Increase In Serum Creatinine Research Articles

Linagliptin ameliorates tacrolimus-induced renal injury: role of Nrf2/HO-1 and HIF-1α/CTGF/PAI-1

BackgroundTacrolimus (TAC) is a frequently used immunosuppressive medication in organ transplantation. However, its nephrotoxic impact limits its long-term usage. This study aims to investigate the effect of linagliptin (Lina) on TAC-induced renal injury and its underlying mechanisms.Methods and resultsThirty-two Sprague Dawley rats were treated with TAC (1.5 mg/kg/day, subcutaneously) and/or Lina (5 mg/kg/day, orally) for 4 weeks. Histological examination was conducted, and serum and urinary biomarkers were measured to assess kidney function and integrity. Furthermore, ELISA, Western blot analysis and immunohistochemical assay were employed to determine signaling molecules of oxidative stress, profibrogenic, hypoxic, and apoptotic proteins. Tacrolimus caused renal dysfunction and histological deterioration evidenced by increased serum creatinine, blood urea nitrogen (BUN), urinary cystatin C, and decreased serum albumin as well as elevated tubular injury and interstitial fibrosis scores. Additionally, TAC significantly increased the expression of collagen type-1, alpha-smooth muscle actin (α-SMA), plasminogen activator inhibitor-1 (PAI-1), and transforming growth factor-beta1 (TGF-β1) renal content. Moreover, TAC decreased the expression of nuclear factor erythroid-2-related factor2 (Nrf2), heme oxygenase 1 (HO-1), and mitochondrial superoxide dismutase (SOD2). In addition, TAC increased protein expression of hypoxia-inducible factor1-alpha (HIF-1α), connective tissue growth factor (CTGF), inducible nitric oxide synthase (iNOS), 8-hydroxy-2-deoxyguanosine (8-OHdG), as well as nitric oxide (NO), 4-hydroxynonenal, caspase-3 and Bax renal contents. Furthermore, TAC decreased Bcl-2 renal contents. The Lina administration markedly attenuated these alterations.ConclusionLina ameliorated TAC-induced kidney injury through modulation of oxidative stress, hypoxia, and apoptosis related proteins.

Chronic kidney disease is accompanied by behavioral deficits in rodents

Clinical reports indicate a bidirectional relationship between mental illness and chronic systemic disease. Kidney injury and inflammation have been linked to brain dysfunction and alterations in learning and memory, as well as development of anxiety and depression, however, the underlying neurophysiological mechanisms remain elusive. In the current study, we investigated whether a chronic kidney disease (CKD) state is suffcient to produce deficits in rodent stress behaviors using a mild or severe model of CKD. Male rats were exposed to either 21 days of 0.75% adenine diet (AD) (model of mild CKD), or a combination of AD with unilateral nephrectomy (AD/Unx), prior to the start of AD (model of severe CKD). Control rats received sham surgery and remained on normal diet/chow throughout the experimental paradigm. CKD development in the rat models was determined by a significant increase in serum creatinine used as index for kidney function. Behavioral testing results demonstrate that mild CKD model, especially in combination with unilateral nephrectomy (severe CKD model), is accompanied by anhedonia (i.e., decreased sucrose preference) and increased anxiety-like behaviors in the novelty-suppressed feeding, open field and elevated plus maze tests. These findings suggest that impairment of kidney functionality is suffcient to increase behavioral emotionality in rodents consistent with development of depressive-like and anxiogenic phenotype. Ongoing studies are focused on identifying neurophysiological mechanisms linking renal disease with neurological abnormalities. Furthering our understanding of these mechanisms may aid in the development of improved treatments and prevention strategies for management of mental health comorbidities associated with kidney disease. Des Moines University IOER Research & Grant Award. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

RENOPROTECTIVE EFFECTS OF DAPAGLIFLOZIN IN NON-DIABETIC CKD PATIENTS

Objective: Sodium-glucose co-transporter 2 inhibitors (SGLT2i) have demonstrated significant cardiorenal protection benefits in recent years, irrespective of the presence of diabetes mellitus (DM). These agents have emerged as pivotal in reducing albuminuria and impeding chronic kidney disease (CKD) progression. This study aimed to evaluate the renal effects of dapagliflozin, an SGLT2i, in in non-diabetic proteinuric patients with CKD. Design and method: In this retrospective observational study we analyzed medical records of adult non-diabetic patients with CKD, in our outpatient department over the period of one year. exhibiting albuminuria, and under stable renin-angiotensin system blockade. The primary objectives were to assess dapagliflozin's impact on estimated glomerular filtration rate (eGFR) within the first month and changes in 24-hour proteinuria from baseline. Results: Between November 2022 and December 2023, dapagliflozin was prescribed to 37 patients (8 women) with a mean age of 59.8±11.6 years. Primary diagnoses of CKD included IgA Nephropathy (7/37), other glomerulonephritis (9/37), hypertension (6/37), unknown (9/37), and other (6/37). Baseline median creatinine was 1.60±0.6 mg/dL, eGFR was 54.1±21.6 mL/min/1.73m2, and proteinuria was 1047 mg/24h (IQR 420-2170), serum potassium 4.77±0.41mEq/L blood pressure 130±15 / 82±9 mmHg, body weight 85.1±16.8 kg. After the first month, median creatinine was 1.75±0.7 mg/dL (p=0.02 vs baseline), eGFR was 50,7±21,3 mL/min/1.73m2 (p=0.006 vs baseline). Two patients experienced >30% serum creatinine increase within 4 weeks, leading to SGLT2i discontinuation. After a median follow-up of 233 days (IQR 80-284), creatinine was 1.71±0.75 mg/dL (p=0.067 vs baseline), eGFR was 51.6±23.6 mL/min/1.73m2 (p=0.019 vs baseline), and proteinuria decreased by 33,7% from baseline (450, IQR 270-1110). One patient stopped SGLT2i due to recurrent urinary tract infection. No change was observed in serum potassium, body weight and blood pressure throughout the study period. Conclusions: Treatment with dapagliflozin in non-diabetic patients with CKD reduced effectively proteinuria with an initial, reversible, decline in serum creatinine.

Acute Kidney Injury In Children

Acute kidney injury (AKI) is a clinical condition characterized by sudden deterioration in kidney functions, increase in blood urea nitrogen (BUN) and serum creatinine levels, hyperkalemia, metabolic acidosis and hypertension. When defining AKI, current guidelines that consist of criterias determined by serum creatinine level and urine output are used. There are three main causes of AKI; prerenal, renal and postrenal. Prerenal AKI is most common etiology in children. Clinical symptoms of AKI vary depending on etiology. When evaluating a child with AKI, it should be noted that an increase in creatinine typically occurs 48 hours after renal injury and is the result of events 2-3 days earlier. The prognosis of AKI varies depending on the etiology.

Dexamethasone promotes renal fibrosis by upregulating ILT4 expression in myeloid-derived suppressor cells.

Studies have shown that adoptive transfer of myeloid-derived suppressor cells (MDSCs) can alleviate various inflammatory diseases, including glomerulonephritis, but the long-term effects of the transferred MDSCs are still unclear. In addition, although glucocorticoids exert immunosuppressive effects on inflammatory diseases by inducing the expansion of MDSCs, the impact of glucocorticoids on the immunosuppressive function of MDSCs and their molecular mechanisms are unclear. In this study, we found that adoptive transfer of MDSCs to doxorubicin-induced focal segmental glomerulosclerosis (FSGS) mice for eight consecutive weeks led to an increase in serum creatinine and proteinuria and aggravation of renal interstitial fibrosis. Similarly, 8 weeks of high-dose dexamethasone administration exacerbated renal interstitial injury and interstitial fibrosis in doxorubicin-induced mice, manifested as an increase in serum creatinine and proteinuria, collagen deposition and α-SMA expression. On this basis, we found that dexamethasone could enhance MDSC expression and secretion of the fibrosis-related cytokines TGF-β and IL-10. Mechanistically, we revealed that dexamethasone promotes the expression of immunoglobulin-like transcription factor 4 (ILT4), which enhances the T-cell inhibitory function of MDSCs and promotes the activation of STAT6, thereby strengthening the expression and secretion of TGF-β and IL-10. Knocking down ILT4 alleviated renal fibrosis caused by adoptive transfer of MDSCs. Therefore, our findings demonstrate that the role and mechanism of dexamethasone mediate the expression and secretion of TGF-β and IL-10 in MDSCs by promoting the expression of ILT4, thereby leading to renal fibrosis.

Evaluation of contrast induced nephropathy related risk factors and long-term results.

We aimed to evaluate the frequency of contrast induced nephropathy (CIN), its relationship with accepted risk factors and long-term renal outcomes in patients who underwent coronary angiography (CAG). All patients who underwent CAG between April 2020 and April 2021 were retrospectively evaluated. CIN was defined as characteristic increase in serum creatinine after CAG. CIN developed in 50 (5.4%) of 934 patients. The CIN rate was found to be statistically significantly higher in patients with diabetes, hypertension, heart failure and those using diuretics. Pre-procedural hemoglobin, albumin and GFR were found to be independent risk factors for CIN. After discharge, the urea and creatinine values of the patients who developed CIN were significantly higher than those who did not. We concluded that in order to reduce the development of CIN, hemoglobin and albumin levels should be evaluated with renal functions before the procedure and they should be kept within normal limits.

Osthole ameliorates early diabetic kidney damage by suppressing oxidative stress, inflammation and inhibiting TGF-β1/Smads signaling pathway

BackgroundOsthole is a natural active ingredient extracted from the traditional Chinese medicine Cnidium monnieri. It has been demonstrated to have anti-inflammatory, anti-fibrotic, and anti-hyperglycemic properties. However, its effect on diabetic kidney disease (DKD) remains uncertain. This study aims to assess the preventive and therapeutic effects of osthole on DKD and investigate its underlying mechanisms. MethodsA streptozotocin/high-fat and high-sucrose diet induced Type 2 diabetic rat model was established. Metformin served as the positive drug control. Diabetic rats were treated with metformin or three different doses of osthole for 8 weeks. Throughout the treatment period, the progression of DKD was assessed by monitoring increases in urinary protein, serum creatinine, urea nitrogen, and uric acid, along with scrutinizing kidney pathology. Enzyme-linked immunosorbent assay (ELISA) was employed to detect inflammatory factors and oxidative stress levels. At the same time, immunohistochemical staining was utilized to evaluate changes in alpha-smooth muscle actin, fibronectin, E-cadherin, and apoptosis. The alterations in TGF-β1/Smads signaling pathway were ascertained through western blot and immunofluorescence. Furthermore, we constructed a high glucose-stimulated HBZY-1 cells model to uncover its molecular protective mechanism. ResultsOsthole significantly reduced fasting blood glucose, insulin resistance, serum creatinine, uric acid, blood urea nitrogen, urinary protein excretion, and glomerular mesangial matrix deposition in diabetic rats. Additionally, significant improvements were observed in inflammation, oxidative stress, apoptosis, and fibrosis levels. The increase of ROS, apoptosis and hypertrophy in HBZY-1 cells induced by high glucose was reduced by osthole. Immunofluorescence and western blot results demonstrated that osthole down-regulated the TGF-β1/Smads signaling pathway and related protein expression. ConclusionOur findings indicate that osthole exhibits potential preventive and therapeutic effects on DKD. It deserves further investigation as a promising drug for preventing and treating DKD.

Long-term Outcomes of Augmentation Cystoplasty in Genitourinary Tuberculosis in Adults: A 12-year Follow-up Experience at a Tertiary Care Center

ObjectivesTo evaluate the long-term effectiveness and consequences of augmentation cystoplasty in adult patients with small capacity bladder due to genitourinary tuberculosis (GUTB). MethodsAfter approval of the institutional ethical committee, we retrospectively analyzed the database of adult patients with small capacity bladder due to GUTB treated by augmentation cystoplasty from January 2010 to December 2022 at our center. The patients were followed up at six weeks postoperatively, then every three monthly for 1st year and six monthly in second year, and then annually. Patients were assessed for symptoms, renal function, blood biochemistry levels, and ultrasound KUB at each follow-up visit. ResultsA total of 40 patients underwent augmentation cystoplasty were included. All patients underwent augmentation cystoplasty either with ileum (n=35) or sigmoid colon (n=5). On long term follow up, there were statistically significant improvement in bladder capacity, decrease in voiding frequency (p=0.00), decrease in eGFR (p=0.02) and increase in serum creatinine (p=0.02). Significant complications were wound infection 4 (10%), intestinal obstruction 1(2.5%), urinary tract infection 6 (15%), bladder stone 2 (5%), mucus retention 3 (7.5%), hypocalcemia with metabolic acidosis 2 (5%) and need of intermittent catheterisation in 11 (27.5%) patients. ConclusionsMultidrug therapy with judicious reconstructive surgery is the optimal treatment modality for GUTB with cicatrization sequelae. In GUTB, augmentation cystoplasty is a safe procedure and strict long term follow up is needed to prevent complications.

Clinical Significance of Hepatobiliary Localization of Tc-99m EC in Diuretic Renography

Abstract Objective Technetium-99m ethylene dicysteine (Tc-99m EC) is a well-established, tubular tracer for diuretic renography. Few occasional cases have been reported in literature regarding visualization of liver, gallbladder (GB), or bowel due to increased hepatobiliary route of excretion of Tc-99m EC on diuretic renography. This study aimed to retrospectively review the incidence of visualization of liver, GB, or bowel and its clinical significance in Tc-99m EC diuretic renography. Materials and Methods Data of all patients who underwent diuretic renography in the department from January 24, 2022 to March 31, 2023 was included in the study. The data was analyzed to assess the incidence of visualization of GB or bowel loops, correlation of the hepatobiliary localization with factors like age of the patient, concentration of 99m TcO4 solution, quality control parameters, presence of renal stone disease, serum creatinine, relative renal function, and effective renal plasma flow. Effect of hepatobiliary localization on scan interpretation and reporting was assessed. Results The retrospective analysis of 437 diuretic renograms revealed the hepatobiliary localization of tracer in 34 patients. Out of these 34 patients, 14 patients had only faint visualization of tracer at 4 hours delayed image. Twenty scans had visualization of both GB and bowel. Out of these 20 scans, GB and bowel were visualized during dynamic imaging in one scan, after initial 20 minutes in two scans and in 2 to 4 hours delayed images in rest of the 17 scans. Two out of 20 patients had increased serum creatinine, 16 patients had either single kidney or relative renal function less than 26%, and 12 patients had renal stone disease. Out of the four patients in whom relative renal function was more than 25%, one patient had raised serum creatinine and three patients had renal stone disease. Interpretation of images was affected only in three patients, in which reporting of the scans required single-photon emission computed tomography imaging and correlation with other imaging modalities. Conclusion Hepatobiliary excretion of Tc-99m EC usually does not usually affect the scan interpretation and quantitative renogram analysis, but reader should be cognizant of the potential pitfalls during scan interpretation. In this study, we reviewed the possible causes of this hepatobiliary clearance and importance of additional views and correlation with other imaging modalities to clarify the suspicion arises for accurate reporting.

Cpd-A1 alleviates acute kidney injury by inhibiting ferroptosis.

Acute kidney injury (AKI) is defined as sudden loss of renal function characterized by increased serum creatinine levels and reduced urinary output with a duration of 7 days. Ferroptosis, an iron-dependent regulated necrotic pathway, has been implicated in the progression of AKI, while ferrostatin-1 (Fer-1), a selective inhibitor of ferroptosis, inhibited renal damage, oxidative stress and tubular cell death in AKI mouse models. However, the clinical translation of Fer-1 is limited due to its lack of efficacy and metabolic instability. In this study we designed and synthesized four Fer-1 analogs (Cpd-A1, Cpd-B1, Cpd-B2, Cpd-B3) with superior plasma stability, and evaluated their therapeutic potential in the treatment of AKI. Compared with Fer-1, all the four analogs displayed a higher distribution in mouse renal tissue in a pharmacokinetic assay and a more effective ferroptosis inhibition in erastin-treated mouse tubular epithelial cells (mTECs) with Cpd-A1 (N-methyl-substituted-tetrazole-Fer-1 analog) being the most efficacious one. In hypoxia/reoxygenation (H/R)- or LPS-treated mTECs, treatment with Cpd-A1 (0.25 μM) effectively attenuated cell damage, reduced inflammatory responses, and inhibited ferroptosis. In ischemia/reperfusion (I/R)- or cecal ligation and puncture (CLP)-induced AKI mouse models, pre-injection of Cpd-A1 (1.25, 2.5, 5 mg·kg-1·d-1, i.p.) dose-dependently improved kidney function, mitigated renal tubular injury, and abrogated inflammation. We conclude that Cpd-A1 may serve as a promising therapeutic agent for the treatment of AKI.

Ketorolac Dosing and Outcomes in Neonates Following Congenital Heart Surgery: A Retrospective Analysis.

Pain management is essential for postoperative surgery. Given the association of opioids with adverse outcomes, interest in the use of nonopioid analgesics, such as ketorolac, has increased. Published data on use in neonates are limited. To describe ketorolac dosing and safety and efficacy outcomes in the first 48 hours postcardiac surgery in neonates. We performed a single-center retrospective cohort study of neonates (ages < 28 d) who received ketorolac following cardiac surgery from November 2020 to July 2023 (inclusive). The primary safety outcome was a clinically significant decline in renal function, as defined by the composite of an increase in serum creatinine by greater than or equal to 0.3 mg/dL from baseline within 96 hours of ketorolac initiation and urine output less than or equal to 0.5 mL/kg/hr for 6 hours. The secondary safety outcome was clinically significant bleeding, defined as the composite of major bleeding by the International Society on Thrombosis and Hemostasis pediatric criteria and severe/fatal bleeding by the criteria of Nellis et al (2019). Efficacy was measured by opioid utilization based on a standardized pain score-driven analgesia protocol. Ketorolac was administered at 0.5 mg/kg every 6 hours as per an institutional clinical management algorithm. Thirty-nine patients met the eligibility criteria. The median ketorolac dose was 0.5 mg/kg/dose, and median (interquartile range [IQR]) duration of therapy was 48 hours (6-48 hr). No patients experienced a significant decline in renal function, and there were no clinically significant bleeding events. The median (IQR) IV morphine milligram equivalents (MMEs)/kg/d of opioid administration was 0.2 MME/kg/d (0.1-0.25 MME/kg/d) at the time of ketorolac initiation and 0.1 MME/kg/d (0.1-0.2 MME/kg/d) at 48 hours post-ketorolac initiation. If validated prospectively, these findings suggest that a ketorolac regimen of 0.5 mg/kg/dose every 6 hours in neonates postcardiac surgery may be safe with regard to renal function and bleeding risk. Additional randomized studies would be needed to determine efficacy with regard to opioid-sparing capacity.

Safety of Nonselective Beta-Blockers in Decompensated Liver Cirrhosis and Their Role in Inducing Hepatorenal Syndrome.

Background Nonselective beta-blockers (NSBBs) have been used in the management of portal hypertension and the prevention of initial and recurrent variceal bleeding in patients with liver cirrhosis. However, there is controversy regarding the use of NSBBs in patients with decompensated cirrhosis (DC) due to concerns over potential adverse effects, such as worsening of hepatic function and risk of hepatorenal syndrome (HRS). HRS is a serious complication of DC characterized by acute kidney injury (AKI) and progressive renal failure, and its development can lead to significant morbidity and mortality in this setting. Therefore, using NSBBs in patients with DC remains an area of ongoing research and debate. Our study aims to investigate the potential effect of NSBBs on HRS development. Methodology A retrospective chart review of 404 patients with cirrhosis was performed across all Northwell Health institutions between January 01, 2019, and December 31, 2020. An analysis was done on 516 patient encounters. Inclusion criteria included patients with an established International Classification of Diseases 10th Revision code of cirrhosis and AKI.After adjusting for clinical predictors, the Student's t-test or Mann-Whitney U-testwas used to compare variables between the two outcome groups (HRS vs. no HRS) for the continuous variables. Pearson's chi-square test or Fisher's exact test was used for the categorical variablesto test if an association existed between the use of NSBBs at home and HRS. A two-sided p-value <0.05 was considered statistically significant. SAS 9.4 (SAS Institute Inc., Cary, NC, USA) was used for statistical analysis. Results The primary outcome was the development of HRS during the hospital stay. With a total of 109 visits with HRS, we had 21 (23.60%) reported HRS in the 89 visits where NSBBs were used at home before the hospitalization, while 88 (20.61%) HRS were observed in the 427 visits with no NSBB use at home. The use of NSBBs at home was not significantly associated with the development of HRS (odds ratio = 1.1, 95% confidence interval = 0.6-1.9, p = 0.7321). We also found that higher serum albumin on admission is associated with lower odds of HRS. In contrast, increased serum creatinine, bilirubin, presence of ascites, and use of pressors were associated with a higher risk of HRS. Conclusions Our study highlights the relevant safety of NSBB use in end-stage liver disease. Their use did not appear to increase the risk of developing HRS during hospitalization with DC. Further randomized controlled trials are warranted to shed more light on the efficacy, dose tolerance limits, and safety of NSBBs in decompensated end-stage liver disease.

Pharmacokinetics and Nephrotoxicity of Polymyxin MRX-8 in Rats: A Novel Agent against Resistant Gram-Negative Bacteria.

MRX-8 is a novel polymyxin for carbapenem-resistant Gram-negative infections that has been recently evaluated in Phase I clinical trials. Herein, its pharmacokinetics (PK) and nephrotoxicity in rats are reported for the first time. This study aimed at pre-clinical PK and safety assessments. An LC-MS/MS method was developed to determine concentrations of MRX-8 and its major deacylation metabolite, MRX-8039, in rat plasma. Animals were administered a single dose of MRX-8 (2, 4, 6, and 8 mg/kg) or comparator polymyxin B (PMB) (4 and 8 mg/kg) to compare the kidney injury known for the polymyxin drug class. Nephrotoxicity was evaluated using serum creatinine, blood urea nitrogen (BUN) biomarkers, and renal histopathology. In rats, MRX-8 displayed linear PK within the range of 2-8 mg/kg, with approximately 4% of MRX-8 converted to MRX-8039. MRX-8 induced only mild increases in serum creatinine and BUN levels, with an apparent decrease in nephrotoxicity within 24 h, in contrast to PMB, which exhibited a significant and more persistent toxicity. Additional nephrotoxicity biomarkers (plasma NGAL and urinary NGAL, KIM-1, and TIMP-1) have confirmed attenuated MRX-8 kidney injury. Histopathology has revealed significantly greater cellular/tissue toxicity for PMB as compared to MRX-8 (variances of p = 0.008 and p = 0.048 vs. saline control, respectively). Thus, MRX-8 induces a mild and reversible kidney injury in rats compared to PMB. These data support a continued evaluation of the novel polymyxin in human trials.

In Vivo Antioxidant and Nephroprotective Effects of Ethanolic Extract of Carica papaya Seeds and Its Isolated Flavonoid on Gentamicin-Induced Nephrotoxicity in Wistar Albino Rats.

Background The nephrotoxic side effects of gentamicin, a potent aminoglycoside antibiotic, significantly restrict its clinical use. Identifying compounds that can mitigate this nephrotoxicity is of paramount importance. The research examines how the ethanolic extract of Carica papaya seeds (EECPS) and isoliquiritigenin (ISL), a flavonoid separated from them, protect the kidneys and fight free radicals in gentamicin-treated Wistar albino rats. Methodology A total of 48 mature Wistar albino rats were divided into eight groups, with each group consisting of six rats. The experimental setup included a normal control group receiving oral saline as a negative control, and a standard control group administered gentamicin intraperitoneally (IP) at 100 mg/kg body weight for 13 days to induce nephrotoxicity, followed by oral silymarin at 100 mg/kg body weight as a positive control from days 14 to 21. A toxicant control group was exposed to gentamicin IP without subsequent treatment. Two test groups were given 400 mg/kg and 800 mg/kg of EECPS orally after being given gentamicin. Three other test groups were given 20 mg/kg, 40 mg/kg, and 80 mg/kg of ISL orally after being given gentamicin. Serum levels of creatinine, urea, and blood urea nitrogen (BUN) were used to test renal function. Malondialdehyde (MDA),nitric oxide (NO), and reduced glutathione (GSH), which are signs of oxidative stress, were also measured in renal tissues. Results Gentamicin administration markedly increased serum creatinine, urea, and BUN levels, confirming its nephrotoxic effect. Nephroprotection depended on the dose of EECPS and ISL used. It was found that 80 mg/kg of ISL had the most powerful effect, which was not what was thought at first. These treatments effectively reduced MDA and NO levels while enhancing GSH levels, exhibiting their strong antioxidant properties. Notably, the nephroprotective efficacy of these treatments exceeded that of silymarin, a known nephroprotective agent. Histopathological analysis confirmed reduced renal damage and enhanced tissue repair in the treated groups. Conclusions These findings demonstrate how effective EECPS and ISL are at shielding the kidneys from gentamicin-caused damage. They do this by acting as antioxidants and nephroprotectants. Their ability to protect kidney function and fight oxidative stress makes them interesting as possible treatments for gentamicin-related kidney damage. These results advocate for further investigation into the utility of these natural compounds in the management of nephrotoxicity.

Differential Protective Effect of Zinc and Magnesium for the Hepatic and Renal Toxicity Induced by Acetaminophen and Potentiated with Ciprofloxacin in Rats.

Background and Objectives: The purpose of this study was to investigate the influence induced by magnesium chloride (MgCl2) and zinc gluconate (ZnG) supplementation on liver and kidney injuries experimentally induced with acetaminophen (AAPh) and potentiated by a ciprofloxacin addition in rats. Material and Methods: The experiment was performed on five animal groups: group 1-control, treated for 6 weeks with normal saline, 1 mL/kg; group 2-AAPh, treated for 6 weeks with AAPh, 100 mg/kg/day; group 3-AAPh + C, treated for 6 weeks with AAPh 100 mg/kg/day and ciprofloxacin 50 mg/kg/day, only in the last 14 days of the experiment; group 4-AAPh + C + Mg, with the same treatment as group 3, but in the last 14 days, MgCl2 10 mg/ kg/day was added; and group 5-AAPh + C + Zn, with the same treatment as group 3, but in the last 14 days, zinc gluconate (ZnG), 10 mg/kg/day was added. All administrations were performed by oral gavage. At the end of the experiment, the animals were sacrificed and blood samples were collected for biochemistry examinations. Results: Treatment with AAPh for 6 weeks determined an alteration of the liver function (increases in alanine aminotransferase, aspartate aminotransferase, lactic dehydrogenase, and gamma-glutamyl transferase) and of renal function (increases in serum urea and creatinine) (p < 0.001 group 2 vs. group 1 for all mentioned parameters). Furthermore, the antioxidant defense capacity was impaired in group 2 vs. group 1 (superoxide dismutase and glutathione peroxidase activity decreased in group 2 vs. group 1, at 0.001 < p < 0.01 and 0.01 < p < 0.05, respectively). The addition of ciprofloxacin, 50 mg/kg/day during the last 14 days, resulted in further increases in alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, urea, and creatinine (0.01 < p < 0.05, group 3 vs. group 2). MgCl2 provided a slight protection against the increase in liver enzymes, and a more pronounced protection against the increase in serum urea and creatinine (0.001 < p < 0.01 group 4 vs. group 3). MgCl2 provided a slight protection against the decrease in superoxide dismutase (0.01 < p < 0.05 group 4 vs. group 3), but not against decrease of glutathione peroxidase. The improvement of mentioned parameters could also be seen in the case of ZnG, to a higher extent, especially in the case of alanine aminotransferase and lactic dehydrogenase (0.01 < p < 0.05 group 5 vs. group 4). Conclusions: This study presents further proof for the beneficial effect of magnesium and zinc salts against toxicity induced by different agents, including antibacterials added to the analgesic and antipyretic acetaminophen; the protection is proven on the liver and kidney's function, and the antioxidant profile improvement has a key role, especially in the case of zinc gluconate.

Magnesium supplementation therapy to prevent cisplatin-induced acute nephrotoxicity in pediatric cancer: a randomized phase-2 trial.

The present study aimed to examine the effect of magnesium (Mg) supplementation on cisplatin-induced nephrotoxicity (CIN) in pediatric cancer patients. The present phase-2, open-label, multicenter, randomized controlled trial enrolled patients aged less than 20years who were scheduled to receive cisplatin-containing chemotherapy and randomly allocated them at a ratio of 1:1 to a Mg supplementation arm with even-numbered chemotherapy courses (arm AB) or another arm with odd-numbered courses (arm BA). Analysis objects were reconstructed into two groups depending on whether the chemotherapy course had Mg supplementation (group B) or not (group A). The primary outcome was the proportion of chemotherapy courses resulting in elevated serum creatinine per chemotherapy course. The secondary outcomes included efficacies evaluated using other biomarkers and the safety of the Mg supplementation. Twenty-eight patients were randomly allocated to either group (16 to arm AB and 12 to arm BA). The baseline characteristics of the groups were similar. There was no significant difference in the proportion of courses with increased serum creatinine between the groups (group A: 10% vs. group B: 6%; P = 0.465) nor was any significant difference observed in other biomarkers during any chemotherapy course. The Mg value during chemotherapy was significantly higher in group B than that in group A. No adverse events related to magnesium administration were observed. The study design, which treated a single chemotherapy course as a study object, failed to detect a statistically significant benefit of Mg supplementation for preventing CIN in pediatric cancer patients. JRCT ( https://jrct.niph.go.jp/ ) Identifier UMIN000029215 jRCTs031180251. UMIN-CTR ( http://www.umin.ac.jp/icdr/index.html ) Identifier UMIN000029215.

Development rat models of nephrotoxic: A pre-clinical test model to discover nephroprotective agents

Background: The use of drugs, including aminoglycoside drugs and anticancer drugs, is one of the things that can cause toxicity to the kidneys. Therefore, the development of agents that function as nephroprotectors continues to be researched. Objective: This study aims to obtain a nephrotoxic experimental animal model for testing nephroprotective agents. Method: The treatment was normal group, groups given a single dose of Cisplatin 7 mg/kgBW i.p (Cis), Doxorubicin single dose 25 mg/kgBW i.p (Dox-25), Doxorubicin repeated dose 4 mg/kgBW i.p twice/week for two weeks (Dox-4 repeated dose), and Gentamicin single dose 112 mg/kgBW i.p (Gen). The nephrotoxic effect was assessed by the parameters of kidney weight ratio, Ureum, Creatinine and Albumin levels in rat serum. Result: The nephrotoxic effect was indicated by an increase in the renal weight ratio of the Cisplatin; Dox-25, Dox-4 repeated, and Gen groups than normal, respectively. There was an increase in serum BUN levels, an increase in serum creatinine, and a decrease in serum albumin levels compared to the normal group. Conclusion: Cisplatin, Doxorubicin and Gentamicin have nephrotoxic effects. The administration of a single dose of cisplatin at 7 mg/kg BW gave the strongest nephrotoxic effect, making it appropriate as a model of acute nephrotoxicity in rats.

Exploration of Risk Factors of the Onset of Antibiotics-induced Acute Kidney Injury and Its Transfer to Chronic Kidney Disease Using the Medical Information Database

Drug-induced acute kidney injury (AKI) is a serious adverse drug reaction, which results in a significant decline in renal function and is known to progress to chronic kidney disease (CKD). Therefore, appropriate drug therapy is important to avoid the risk of drug-induced AKI and CKD, which are serious concerns in clinical practice. In this study, using the medical information database of Hamamatsu University Hospital, we investigated the risk factors that accelerate the onset of drug-induced AKI or its progression to CKD in patients who received aminoglycoside antibiotics (AGs) or glycopeptide antibiotics (GPs), which are strongly associated with drug-induced AKI and CKD. We performed logistic regression analysis using patients' background, laboratory test results, and concomitant drug use, among other such factors as explanatory variables and drug-induced AKI or CKD onset as objective variables to explore the risk factors for drug-induced AKI and CKD. Our results showed that co-administration of amphotericin B, piperacillin-tazobactam and other AGs and GPs, increased serum creatinine (Scr) and chloride concentrations, serum lactate dehydrogenase activity, and decreased serum albumin concentration were risk factors for drug-induced AKI onset. Moreover, a reduced blood urea nitrogen:Scr ratio at drug-induced AKI onset served as a risk factor for CKD. These results suggest that careful monitoring of the aforementioned factors is important to ensure appropriate usage of these drugs in patients treated with AGs and GPs.

Evaluation of Six eGFR Equations in Predicting Acute Kidney Injury in Patients after Off-Pump Coronary Artery Bypass Grafting: A Case Control Study.

There are six widely used equations to calculate the estimated glomerular filtration rate (eGFR) of patients. We aimed to assess the predictive power of preoperative eGFR calculated by these equations for the occurrence of postoperative acute kidney injury (AKI). Patients who underwent isolated coronary surgery from January 2016 to January 2021 were continuously enrolled. Serum creatinine and cystatin C used to calculate eGFR were both measured within 1 week before surgery. The eGFR was calculated using six equations: Cockcroft Gault (CG) equation, Chinese abbreviated modification of diet in renal disease (MDRD) equation, chronic kidney disease-epidemiology (CKD-EPI) equation, and full age spectrum (FAS) equation. Postoperative AKI was diagnosed by Kidney Disease Improving Global Outcomes criteria (KDIGO) (① urine volume 0.5 mL/kg/h for 6 h; ② an increase in serum creatinine by 26.5 µmol/L within 48 h; ③ an increase in serum creatinine to 1.5 times baseline levels, which is known or presumed to have occurred within the prior 7 days), and the occurrence of AKI within 7 days after surgery was followed. A total of 1428 patients were included, of which 319 patients (25.5%) developed postoperative AKI. After adjustment, all eGFRs (CG OR = 0.983, MDRD OR = 0.983, OR = 0.97, OR = 0.955, OR = 0.978, OR = 0. 941, all p 0.001) were significantly associated with AKI. The area under the receiver operating characteristic curve (AUC) was 0.621 for CG, 0.614 for MDRD, 0.643 for , 0.739 for , 0.643 for , 0.744 for , respectively. There was no difference in predictive power between and (p = 0.33, DeLong's test). Preoperative eGFR calculated by and equations have better performance in predicting AKI after off-pump coronary artery bypass grafting than other equations.

Outpatient mean arterial pressure: A potentially modifiable risk for acute kidney injury and death among patients with cirrhosis.

Mean arterial blood pressure (MAP), which decreases as portal hypertension progresses, may be a modifiable risk factor among patients with cirrhosis. We included adults enrolled in the Functional Assessment in Liver Transplantation study. We completed latent class trajectory analyses to define MAP trajectories. We completed time-dependent Cox-regression analyses to test the association between outpatient MAP and 3 cirrhosis-related outcomes: (1) stage 2 acute kidney injury (AKI), defined as a ≥200% increase in serum creatinine from baseline; (2) a 5-point increase in the MELD-Na score, defined as the incidence of increase from initial MELD-Na; (3) waitlist mortality, defined as death on the waitlist. For each outcome, we defined MAP cut points by determining the maximally selected Log-rank statistic after univariable Cox-regression analyses. Among the 1786 patients included in this analysis, our latent class trajectory analyses identified 3 specific outpatient MAP trajectories: "stable-low," "stable-high," and "increasing-to-decreasing." However, >80% of patients were in a "stable-low" trajectory. We found in adjusted analyses that outpatient MAP was associated with each of our outcomes: Stage 2 AKI (adjusted hazard ratio 0.88 per 10mmHg increase in MAP [95% CI: 0.79-0.99]); 5-point increase in MELD-Na (adjusted hazard ratio: 0.91 [95% CI: 0.86-0.96]; waitlist mortality (adjusted hazard ratio: 0.89 [95% CI: 0.81-0.96]). For each outcome, we found that an outpatient MAP of 82mmHg was most associated with outcomes ( p <0.05 for all). Our study informs the association between outpatient MAP and cirrhosis-related outcomes. These findings, coupled with the identification of specific thresholds, lay the foundation for the trial of targeted outpatient MAP modulation in patients with cirrhosis.