly different between the groups (37ï, ± 19 vs. 24ï, ± 14 vs. 10ï, ± 8; nmolO2/min/mg; p = 0.049). Lactate levels were significantly lower in IMa versus IMb (p = 0.028). Mitochondrial respiration levels during NMP may be suggestive of kidney viability. Oxygen consumption, renal blood flow and lactate can differentiate severity of kidney injury during NMP.

Applicability of Novel Urinary Biomarkers for the Assessment of Renal Injury in Selected Occupational Groups in Sri Lanka: A Comparative Study with Conventional Markers.

Screening approaches with more robust biomarkers, are of the utmost importance in the characterization of renal injuries, particularly among communities with high burdens of chronic kidney disease of uncertain etiology (CKDu). The present study aimed to assess the utility of two emerging biomarkers: kidney injury molecule (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL) in predicting renal injury in different occupational groups in Sri Lanka. A cross-sectional study was conducted with six occupational groups (n = 188): fisherfolk (FF), paddy farmers (PF), sugarcane farmers (SF), factory workers (FW) and plantation workers (PW) to assess the predictive performance of KIM-1 and NGAL against a CKDu patient (PT) group (n = 40). The median KIM-1 levels of the study groups; FF, PF, SF, FW, PW and PT were 0.67, 0.59, 0.49, 1.62, 0.67 and 5.24 ng/mgCr, respectively, while the median NGAL levels were 1.16, 2.52, 1.42, 1.71, 1.06 and 22.41 ng/mgCr respectively. In ROC analysis to predict CKDu susceptibility, the area under the curve for KIM-1 ranged from 0.88 to 0.99 for the study groups, and in overall analysis, the sensitivity and specificity were 100% and 96%, respectively, for a cutoff value of 2.76 ng/mgCr. Similarly, for NGAL the range of AUC was 0.78-0.94, and a cutoff value of 3.12 ng/mgCr produced 88% sensitivity and 82% specificity. Compared with conventional markers, KIM-1 was the best biomarker for the characterization of renal injury in the participants of the occupational groups. With further validations, KIM-1 may be adopted as a prognostic marker to identify early renal injury and CKDu susceptibilities in community screening.

Simultaneous and ultra-sensitive SERS detection of SLPI and IL-18 for the assessment of donor kidney quality using black phosphorus/gold nanohybrids.

Due to the global challenge of donor kidney shortage, expanding the pool of deceased donors has been proposed to include expanded criteria donors. However, the lack of methods to precisely measure donor kidney injury and predict the outcome still leads to high discard rates and recipient complications. As such, evaluation of deceased donor kidney quality is critical prior to transplantation. Biomarkers from donor urine or serum provide potential advantages for the precise measure of kidney quality. Herein, simultaneous detection of secretory leukocyte peptidase inhibitor (SLPI) and interleukin 18 (IL-18), two important kidney injury biomarkers, has been achieved, for the first time, with an ultra-high sensitivity using surface enhanced Raman scattering (SERS). Specifically, black phosphorus/gold (BP/Au) nanohybrids synthesized by depositing Au nanoparticles (NPs) onto the BP nanosheets serve as SERS-active substrates, which offer a high-density of inherent and accessible hot-spots. Meanwhile, the nanohybrids possess biocompatible surfaces for the enrichment of target biomarkers through the affinity with BP nanosheets. Quantitative detection of SLPI and IL-18 were then achieved by characterizing SERS signals of these two biomarkers. The results indicate high sensitivity and excellent reproducibility of this method. The limits of detection reach down to 1.53×10-8 mg/mL for SLPI and 0.23×10-8 mg/mL for IL-18. The limits of quantification are 5.10×10-8 mg/mL and 7.67×10-9 mg/mL for SLPI and IL-18. In addition, simultaneous detection of these biomarkers in serum was investigated, which proves the feasibility in biologic environment. More importantly, this method is powerful for detecting multiple analytes inheriting from excellent multiplexing ability of SERS. Giving that the combined assessment of SLPI and IL-18 expression level serves as an indicator of donor kidney quality and can be rapidly and reproducibly conducted, this SERS-based method holds great prospective in clinical practice.

Comparative assessment on the probable mechanisms underlying the hepatorenal toxicity of commercial imidacloprid and hexaflumuron formulations in rats.

Pesticides are viewed as a major wellspring of ecological contamination and causing serious risky consequences for people and animals. Imidacloprid (IM) and hexaflumuron (HFM) are extensively utilized insect poisons for crop assurance on the planet. A few investigations examined IM harmfulness in rodents, but its exact mechanism hasn't been mentioned previously as well as the toxicity of HFM doesn't elucidate yet. For this reason, the present study was designed to explore the mechanism of each IM and HFM-evoked rat liver and kidney toxicity and to understand its molecular mechanism. 21 male Wistar albino rats were divided into 3 groups, as follows: group (1), normal saline; group (2), IM; and group (3), HFM. Both insecticides were orally administered every day for 28 days at a dose equal to 1/10 LD50 from the active ingredient. After 28 days postdosing, rats were anesthetized to collect blood samples then euthanized to collect liver and kidney tissue specimens. The results showed marked changes in walking, body tension, alertness, and head movement with a significant reduction in rats' body weight in both IM and HFM receiving groups. Significant increases in MDA levels and decrease of GHS levels were recorded in liver and kidney homogenates of either IM or HFM groups. Liver and kidney tissues obtained from both pesticide receiving groups showed extensive histopathological alterations with a significant increase in the serum levels of ALT, AST, urea, and creatinine and a decrease in total proteins, albumin, and globulin levels. In addition, there was upregulation of the transcript levels of casp-3, JNK, and HO-1 genes with strong immunopositivity of casp-3, TNF-á½°, and NF-KB protein expressions in the liver and kidneys of rats receiving either IM or HFM compared with the control group. In all studied parameters, HFM caused hepatorenal toxicity more than those induced by IM. We can conclude that each IM and HFM provoked liver and kidneys damage through overproduction of ROS, activation of NF-KB signaling pathways and mitochondrial/JNK-dependent apoptosis pathway.

Assessment of renal function among covid-19 patients admitted to the intensive care unit.

Severe acute respiratory viral infections are frequently associated with multiple organ failure, including acute kidney damage. The present study aimed to investigate the associated influence of COVID-19 on renal function in patients admitted to the intensive care unit in Asir region, Saudi Arabia. Thirty patients infected with COVID-19 who were referred to the intensive care unit during November and October 2020 at Asir central hospital, Asir region, Saudi Arabia were recruited. The age of patients ranged between 30 and 90 years old. Renal function tests exhibited dramatic changes in the renal biomarkers in patients with COVID-19. Blood urea levels in COVID-19 patients were significantly higher than in the control group. In addition, significantly lower albumin levels with abnormally decreased total protein levels were found in COVID-19 patients. Among the different electrolytes analyzed, a significantly lower calcium level was observed in COVID-19 patients' groups than in the controls. Renal function tests for COVID-19-infected ICU patients revealed significant changes, indicating the major impact of COVID-19 on kidney function. Monitoring renal function tests may assist in the early prognosis of COVID-19 patients. It is, therefore, crucial to increase the understanding of renal function tests in COVID-19 patients who were admitted to the hospital before their condition deteriorated.

Assessment of renal and hepato-protective potential of guava leaves in male Sprague dawley rats.

Present research project was an attempt to explore the functional/nutraceutical worth of guava leaves from two locally grown varieties (Ruby & Safeda). For the purpose, guava leaves extract was fed to experimental male Sprague Dawley rats to explore the nutraceutical potential of guava leaves against hepatotoxicity. Two studies were performed on two types of rats i.e. study I (normal rats), study II (hepatotoxic rats). In both studies, 250 mg/kg each of pink guava leaves extracts (T1) and white guava leaves extracts (T2) was added in the feed. Feed intake and body weights of the rats were recorded. At the end of the first and eighth week of study, the blood samples of the rats were analyzed to check the effect of guava leaves extracts on renal functioning (Alkaline Phosphatase, Alanine Transaminase and Aspartate Transaminase) as well as liver functioning parameters including urea and creatinine. In both studies, comparatively higher feed consumption was observed in the control group than the rest of the treatments. At the end of study I, the highest weight (207±9.21 g) was observed in T0 whereas, during study II, the maximum value (202±5.58 g) was found in T2 (rats consuming white guava leaves extract) that indicates its effectiveness against hepatotoxicity. Regarding renal functioning tests, pink guava leaves were more effective in decreasing urea and creatinine levels in rats as compared to the white guava leaves in both study plans. Likewise, in each of study trial, pink guava leaves were more effective in reducing AST, ALT and ALP than white guava leaves and control. From the present investigation, it is deduced that guava leaves were effective against hepatotoxicity.

Glycogen Storage Disease Type Ia: Current Management Options, Burden and Unmet Needs.

Glycogen storage disease type Ia (GSDIa) is caused by defective glucose-6-phosphatase, a key enzyme in carbohydrate metabolism. Affected individuals cannot release glucose during fasting and accumulate excess glycogen and fat in the liver and kidney, putting them at risk of severe hypoglycaemia and secondary metabolic perturbations. Good glycaemic/metabolic control through strict dietary treatment and regular doses of uncooked cornstarch (UCCS) is essential for preventing hypoglycaemia and long-term complications. Dietary treatment has improved the prognosis for patients with GSDIa; however, the disease itself, its management and monitoring have significant physical, psychological and psychosocial burden on individuals and parents/caregivers. Hypoglycaemia risk persists if a single dose of UCCS is delayed/missed or in cases of gastrointestinal intolerance. UCCS therapy is imprecise, does not treat the cause of disease, may trigger secondary metabolic manifestations and may not prevent long-term complications. We review the importance of and challenges associated with achieving good glycaemic/metabolic control in individuals with GSDIa and how this should be balanced with age-specific psychosocial development towards independence, management of anxiety and preservation of quality of life (QoL). The unmet need for treatment strategies that address the cause of disease, restore glucose homeostasis, reduce the risk of hypoglycaemia/secondary metabolic perturbations and improve QoL is also discussed.

Improving SIRT1 by trehalose supplementation reduces oxidative stress, inflammation, and histopathological scores in the kidney of aged rats.

The aging process leads to progressive loss of kidney function. Sirtuin1 (SIRT1) exerts renoprotective effects by conferring resistance to cellular stresses. Trehalose potentially displayed various beneficial effects to promote health span. In this study, we investigated the effects of trehalose on renal SIRT1 and kidney function in senescent rats. Trehalose (2% w/v) was administrated in drinking water for 1 month to male aged rats (24 months). Then, the level of SIRT1 mRNA and protein, malondialdehyde, total antioxidant capacity, tumor necrosis factor α as well as parameters related to the function and histology of the kidneys were evaluated. Trehalose supplementation increased the level of SIRT1, whereas alleviated the level of oxidative stress, inflammation, and histopathology scores in senescent tissues. However, trehalose administration did not alter kidney function indices in old rats. Collectively, these findings suggested that trehalose was an effective intervention to ameliorate some aspects of age-associated injury in the old kidneys. PRACTICAL APPLICATIONS: Aging is associated with impairment in renal structure and function. Trehalose is a natural disaccharide, which is widely distributed in many organisms. The consumption of trehalose as a dietary supplement is increasing worldwide. This study showed that trehalose administration to aged rats had renoprotective effects through reducing oxidative stress and inflammation, which was mediated by SIRT1. Our results provide useful information for individuals using this sugar as a supplement.

In vivo assessment of molybdenum and cadmium co-induce nephrotoxicity via NLRP3/Caspase-1-mediated pyroptosis in ducks.

Excessive molybdenum (Mo) and cadmium (Cd) cause toxic effects on animals, but their joint effects on pyroptosis in kidney of ducks remain unclear. 160 healthy 7-day-old ducks were randomly divided into four groups which were fed with basal diet containing different dosages of Mo or/and Cd for 16 weeks. On the 4th, 8th, 12th and 16th weeks, kidney tissue and serum were collected. The results showed that Mo or/and Cd could significantly elevate their contents in kidney, disturb the homeostasis of trace elements, cause renal function impairment and histological abnormality, and oxidative stress as accompanied by increasing hydrogen peroxide (H2O2) and malondialdehyde (MDA) concentrations and decreasing glutathione peroxidase (GSH-Px), catalase (CAT) and total-superoxide dismutase (T-SOD) activities. Simultaneously, Mo or/and Cd could markedly increase interleukin-1ß (IL-1ß), interleukin-18 (IL-18) contents and the expression levels of pyroptosis-related genes (NOD-like receptor protein-3 (NLRP3), Caspase-1, apoptosis-associated speck-like protein (ASC), NIMA-related kinase 7 (NEK7), Gasdermin A (GSDMA), Gasdermin E (GSDME), IL-1ß and IL-18) and proteins (NLRP3, Caspase-1 p20, ASC and Gasdermin D (GSDMD)). Moreover, the changes of above these indicators were more obvious in combined group. Taken together, the results illustrate that Mo and Cd might synergistically lead to oxidative stress and induce pyroptosis via NLRP3/Caspase-1 pathway, whose mechanism is somehow related to Mo and Cd accumulation in duck kidneys.

Assessment of Renal Function Status in Steady-State Sickle Cell Anaemic Children Using Urine Human Neutrophil Gelatinase-Associated Lipocalin and Albumin:Creatinine Ratio.

INTRODUCTION: Sickle cell anaemia is characterized by defective haemoglobin synthesis and is associated with both endocrine and metabolic alterations. The effects of this clinical condition on kidney function are multifactorial and often begin early in childhood. This study aims to assess renal function in children with sickle cell anaemia using urine albumin:creatinine ratio (ACR) and urine human neutrophil gelatinase-associated lipocalin (NGAL). METHODS: This case-control study was conducted on 200 children aged 5-15 years in 2 tertiary hospitals in South West Nigeria: 150 were of haemoglobin S genotype and 50 were of haemoglobin A genotype. Serum urea, creatinine, urine albumin, and NGAL were assayed by known standard methods. eGFR, urine ACR, and urine NGAL/creatinine ratio (urine NCR) were calculated. RESULTS: The weight, height, BMI, systolic blood pressure, plasma urea, plasma creatinine, and spot urine creatinine of the HbS genotype children were significantly lower compared to that of the HbA genotype children. The eGFR, spot urine albumin, and urine ACR were significantly higher in the HbS group compared to the HbA group. There was no significant difference in the spot urine NGAL and urine NCR between the 2 groups, though both were higher in the HbS group compared to the HbA group. CONCLUSIONS: Kidney injury probably starts early in childhood in sickle cell individuals as indicated by the higher urine ACR detected in them. We infer that urine NGAL and uNCR are not sensitive markers of kidney disease especially in young sickle cell individuals possibly because of the hyperfiltration present at this age.