Renal Content Research Articles

Evaluation of renoprotective effect of grape seed proanthocyanidin extract on Cyclosporine A- induced Nephrotoxicity by mitigating inflammatory response, oxidative stress and apoptosis in rats

Cyclosporine A (CsA) is a drug used as immunosuppressive agent in organ transplant and non-transplant medicine. The main secondary effect results from CsA treatment is nephrotoxicity. A protective effect of Grape seed proanthocyanidin extract (GSPE) against CsA-induced nephrotoxicty in rats was assessed. Thirty male rats were divided into three equal groups. Group I: (Normal control), received no drugs, Group II: (CsA treated), rats received oral dose of CsA (25 mg/kg b.wt/day) for 21 successive days. Group III: (GSPE protected+ CsA), rats received GSPE (200 mg/kg b.wt/day) orally 7 days before and during 21 days of CsA treatment. The obtained results showed a significant increase in serum urea and creatinine concentration in addition to L-MDA levels in kidney tissue while a marked decrease in renal catalase activity and GSH concentration in CsA treated rats. Moreover, a significant down-regulation in Bcl-2 and up-regulation of NF-κB, PAI-1, Caspase-3 and p53 gene expressions were observed in kidney tissues of CsA treated rats. Meanwhile, GSPE potentially improved renal function and oxidative alterations related to CsA near its normal ranges. Also, various histopathological alterations were detected in kidneys of CsA treated rats. Interestingly, histopathological findings supported that where GSPE markedly attenuated the harmful effects induced by CsA and protected kidney tissues. Our research could conclude that, GSPE has an ameliorating role as potent antioxidant, anti-inflammatory and anti-apoptotic agent via inhibition of inflammatory (NF-κB, PAI-1) and apoptotic (Caspase-3, p53) signaling pathway in modulation of CsA-induced nephrotoxicity.

Feasibility of using post-contrast dual-energy CT for pediatric radiation treatment planning and dose calculation.

When iodinated contrast is administered during CT simulation, standard practice requires a separate non-contrast CT for dose calculation. The objective of this study is to validate our hypothesis that since iodine affects Hounsfield units (HUs) more than electron density (ED), the information from post-contrast dual-layer CT (DLCT) would be sufficient for accurate dose calculation for both photon and proton therapy. 10 pediatric patients with abdominal tumors underwent DLCT scans before and after iodinated contrast administration for radiotherapy planning. Dose distributions with these DLCT-based methods were compared to those with conventional calibration-curve methods that map HU images to ED and stopping-power ratio (SPR) images. For photon plans, conventional and DLCT approaches based on post-contrast scans underestimated the PTV D99 by 0.87 ± 0.70% (p = 0.18) and 0.36 ± 0.31% (p = 0.34), respectively, comparing to their non-contrast optimization plans. Renal iodine concentration was weakly associated with D99 deviation for both conventional (R2 = 0.10) and DLCT (R2 = 0.02) approaches. For proton plans, the clinical target volume D99 errors were 3.67 ± 2.43% (p = 0.0001) and 0.30 ± 0.25% (p = 0.40) for conventional and DLCT approaches, respectively. The proton beam range changed noticeably with the conventional approach. Renal iodine concentration was highly associated with D99 deviation for the conventional approach (R2 = 0.83) but not for DLCT (R2 = 0.007). Conventional CT with iodine contrast resulted in a large dosimetric error for proton therapy, compared to true non-contrast plans, but the error was less for photon therapy. These errors can be greatly reduced in the case of the proton plans if DLCT is used, raising the possibility of using only a single post-contrast CT for radiotherapy dose calculation, thus reducing the time and imaging dose required. This study is the first to compare directly the differences in the calculated dose distributions between pre- and post-contrast CT images generated by single-energy CT and dual-energy CT methods for photon and proton therapy.

Case Review of lgG4-Related Disease Patient with Combined Tubulointerstitial Nephritis and Membranous Nephropathy Coexisting with Cholangiocarcinoma: Case Report

Immunoglobulin G4-related disease (IgG4-RD) has recently been recognized as an autoimmune disorder involving multiple organs. The kidney is a represented organ with a wide range of renal manifestations. The authors report a case of an 83-year-old Thai male with combined IgG4 tubulointerstitial nephritis and membranous nephropathy coexisting with cholangiocarcinoma. The patient presented with proteinuria, acute renal failure, eosinophilia, hypocomplementemia, and high serum IgG4 concentration. The diagnosis was IgG 4-related tubulointerstitial nephritis and membranous nephropathy on renal biopsy, with negative immunohistochemistry for anti-phospholipase A2 receptor antibodies. Magnetic resonance imaging (MRI) abdomen showed two wedge shaped arterial enhancing lesions of liver. Liver biopsy revealed adenocarcinoma, compatible with cholangiocarcinoma. Proteinuria and renal failure were resolved with initial steroid treatment. Meanwhile, IgG4-related membranous nephropathy should be considered in the differential diagnosis for patients with proteinuria. Potentially, IgG4-RD may be rarely associated with carcinoma development. However, further studies are recommended to ratify and confirm the association between IgG4-RD and incidence of malignancies. Keywords: IgG4-related disease, Membranous nephropathy, Secondary membranous nephropathy, Tubulointerstitial nephritis, Cholangiocarcinoma

Ability of different assay platforms to measure renal biomarker concentrations during ischaemia-reperfusion acute kidney injury in dogs

Several protein biomarkers have been shown to be useful for the early diagnosis of acute kidney injury (AKI) in animals and people. Multiplex assays for measurement of a panel of renal biomarkers in canine samples have recently become available. This study compared the use of two such assays, versus previously validated ELISAs, to measure five biomarkers in canine samples during ischaemia-reperfusion (IR) AKI. Blood and urine was collected from six male anaesthetised greyhounds that underwent 1-h of renal ischaemia (severe hypotension induced by acute haemorrhage) and 2-h of reperfusion (intravenous fluid resuscitation). Histology confirmed presence of acute tubular injury at 2 h of reperfusion. Concentrations of clusterin, cystatin C, kidney-injury molecule 1 (KIM-1), monocyte chemoattractant protein 1, and neutrophil gelatinase-associated lipocalin (NGAL) at baseline and following IR, measured by two different multiplex assays and previously-validated single analyte immunoassays, were compared. Only NGAL was significantly elevated following IR with all assays investigated. Whether concentrations of the other four biomarkers were significantly increased following IR depended on the assay used. Concentrations of cystatin C and KIM-1 measured with the multiplex assays were of a vast magnitude lower than those measured with the corresponding single analyte ELISAs. We conclude that further validation is required before these assays can reliably be used to measure AKI biomarkers in canine samples.

Thymoquinone suppressed Cyclosporine A- induced Nephrotoxicity in rats via antioxidant activation and inhibition of inflammatory and apoptotic signaling pathway

Cyclosporine A (CsA) is a strong immunosuppressive drug, but its use is frequently accompanied by severe renal toxicity. The potential renoprotective effect of Thymoquinone (TQ) against CsA-induced nephrotoxicity in rats was assessed. Thirty adult white male albino rats were divided into three equal groups. Group I: (Normal control), received no drugs, Group II: (CsA treated), rats received oral dose of Cyclosporine A (25 mg/kg b.wt/day) for 21 days. Group III: (TQ protected + CsA), received Thymoquinone (10 mg/kg b.wt/day) orally 7 days before and during 21 days of CsA treatment. The obtained results showed a significant increase in the concentration of urea and creatinine in serum and L-MDA level in kidney tissue with marked decrease in renal catalase activity and GSH concentration in CsA treated rats. Moreover, a significant down-regulation in Bcl-2 and up-regulation of NF-κB, PAI-1, Caspase-3 and p53 gene expressions levels were observed in kidney tissues of CsA treated rats. Also, various histopathological alterations were detected in kidneys of CsA treated rats. Meanwhile, TQ potentially improved renal function and oxidative alterations related to CsA near its normal ranges. Interestingly, histopathological findings supported that TQ markedly attenuates harmful effects that CsA induced and protected kidney. Our research could conclude that, TQ has an ameliorating role as potent antioxidant, anti-inflammatory and anti-apoptotic agent via inhibition of inflammatory (NF-κB, PAI-1) and apoptotic (Caspase-3, p53) signaling pathway in modulation of CsA-induced nephrotoxicity.

Evidence of Renal Iron Accumulation in a Male Mouse Model of Lupus.

Lupus nephritis represents a common and serious complication of the autoimmune disease Systemic Lupus Erythematosus (SLE). Clinical studies suggest that several proteins related to iron metabolism, including transferrin, serve as urinary biomarkers of lupus nephritis. We previously reported that in female NZBWF1 mice, a commonly used mouse model of SLE with a female sex bias, increased urinary transferrin excretion and renal iron accumulation occur around the onset of albuminuria. The current study investigated whether similar findings occur in male mice of a different mouse model of SLE, the MRL/lpr mouse. Two different cohorts were studied: MRL/lpr mice at an early, pre-albuminuric age (8 weeks), and after developing albuminuria (>100 mg/dL, confirmed by ELISA); age-matched MRL/MpJ control strain mice served for comparison. Urinary transferrin excretion was dramatically increased in the older, albuminuric MRL/lpr mice compared to the age-matched MRL/MpJ (P < 0.05), but there was no significant difference between strains at 8 weeks of age. Similarly, there were no significant differences between strains in renal cortical or outer medullary non-heme iron concentrations at 8 weeks. In the older, albuminuric MRL/lpr mice, renal cortical and outer medullary non-heme iron concentrations were significantly increased compared with age-matched MRL/MpJ mice, as was the expression of the iron storage protein ferritin (P < 0.01). Together, these data show that increased urinary transferrin excretion and renal tissue iron accumulation also occurs in albuminuric male MRL/lpr mice, suggesting that renal iron accumulation may be a feature of multiple mouse models of SLE.

Abstract P231: Macrophage Neutrophil Gelatinase-associated Lipocalin Has A Critical Role In Aldosterone-induced Renal Fibrosis Via The Ccl5-il4 Pathway.

Introduction: Neutrophil Gelatinase-Associated Lipocalin (NGAL) (or lipocalin 2) is a novel mineralocorticoid biotarget in the cardiovascular system. NGAL is also described as an acute renal lesion biomarker and NGAL serum concentration is associated with the severity of renal damages patients with a chronic kidney disease (CKD). Lipocalin2 (Lcn2) gene invalidation in a CKD mouse model protects from proteinuria and renal lesions. Objective: We hypothesized that the NGAL from macrophages promotes expression of chemoattractant molecules involved in renal lesions induced by mineralocorticoid excess. Methods: The role of Lcn2 was analyzed using full Lcn2 knock out mice (NGAL KO) challenged with uni-Nephrectomy, Aldosterone 200μg/kg/day, Salt 1% (NAS model) during 6 weeks. Assessment of CCL5/IL4 in kidney fibrosis were studied using maraviroc administration (50mg/kg/d in chow diet) or by injections of anti-IL4 antibody (600μg/week). Results: NAS induced a significant increase in the expression (relative values, mean±SEM, compared to 1 in the control samples, p&amp;lt0.05) of extracellular matrix proteins such as collagen I (2.35±0.33), α-SMA (2.04±0.44) and fibronectin (3.38±0.42) in the kidney of WT mice associated with interstitial kidney fibrosis (6.49±0.70). These modifications were fully prevented by NGAL deletion. Expression of macrophages markers F4/80 , CD80 and CD86 was increased (5.11±0.46, 4.84±0.19 and 5.22±0.45 respectively) in WT NAS mice and partly prevented in NGAL KO mice. Macrophages isolated from NGAL KO or WT mice were co-treated with aldosterone (10 -8 M) and NaCl (40mM). In WT macrophages, expression of Lcn2 (2.81±0.30) and the CCL5 chemokine (2.48±0.32) was increased. The increase of CCL5 was prevented in NGAL KO macrophages. Such as total deletion of NGAL, CCL5 receptor blockade improved renal fibrosis and high level of Th2 CD4 + cell markers induced by NAS. Neutralization of IL4 Th2 cytokine in NAS mice injected with anti-IL4 antibody blunted kidney fibrosis and overexpression of profibrotic proteins such as collagen I, α-SMA and fibronectin. Conclusion: NGAL produced by macrophages plays a critical role in renal interstitial fibrosis through CCL5/IL4 pathways in mice exposed to mineralocorticoid excess.

Endogenous Activation of Glucagon-Like Peptide-1 Receptor Contributes to Blood Pressure Control: Role of Proximal Tubule Na+/H+ Exchanger Isoform 3, Renal Angiotensin II, and Insulin Sensitivity.

The pharmacological administration of GLP-1R (glucagon-like peptide-1 receptor) agonists reduces blood pressure (BP) in type 2 diabetes mellitus and nondiabetic patients. This study tested the hypothesis that endogenous GLP-1R signaling influences the regulation of BP. To this end, SHRs (spontaneously hypertensive rats) and Wistar rats were treated with the GLP-1R antagonist Ex9 (exendin-9) or vehicle for 4 weeks. Rats receiving the GLP-1R agonist Ex4 (exenatide) were used as an additional control. We found that blockade of baseline GLP-1R signaling by Ex9 increased systolic BP in both SHR and Wistar rats, compared with vehicle-treated animals, while Ex4 only reduced systolic BP in SHR. Higher systolic BP induced by Ex9 was accompanied by reduced lithium clearance and lower levels of NHE3 (Na+/H+ exchanger isoform 3) phosphorylation at the serine 552, indicative of increased proximal tubule sodium reabsorption. Additionally, urinary AGT (angiotensinogen) and renal cortical concentration of Ang II (angiotensin II) were enhanced by Ex9. Conversely, Ex4 decreased both urinary AGT and cortical Ang II but exclusively in SHRs. Moreover, both SHR and Wistar rats treated with Ex9 displayed hyperinsulinemia as compared with vehicle-treated rats, whereas Ex4 reduced fasting insulin concentration in SHR. Collectively, these results suggest that endogenous GLP-1R signaling exerts a physiologically relevant effect on BP control, which may be attributable, in part, to its tonic actions on the proximal tubule NHE3-mediated sodium reabsorption, intrarenal renin-angiotensin system, and insulin sensitivity. The possible role of impaired GLP-1R signaling in the pathogenesis of hypertension warrants further investigation.

Human carnosinase 1 overexpression aggravates diabetes and renal impairment in BTBROb/Ob mice

ObjectiveTo assess the influence of serum carnosinase (CN1) on the course of diabetic kidney disease (DKD).MethodshCN1 transgenic (TG) mice were generated in a BTBROb/Ob genetic background to allow the spontaneous development of DKD in the presence of serum carnosinase. The influence of serum CN1 expression on obesity, hyperglycemia, and renal impairment was assessed. We also studied if aggravation of renal impairment in hCN1 TG BTBROb/Ob mice leads to changes in the renal transcriptome as compared with wild-type BTBROb/Ob mice.ResultshCN1 was detected in the serum and urine of mice from two different hCN1 TG lines. The transgene was expressed in the liver but not in the kidney. High CN1 expression was associated with low plasma and renal carnosine concentrations, even after oral carnosine supplementation. Obese hCN1 transgenic BTBROb/Ob mice displayed significantly higher levels of glycated hemoglobin, glycosuria, proteinuria, and increased albumin-creatinine ratios (1104 ± 696 vs 492.1 ± 282.2 μg/mg) accompanied by an increased glomerular tuft area and renal corpuscle size. Gene-expression profiling of renal tissue disclosed hierarchical clustering between BTBROb/Wt, BTBROb/Ob, and hCN1 BTBROb/Ob mice. Along with aggravation of the DKD phenotype, 26 altered genes have been found in obese hCN1 transgenic mice; among them claudin-1, thrombospondin-1, nephronectin, and peroxisome proliferator–activated receptor-alpha have been reported to play essential roles in DKD.ConclusionsOur data support a role for serum carnosinase 1 in the progression of DKD. Whether this is mainly attributed to the changes in renal carnosine concentrations warrants further studies.Key messagesIncreased carnosinase 1 (CN1) is associated with diabetic kidney disease (DKD).BTBROb/Ob mice with human CN1 develop a more aggravated DKD phenotype.Microarray revealed alterations by CN1 which are not altered by hyperglycemia.These genes have been described to play essential roles in DKD.Inhibiting CN1 could be beneficial in DKD.

A Global Cndp1-Knock-Out Selectively Increases Renal Carnosine and Anserine Concentrations in an Age- and Gender-Specific Manner in Mice.

Carnosinase 1 (CN1) is encoded by the Cndp1 gene and degrades carnosine and anserine, two natural histidine-containing dipeptides. In vitro and in vivo studies suggest carnosine- and anserine-mediated protection against long-term sequelae of reactive metabolites accumulating, e.g., in diabetes mellitus. We have characterized the metabolic impact of CN1 in 11- and 55-week-old Cndp1-knockout (Cndp1-KO) mice and litter-matched wildtypes (WT). In Cndp1-KO mice, renal carnosine and anserine concentrations were gender-specifically increased 2- to 9-fold, respectively in the kidney and both most abundant in the renal cortex, but remained unchanged in all other organs and in serum. Renal oxidized/reduced glutathione concentrations, renal morphology and function were unaltered. In Cndp1-KO mice at week 11, renal asparagine, serine and glutamine levels and at week 55, renal arginine concentration were reduced. Renal heat-shock-protein 70 (Hspa1a/b) mRNA declined with age in WT but not in Cndp1-KO mice, transcription factor heat-shock-factor 1 was higher in 55-week-old KO mice. Fasting blood glucose concentrations decreased with age in WT mice, but were unchanged in Cndp1-KO mice. Blood glucose response to intraperitoneal insulin was gender- but not genotype-dependent, the response to intraperitoneal glucose injection was similar in all groups. A global Cndp1-KO selectively, age- and gender-specifically, increases renal carnosine and anserine concentrations, alters renal amino acid- and HSP70 profile and modifies systemic glucose homeostasis. Increase of the natural occurring carnosine and anserine levels in the kidney by modulation of CN1 represents a promising therapeutic approach to mitigate or prevent chronic kidney diseases such as diabetic nephropathy.

EFFECT OF RENAL SPECIFIC ORAL NUTRITION (ONCE RENAL) ON DIETARY INTAKE AND SERUM ELECTROLYTES IN CHRONIC KIDNEY DISEASE STAGE IV

Background and Objectives: Low nutritional intake is common in advanced chronic kidney disease (CKD) and poses a direct risk for malnutrition. Our study evaluated the effects of a renal specific oral nutrition (ONCE Renal) supplement concerning nutritional status, minerals and electrolytes among patients with stage IV CKD.&#x0D; Methods and Study Design: A total of 32 CKD patients with an estimated glomerular filtration rate 16-29 mL/min/1.73 m2, well nourished subjects and anticipated good compliance with the diet received the ONCE Renal diet instead of 1 meal daily for 30 days. Dietary protein and energy intake, body compositions, and serum concentrations of urea, creatinine, calcium, magnesium, phosphate and albumin were assessed at baseline, and at 30 days. A dietary intake by three-day food record were also evaluated by a registered dietitian.&#x0D; Results: At the end of 30 days, significant improvements in energy, fat, fiber and magnesium intake by dietary interview were noted. In addition, the patients also increased body weight and body mass index after supplement. No significant changes in renal function, serum electrolytes, calcium, phosphorus, magnesium concentration and other nutritional markers including serum albumin, body compositions and protein equivalence of total nitrogen appearance were observedduring study. The compliance with the ONCE Renal diet was good among enrolled patients and no adverse reactions were found.&#x0D; Conclusions: Renal specific oral diet supplement can improve energy intake, body weight and maintain serum electrolytes concentrations among patients with stage IV CKD.

Physiologically Based Pharmacokinetic Models Predicting Renal and Hepatic Concentrations of Industrial Chemicals after Virtual Oral Doses in Rats.

Recently developed high-throughput in vitro assays in combination with computational models could provide alternatives to animal testing. The purpose of the present study was to model the plasma, hepatic, and renal pharmacokinetics of approximately 150 structurally varied types of drugs, food components, and industrial chemicals after virtual external oral dosing in rats and to determine the relationship between the simulated internal concentrations in tissue/plasma and their lowest-observed-effect levels. The model parameters were based on rat plasma data from the literature and empirically determined pharmacokinetics measured after oral administrations to rats carried out to evaluate hepatotoxic or nephrotic potentials. To ensure that the analyzed substances exhibited a broad diversity of chemical structures, their structure-based location in the chemical space underwent projection onto a two-dimensional plane, as reported previously, using generative topographic mapping. A high-throughput in silico one-compartment model and a physiologically based pharmacokinetic (PBPK) model consisting of chemical receptor (gut), metabolizing (liver), central (main), and excreting (kidney) compartments were developed in parallel. For 159 disparate chemicals, the maximum plasma concentrations and the areas under the concentration-time curves obtained by one-compartment models and modified simple PBPK models were closely correlated. However, there were differences between the PBPK modeled and empirically obtained hepatic/renal concentrations and plasma maximal concentrations/areas under the concentration-time curves of the 159 chemicals. For a few compounds, the lowest-observed-effect levels were available for hepatotoxicity and nephrotoxicity in the Hazard Evaluation Support System Integrated Platform in Japan. The areas under the renal or hepatic concentration-time curves estimated using PBPK modeling were inversely associated with these lowest-observed-effect levels. Using PBPK forward dosimetry could provide the plasma/tissue concentrations of drugs and chemicals after oral dosing, thereby facilitating estimates of nephrotoxic or hepatotoxic potential as a part of the risk assessment.

Histological, metabolic, and inflammatory changes in the renal tissues of high-fat diet-induced obese rats after vitamin D supplementation

PurposeObesity is a major risk factor for chronic renal fibrosis and kidneys’ structural and inflammatory impairments. This study aims to examine the possible therapeutic effects of vitamin D supplementation against renal inflammatory and kidney’s structural fibrosis and degeneration.Design/methodology/approachForty male Wistar rats were divided into two groups for 16 weeks: normal diet (ND) and high-fat diet (HFD); then, each group was subdivided into two groups including ND, ND + vitamin D and HFD, HFD + vitamin D. Vitamin D supplementation was done for five weeks at 500 IU/kg dosage. Renal tissue concentrations of tumor necrosis factor (TNF)-α, interleukin 6, interleukin 1 beta, monocyte chemoattractant protein (MCP)-1 and transforming growth factor-beta (TGF-β), serum values of lipids, markers of glucose homeostasis and urea, creatinine and uric acid and renal tissue histological and structural changes were determined.FindingsHFD feeding caused remarkable histological and structural changes including higher TNF-α, MCP-1 and TGF-βconcentrations in renal tissues of rats, whereas vitamin D has potent anti-inflammatory effects (P= 0.036, 0.047 and 0.02, respectively). Vitamin D administration also reduced urea and uric acid concentrations (P= 0.023 and 0.049, respectively). Moreover, vitamin D reduced glomerulomegaly, reduced lipid accumulation and limited dilated Bowman’s space in rats and improved glycemic status by increasing insulin (P= 0.04) and reducing insulin resistance (P= 0.006).Research limitations/implicationsThe current study has some limitations. It was better to measure the level of inflammatory cytokines’ expression in the kidney tissues. Additionally, the measurement of baseline values of inflammatory cytokines was not possible because of the possibility of animals’ drop-out.Practical implicationsAccording to the study findings, vitamin D treatment in the current report showed a significant therapeutic role in reducing inflammation, improving glycemic and lipid abnormalities and structural and histological modifications in renal tissues of rats. These findings have a great value because after confirming in a human model, vitamin D can be suggested as a potential therapeutic tool in clinical practice.Social implicationsAfter being confirmed by other animal or human researches, the results of the current work could have great social implications by reducing the prevalence of obesity-related renal complications and highlighting the beneficial roles of vitamin D.Originality/valueTo the best of the authors’ knowledge, this is the first study to investigate the histological and inflammatory changes in the kidneys and metabolic parameters in the HFD induced rats and also clarified the therapeutic roles of vitamin D in ameliorating the inflammatory, histological, metabolic and functional changes in the kidneys of obese rats.

Association between dexamethasone treatment and alterations in serum concentrations of trace metals.

Previously, a significant elevation in the serum levels of iron (Fe) was observed within a few days after the initiation of cisplatin (CDDP)-based chemotherapy. To clarify the underlying mechanisms, the serum concentration of hepcidin, a negative regulator of Fe release, was determined in the clinical samples obtained from six patients with cancer. The result showed that the serum concentration of hepcidin in patients receiving CDDP-based chemotherapy was significantly increased after 4-6 days of treatment, in comparison to the baseline level, suggesting that aforementioned excessive systemic Fe was not explained by the change of serum hepcidin level. All these patients received antiemetic premedication. We next evaluated of the effects of Pt-containing drugs and prophylactic antiemetic dexamethasone medication on the serum concentration of trace metals in mice, and on the hepatic and renal concentration of trace metals. The serum concentrations of Fe, Cu, and Zn in the CDDP-treated and oxaliplatin-treated mice were not significantly altered in comparison to those of the vehicle-treated control group. The serum concentrations of Fe, Cu, and Zn were increased after 24 h of dexamethasone treatment, compared to those of the control group (P < 0.05). The hepatic concentration of Mn was significantly reduced, whereas those of Fe and Cu inclined to diminish. The present findings suggest that dexamethasone can partly contribute to the changes in the serum concentrations of trace metals during anticancer chemotherapy.

Application of immunosuppressants in patients with autosomal dominant polycystic kidney disease after kidney transplantation

To investigate the optimal dose range of immunosuppressants in patients with autosomal dominant polycystic kidney disease (ADPKD) after renal transplantation. A cohort of 68 patients with ADPKD who received their first renal transplantation between March, 2000 and January, 2018 in our institute were retrospectively analyzed, with 68 non-ADPKD renal transplant recipients matched for gender, age and date of transplant as the control group. We analyzed the differences in patient and renal survival rates, postoperative complications and concentrations of immunosuppressive agents between the two groups at different time points within 1 year after kidney transplantation. The concentrations of the immunosuppressants were also compared between the ADPKD patients with urinary tract infections (UTI) and those without UTI after the transplantation. The recipients with ADPKD and the control recipients showed no significantly difference in the overall 1-, 5-, and 10- year patient survival rates (96.6% vs 96.0%, 94.1% vs 93.9%, and 90.6% vs 93.9%, respectively; P &gt; 0.05), 1-, 5-, and 10-year graft survival rates (95.2% vs 96.0%, 90.8% vs 87.2%, and 79.0% vs 82.3%, respectively; P &gt; 0.05), or the incidences of other post- transplant complications including acute rejection, gastrointestinal symptoms, cardiovascular events, pneumonia, and neoplasms (P &gt; 0.05). The plasma concentrations of both tacrolimus and mycophenolate mofetil (MPA) in ADPKD group were significantly lower than those in the control group at 9 months after operation (P &lt; 0.05). The incidence of UTI was significantly higher in ADPKD patients than in the control group (P &lt; 0.05). In patients with ADPKD, those with UTI after transplantation had a significantly higher MPA plasma concentration (P &lt; 0.05). In patients with ADPKD after renal transplant, a higher dose of MPA is associated with a increased risk of UTI, and their plasma concentrations of immunosuppressants for long-term maintenance of immunosuppression regimen can be lower than those in other kidney transplantation recipients.

Acute Uterine Torsion Mimicking Tumor Lysis Syndrome

Background: Non-gravid uterine torsion is rare and mostly diagnosed at surgery. This report describes a patient with a large abdominal mass, critical illness, and tumor lysis syndrome. Case: A female presented with acute abdominal pain. Physical exam showed a large abdominal mass and abdominal rigidity. Serial laboratory tests showed a drop in hemoglobin level, progressive renal failure and serum uric acid and phosphate concentrations compatible with tumor lysis syndrome. Computed tomography showed a 30 cm mass filling the pelvis and abdomen. At an emergency exploratory laparotomy, a 360 degrees torsion of the uterus was found. An uneventful total hysterectomy was done. After surgery renal function restored. Conclusion: Uterine torsion is rare and can be potentially life threatening when presenting as tumor lysis syndrome

Impaired NCC Activity and Regulation on Dietary High Dietary Salt Intake in Aged Sprague Dawley Rats Is Associated with Increased Salt Sensitivity of Blood Pressure

BackgroundHypertension (HTN) is one of the leading causes of death worldwide and its prevalence increases with age. Studies revealed that enhanced global sympathetic tone is related to increases in blood pressure (BP) in aged human subjects. Dietary sodium intake is associated with the regulation of blood pressure, as increased sodium retention is a well‐established precursor of hypertension risk. An excessive dietary sodium intake leads to increases in BP in individuals that demonstrate the salt sensitivity of BP and evoke the development of salt sensitive HTN (SSH). Recent studies have demonstrated that excessive release of norepinephrine by increased sympathetic nerve activity upregulates renal sodium chloride cotransporter (NCC) activity to promote sodium reabsorption. However, the underlying mechanisms of the regulation of sodium homeostasis and blood pressure in response to increase in sympathetic tone with age remain unclear.HypothesisNCC‐mediated sodium retention driven by increased sympathetic tone with age contributes to age‐related HTN. Furthermore, the activity and regulation of NCC are impaired on a high salt (HS) diet and this impaired NCC activity and regulation drives the development of age‐dependent SSH.MethodsThree different age groups (3, 8, 16 month old (MO)) of male Sprague‐Dawley (SD) rats were fed a normal salt (NS; 0.6% NaCl) or HS (4% NaCl) diet for 21 days respectively. On day 21, basal MAP, NCC activity (peak natriuresis to IV hydrochlorothiazide (2mg/kg) infusion), and vascular sympathetic tone (peak MAP change in response to ganglionic blockade (IV hexamethonium; 30mg/kg)) were measured in vivo. Plasma and renal NE concentrations were also assessed via ELISA. The expression of total NCC, phosphorylated NCC, with‐no‐lysine [K] kinases (WNK) 1, WNK4, STE20/SPS1‐related proline‐alanine‐rich protein kinase (SPAK), oxidative stress responsive kinase 1 (OxSR1), and phosphorylated SPAK/OxSR1 were assessed via immunoblotting (N=6/gp).ResultsFirst, 3MO SD rats are normotensive in both diet groups and show dietary sodium‐evoked suppression of NCC activity, expression, and phosphorylation and upstream regulatory kinases including WNK1, SPAK, and OxSR1 on a HS diet relative to a NS diet. Second, SD rats show age‐dependent HTN, increases in renal sympathetic tone, NCC activity and expression, and WNK1 expression. Last, SD rats show aged‐dependent SSH, increased sympathetic tone, and impaired suppression of NCC activity, phosphorylation, and the expression of kinases SPAK and OxSR1.ConclusionSD rats show age‐dependent HTN that is coupled with increases in sympathetic tone, NCC activity and expression, which strongly suggests that the NCC contributes to the development of age‐dependent HTN. Moreover, the NCC may play a pivotal role in the development of age‐dependent SSH as aged SD rats show impaired dietary‐sodium evoked suppression of NCC activity and regulation. Collectively, these findings suggest that increased sympathetic tone may drive NCC activity that evokes age‐dependent HTN and SSH. MO, month old; NS, 0.6% NaCl; HS, 4% NaCl. Variables 3 MO 8 MO 16 MO NS HS NS HS NS HS MAP (mmHg) 124 ± 2 126 ± 3 135 ± 4 # 143 ± 5 # 149 ± 3 # † 169 ± 1 * # † ΔUNaV to HCTZ (μeq/min) 9 ± 1 7 ± 1 * 18 ± 2 # 16 ± 1 # 15 ± 5 # 16 ± 6 # Plasma NE (nmol/L) 44 ± 4 28 ± 4 * 55 ± 3 # 42 ± 4 * # 54 ± 4 # 41 ± 4 * # Renal NE (pg/mg) 612 ± 36 368 ± 32 * 835 ± 48 # 722 ± 44 * # 974 ± 13 # † 1019 ± 134 # † ΔMAP to hexamethonium (mmHg) −33 ± 4 −24 ± 3 * −64 ± 5 # −65 ± 6 # −60 ± 3 # −67 ± 7 # Total NCC expression (fold change) 1.00 ± 0.22 0.32 ± 0.09 * 1.91 ± 0.25 # 1.13 ± 0.15 * # 1.82 ± 0.23 # 0.75 ± 0.11 * Total pNCCT53 expression (fold change) 1.00 ± 0.20 0.19 ± 0.05 * 1.24 ± 0.46 0.87 ± 0.22 0.49 ± 0.18 1.73 ± 0.22 * # WNK1 expression (fold change) 1.00 ± 0.20 0.49 ± 0.06 * 1.07 ± 0.34 1.36 ± 0.15 2.15 ± 0.38 # † 1.60 ± 0.29 # WNK4 expression (fold change) 1.00 ± 0.11 0.86 ± 0.07 1.95 ± 0.14 # 1.28 ± 0.10 # 1.05 ± 0.07 † 1.17 ± 0.09 SPAK expression (fold change) 1.00 ± 0.12 0.48 ± 0.09 * 1.25 ± 0.09 1.30 ± 0.23 # 0.42 ± 0.04 # † 0.41 ± 0.13 † OxSR1 expression (fold change) 1.00 ± 0.12 0.62 ± 0.05 * 1.09 ± 0.12 1.10 ± 0.06 # 1.19 ± 0.20 1.17 ± 0.08 # pSPAK/OxSR1 expression (fold change) 1.00 ± 0.24 0.84 ± 0.30 0.55 ± 0.23 1.42 ±0.24 * 1.12 ± 0.17 2.86 ± 0.43 * # † *p&lt;0.05 vs. respective NS group; #p&lt;0.05 vs. respective 3 MO group; † p&lt;0.05 vs. respective 8 MO group.

Involvement of estrogen in phosphorus-induced nephrocalcinosis through fibroblast growth factor 23

Excessive phosphorus intake adversely affects bone and mineral metabolism. Estrogen is one of the factors affecting fibroblast growth factor 23 (FGF23), a phosphorus-regulating hormone. However, the interaction between excess phosphorus and estrogen status has not been fully elucidated. This study investigated the involvement of estrogen in the effects of high phosphorus intake on bone metabolism and ectopic calcification in ovariectomized (OVX) rats. The interaction between high phosphorus diet and OVX was not observed in bone mineral density and aortic calcium. In contrast, high phosphorus intake markedly increased renal calcium concentration in sham rats, whereas the effect was attenuated in OVX rats, which was reversed by a selective estrogen-receptor modulator treatment. A strong positive correlation between renal calcium and serum FGF23 was observed. In addition, fibroblast growth factor receptor 1 (FGFR1: a predominant receptor of FGF23) inhibitor treatment partially decreased renal calcium concentrations in rats with high phosphorus intake. In conclusion, the effect of high phosphorus intake on bone metabolism and aortic calcification did not depend on the estrogen status; in contrast, high phosphorus intake synergistically induced nephrocalcinosis in the presence of estrogenic action on the bone. Furthermore, FGF23 was involved in the nephrocalcinosis induced by high phosphorus intake partially through FGFR1 signaling.

The Influence of Taurine Supplementation on Serum and Tissular Fe, Zn and Cu Levels in Normal and Diet-Induced Insulin-Resistant Rats

Taurine (Tau) is a β-sulphonated amino acid postulated to improve glucose homeostasis in insulin resistance and diabetes. Changes in carbohydrate metabolism are accompanied by oxidative stress, which may disturb the mineral balance. Therefore, the aim of this study was to assess the effect of Tau supplementation on the levels of trace elements in rats fed either a standard (AIN-93M, 4% fat) diet or a modified high-fat diet (30% fat). For 8 weeks, male Wistar rats were fed these diets supplemented with 3% Tau. Taurine supplementation normalized increased serum insulin concentration and insulin resistance index; however, it did not improve serum CRP concentration in high-fat diet fed rats. The high-fat diet supplemented with Tau decreased the renal and splenic Zn levels, but the tissular Fe content did not change. The effect of Tau supplementation on the mineral balance to some extent depended on the fat content in the rats’ diet. The high-fat diet supplemented with Tau decreased the rats’ splenic Zn levels but increased their femur levels. In the group fed the standard diet, Tau reduced the rats’ femur Zn level, whereas their splenic Zn level was comparable. Tau supplementation decreased the renal Cu level and serum ceruloplasmin concentration in the rats fed the standard diet, but this effect was not observed in the rats fed the high-fat diet. In conclusion, supplementary taurine failed to ameliorate disturbances in mineral homeostasis caused by high-fat diet feeding and led to tissular redistribution of Zn and Cu in the rat.

New insights into the vancomycin-induced nephrotoxicity using in vitro metabolomics combined with physiologically based pharmacokinetic modeling.

Vancomycin is a first-line treatment for invasive infections caused by multidrug-resistant gram-positive bacteria. However, vancomycin-induced nephrotoxicity is an increasing burden, particularly in patients with complex life-threatening conditions. Vancomycin-induced nephrotoxicity associated with clinically relevant exposure on the target site has not been well defined. This study aimed to acquire the concentration of vancomycin in the renal tubules and kidneys in humans using physiologically based pharmacokinetic (PBPK) modeling and simulation. Based upon the exposure of vancomycin in the renal tubule, the toxicity of vancomycin in human renal proximal tubular epithelial cells was examined with the XTT assay and in vitro metabolomics analysis. A rat PBPK model predicting plasma and kidney concentration-time profiles of vancomycin matched the observed behavior after a single administration of 10 mg/kg. The concentration of vancomycin in renal tubules was about 40-50 times higher than that in plasma. The human PBPK model transferred from the rat model predicted renal tubule concentrations of vancomycin as 316.1-2136.6 μg/mL at 500 mg every 6 hours, and 199.0-3932.5 μg/mL at 1000 mg every 12 hours. Vancomycin showed significant nephrotoxicity at 4 mg/mL in XTT assessment. In total, 11 lysophosphatidylcholines and one lysophosphatidylethanolamine were identified by metabolomics analysis. The concentration-dependent increase was evident in the release of lysophospholipids after vancomycin treatment (0.125-4 mg/mL) for 24 hours. Our study revealed the relationship between the exposure of vancomycin in the kidney and toxicity of vancomycin at clinically relevant concentrations achieved from a mechanical PBPK model. A series of lysophospholipids as potential metabolic markers of renal toxicity were identified.