Losartan improves renal function and pathology in obese ZSF-1 rats

2018 ◽  
Vol 29 (3) ◽  
pp. 281-290 ◽  
Author(s):  
Zhi Su ◽  
Deborah Widomski ◽  
Arthur Nikkel ◽  
Laura Leys ◽  
Marian Namovic ◽  
...  

AbstractBackground:Losartan, a blocker of the angiotensin II type I receptor, is an important part of the standard of care for diabetic nephropathy (DN). The obese ZSF-1 rats display many aspects of the clinical features of human Type II DN. The current study was designed to examine the treatment effects of losartan on obese ZSF-1 rats and to evaluate the impact of the onset of dosing on efficacy.Methods:The rats (7–10 weeks) underwent a right uninephrectomy (Unx) or sham surgery. Losartan (3, 10, 30 mg/kg) was dosed 3 or 9 weeks post-Unx and continued for 12 weeks.Results:Treatment with losartan reduced urinary protein excretion and blood lipids (triglyceride and cholesterol) dose-dependently in both studies. The glomerular filtration rate (GFR) was significantly lower in obese ZSF-1 rats compared with those in lean rats, and losartan was efficacious against this endpoint, in particular with the earlier onset of treatment. Losartan also decreased tubulointerstitial fibrosis, and similar to GFR, earlier treatment conferred beneficial actions even at the lowest dose of 3 mg/kg. Several urinary biomarkers were elevated in the obese ZSF-1 rats, but the levels of sTNFR1, TIMP-1, L-FABP and KIM-1 were the only markers decreased by losartan.Conclusions:Losartan was renoprotective in the ZSF-1 rats with DN, improving both the pathological and functional parameters of the disease. Importantly, the data also highlight the importance of treatment at earlier stages of the disease for protecting against decline in the GFR and the development of fibrosis.

2021 ◽  
Vol 36 (Supplement_1) ◽  
Author(s):  
Xenophon Kassianides ◽  
Adil Hazara ◽  
Philip A Kalra ◽  
Iain Macdougall ◽  
Sunil Bhandari

Abstract Background and Aims High dose intravenous (IV) iron is commonly used in patients with chronic kidney disease (CKD) but it remains unclear whether any short or long term impact on renal function exists. Studies using iron sucrose, a second generation IV iron compound suggest effects on proteinuria while evidence with third generation iron products revealed no impact on estimated glomerular filtration rate (eGFR). These newer iron compounds have compact iron-carbohydrate cores, potentially limiting the nephrotoxic effects of labile free iron. As a part of the Iron & Heart study, we examined the impact of high dose ferric derisomaltose (FDI), a third generation IV iron product, in patients with non-dialysis dependent CKD and iron deficiency on markers of renal injury and function using both established (serum creatinine, eGFR, 24-hour excretion of protein) and novel methods (Cystatin C, Neutrophil gelatinase-associated lipocalin (NGAL)). In addition, correlations between the different markers of renal dysfunction were examined alongside the impact of various confounders including age and diabetes mellitus on the reliability of such markers. Method This was a multicentre randomized double-blinded placebo-controlled study involving three tertiary renal centres in the United Kingdom. Patients with CKD stages 3b-5 (non-dialysis), a serum ferritin <100 micrograms/L and/or transferrin saturation <20% and a haemoglobin value of 110 – 150 g/L were enrolled. The participants were randomized 1:1 to receive either 1000 mg of FDI or placebo. Cystatin C, NGAL, serum creatinine eGFR and 24-hour urinary excretion of protein were measured at baseline and then repeated at 1- and 3- months. Changes in the levels of these were analysed both in terms of their absolute values and percentage change from baseline. Pearson’s coefficient (r) was calculated as a measure of correlation between changes in the follow-up values, and the level of statistical significance was set at less than 0.05. Results 54 patients were randomized; 26 to FDI and 28 to placebo. Patients in the two treatment arms were similar in age, gender, the prevalence of diabetes, baseline eGFR and urinary protein excretion (200mg vs 350mg/24hr in the FDI and placebo groups respectively, p = 0.2713). Compared to baseline levels, serum creatinine, cystatin C and NGAL did not change significantly in either arm (figure 1). There were no significant changes in urinary protein excretion both within and between groups (median change in urinary protein excretion: FDI: -10mg and -39mg/24hr; placebo: 0mg and 0mg/24hr at 1- and 3- months respectively, p>0.05) There was a significant correlation between changes in cystatin C levels and serum creatinine (r = 0.6994, p<0.0001) during follow-up. This correlation persisted when patients were stratified by an age of 65 years and presence of diabetes (figure 2). Changes in Cystatin C levels did not correlate well with changes in NGAL. Conclusion This post-hoc analysis of data from the Iron & Heart study indicates that high dose FDI did not cause any significant detriment in the short-term to renal function compared to placebo. This complements the safety profile of high dose third generation IV iron products and improves our understanding of their use in patients with CKD at their approved doses. There was a good correlation between cystatin C and creatinine, which was not affected by various sub-groups such as age or presence of diabetes mellitus. The analysis confirms the role of cystatin C as a robust biomarker of measuring renal function at least when compared to other established methods.


2003 ◽  
Vol 10 (3) ◽  
pp. 424-432 ◽  
Author(s):  
Chuh K. Chong ◽  
Thien V. How ◽  
Geoffrey L. Gilling-Smith ◽  
Peter L. Harris

Purpose: To investigate the effect on intrasac pressure of stent-graft deployment within a life-size silicone rubber model of an abdominal aortic aneurysm (AAA) maintained under physiological conditions of pressure and flow. Methods: A commercial bifurcated device with the polyester fabric preclotted with gelatin was deployed in the AAA model. A pump system generated physiological flow. Mean and pulse aortic and intrasac pressures were measured simultaneously using pressure transducers. To simulate a type I endoleak, plastic tubing was placed between the aortic wall and the stent-graft at the proximal anchoring site. Type II endoleak was simulated by means of side branches with set inflow and outflow pressures and perfusion rates. Type IV endoleak was replicated by removal of gelatin from the graft fabric. Results: With no endoleak, the coated graft reduced the mean and pulse sac pressures to negligible values. When a type I endoleak was present, mean sac pressure reached a value similar to mean aortic pressure. When net flow through the sac due to a type II endoleak was present, mean sac pressure was a function of the inlet pressure, while pulse pressure in the sac was dependent on both inlet and outlet pressures. As perfusion rates increased, both mean and pulse sac pressures decreased. When there was no outflow, mean sac pressure was similar to mean aortic pressure. In the presence of both type I and type II endoleaks, mean sac pressure reached mean aortic pressure when the net perfusion rate was low. Conclusions: In vitro studies are useful in gaining an understanding of the impact of different types of endoleaks, in isolation and in combination, on intrasac pressure after aortic stent-graft deployment.


2018 ◽  
Vol 28 (3) ◽  
pp. 586-593 ◽  
Author(s):  
Mette Calundann Noer ◽  
Sofie Leisby Antonsen ◽  
Bent Ottesen ◽  
Ib Jarle Christensen ◽  
Claus Høgdall

ObjectiveTwo distinct types of endometrial carcinoma (EC) with different etiology, tumor characteristics, and prognosis are recognized. We investigated if the prognostic impact of comorbidity varies between these 2 types of EC. Furthermore, we studied if the recently developed ovarian cancer comorbidity index (OCCI) is useful for prediction of survival in EC.Materials and MethodsThis nationwide register-based cohort study was based on data from 6487 EC patients diagnosed in Denmark between 2005 and 2015. Patients were assigned a comorbidity index score according to the Charlson comorbidity index (CCI) and the OCCI. Kaplan-Meier survival statistics and adjusted multivariate Cox regression analyses were used to investigate the differential association between comorbidity and overall survival in types I and II EC.ResultsThe distribution of comorbidities varied between the 2 EC types. A consistent association between increasing levels of comorbidity and poorer survival was observed for both types. Cox regression analyses revealed a significant interaction between cancer stage and comorbidity indicating that the impact of comorbidity varied with stage. In contrast, the interaction between comorbidity and EC type was not significant. Both the CCI and the OCCI were useful measurements of comorbidity, but the CCI was the strongest predictor in this patient population.ConclusionsComorbidity is an important prognostic factor in type I as well as in type II EC although the overall prognosis differs significantly between the 2 types of EC. The prognostic impact of comorbidity varies with stage but not with type of EC.


2007 ◽  
Vol 16 (4-5) ◽  
pp. 179-186
Author(s):  
S. Van Cleave ◽  
M.S. Shall

Children with hearing deficits and hypofunctioning vestibular receptors frequently have delayed motor development. This study focuses on when the vestibular system needs to be active for normal motor behavior development and the maturation of the soleus muscle in the ferret. Both vestibular labyrinths were removed from ferrets at Postnatal day 10 (P10), P21, or P45 and the resulting data were compared with ferrets that had undergone a sham surgery at the same ages. The animals were sacrificed at P120 (young adult ferret). The resulting data from these ferrets revealed that standing and walking balance was significantly affected when the vestibular system was eliminated at or before P21. The soleus of P10 and P21 animals generally had smaller diameter muscle fibers and proportionally less type I Myosin Heavy Chain (MHC) and more type IIX MHC. The twitch contraction time of the soleus of the P21 group was significantly slower than the other groups. It appears that the vestibular system is important to motor and muscle fiber development in the ferret during the period before P21. The eyes are still closed at that age and all of the vestibular receptors are not fully mature. These findings imply a "critical period" for vestibular sensation and the development of a muscle that is important to standing balance.


Hypertension ◽  
2020 ◽  
Vol 76 (Suppl_1) ◽  
Author(s):  
Annie L Bell ◽  
Weijian A Shao ◽  
Akemi Katsurada ◽  
Ryosuke Sato ◽  
L Gabriel G NAVAR

Despite growing evidence of sex differences in the progression of hypertension, there are no guidelines that differentiate treatment between men and women. Intrarenal renin-angiotensin system (RAS) activation and tissue injury in 2-kidney, 1-clip (2K1C) hypertensive rats have been characterized in previous studies of male but not female rats. To evaluate possible sex differences in response to renovascular hypertension, urinary angiotensinogen (uAGT) excretion, systolic blood pressure (BP), urinary protein excretion, and renal function were assessed in female rats.Female (n=8) and male (n=6) rats underwent placement of a 0.2 mm clip on the left renal artery to simulate unilateral renal artery stenosis. BP was measured by tail-cuff plethysmography, and clearance studies were conducted in anesthetized rats to assess renal function. Urine protein concentration was determined by pyrogallol red method. uAGT was measured by ELISA as an index of intrarenal RAS activity. Systolic BP increased from 120±1 to 176±8 mmHg, and urinary protein excretion reached 20.2±5.6 mg/day in female rats. Although uAGT excretion increased from 13.2±7.7 ng/day to 74.1±29.9 ng/day in female rats, male rats had a significantly higher uAGT excretion of 1572.6±750 ng/day. Nonclipped kidneys exhibited more uAGT excretion compared to clipped kidneys, consistent with previous findings in males. Although 2K1C female rats demonstrate significantly lower renal function than sham females, they show more preserved renal function than male rats. Female rats also demonstrate significantly lower increases in systolic BP and urinary protein excretion compared to male rats. The data support substantial sex-dependent differences in renal responses to unilateral renal artery stenosis. The results show substantial increases in systolic BP, uAGT, and urinary protein excretion and decreased renal function after renal artery clipping in females, but the magnitude of the changes is markedly lower than in males. Nonclipped kidneys of both sexes exhibit greater uAGT excretion than clipped kidneys. Notably, females show less augmentation of the intrarenal RAS compared to male rats in renovascular hypertension.


2018 ◽  
Vol 2018 (1) ◽  
pp. 000712-000717
Author(s):  
Joshua S. Petko ◽  
Philip A. Lovell ◽  
Jeremy D. Clifton ◽  
Alexander J. Bersani ◽  
Karl F. Schoch

Abstract Conversion coatings are treatments applied to aluminum structures to inhibit corrosion while maintaining electrical conductivity. In aerospace applications, the most common type of conversion coatings (MIL-DTL-5541 Type I) contain hexavalent chromium compounds as the corrosion-inhibiting agent. These Type I conversion coatings have a long pedigree and are highly effective in preventing corrosion; however, the hexavalent chromium compounds in these coatings are carcinogenic and water-soluble. Therefore, the use of these compounds is highly regulated in order to protect both workers and the public, leading to high cost in both use and disposal. Regulations are also beginning to restrict outright use, where new designs for the DOD are prohibited from using Type I coatings by DFARS 48 CFR Parts 223 and 252 and all use has been prohibited by Europe by REACH regulations since September 2017. In response, more environmentally friendly non-hexavalent chromium-based processes, referred to as MIL-DTL-5541 Type II conversion coatings, have become available. However, the long term reliability and performance impacts resulting from the use of these coatings are not fully understood and there is an ongoing effort in the aerospace industry organized by NASA to fully define these impacts while hardware is still in the design stage. While significant work has been performed to define the corrosion performance of various type-II conversion coatings, there has been minimal work performed to quantify the impact a type-II conversion coating would have on RF electrical assemblies. The standard methodologies defined by MIL-DTL-81706B have significant limitations and cannot fully capture the impact at microwave frequencies. For this reason, an investigation is underway at Northrop Grumman to quantify the impact these coatings may have on the quality, reliability, and performance of our electronic systems. At IMAPS 2017, Northrop Grumman introduced a RF test article designed to assess the longitudinal impact a Type II conversion coating would have on RF electrical assemblies where plated printed wiring boards (PWBs) and aluminum structures come in intimate contact. The test article features a specialized suspended stripline/microstrip stepped impedance filter designed to de-tune in the presence of galvanic corrosion. This talk follows the work presented in IMAPS 2017 by discussing an experiment where three different populations of test articles, each coated with a different type of conversion coating, are subjected to environmental testing. This talk also discusses how an initial measurement of these test articles before environmental exposure showed little difference between these populations. Finally, this talk reviews the initial results of this experiment, discussing environmental testing and the RF measurements captured during these tests.


2017 ◽  
Vol 2017 (1) ◽  
pp. 000146-000150
Author(s):  
Joshua S. Petko ◽  
Philip A. Lovell ◽  
Jeremy D. Clifton ◽  
Paul H. Cohen ◽  
Karl F. Schoch

Abstract Conversion coatings are used to inhibit corrosion on aluminum structures while maintaining electrical conductivity. The most common type of conversion coatings in aerospace applications (MIL-DTL-5541 Type I), contain hexavalent chromium compounds as the corrosion-inhibiting additive. These Type I conversion coatings have a long pedigree and are highly effective in preventing corrosion; however, the hexavalent chromium compounds in these coatings are carcinogenic and water-soluble. Therefore, the use of these compounds is highly regulated in order to protect both workers and the public leading to high cost in both use and disposal. In addition to these regulations, use of these materials on new designs for DOD is prohibited by DFARS 48 CFR Parts 223 and 252, and is scheduled to be prohibited in Europe in September 2017 by REACH regulations. In response, new more environmentally friendly non-hexavalent chromium-based processes are becoming available. Coatings resulting from these types of processes are referred to as MIL-DTL-5541 Type II conversion coatings. The long term reliability and performance impacts resulting from the use of these coatings are not fully understood and there currently is an effort in the aerospace industry organized by NASA to fully define these impacts while hardware is still in the design stage. While significant work has been performed to define the corrosion performance of various type-II conversion coatings, there has been minimal work performed to quantify the impact a type-II conversion coating would have on RF electrical assemblies. Of particular interest is the impact a conversion coating can have on microwave loss at higher frequencies. Many RF electrical assemblies use aluminum radiator and waveguide structures to transfer energy between components and radiate into freespace. If microwave losses increase due to a change in conversion coating, there could be negative impacts to key performance parameters such as system sensitivity, dynamic range, noise figure, and radiated power. Understanding this impact is critical in determining whether the design change impact is isolated only to the conversion coating or whether it propagates to other subcomponents to compensate for the loss in performance. The standard way to quantify the electrical resistance of conversion coatings is defined by MIL-DTL-81706B. The test involves collecting a DC resistance measurement on a processed panel using a two-probe measurement with 200 psi of pressure applied to the probes. The resulting value is averaged from 10 samples of data collected across the panel. While this test in MIL-DTL-81706B is well defined, it has significant limitations that caused this research to seek another way to quantify this value. First, the repeatability of the two-point probe is not consistent across the panel. Some of the conversion coatings can be brittle and can easily be disturbed by the force applied by the probes. The poor repeatability is exacerbated when the test articles are environmentally exposed, leaving a non-uniform surface. Finally, this test methodology is performed at DC, which does not directly quantify the impact of the coating at microwave frequencies due to phenomena such as skin effect and potential plasmonic response. This talk discusses an experiment performed to assess the impact of the use of type-II conversion coatings on microwave loss. In order to assess this impact, a set of precision machined waveguide structures were used as test articles in the experiment. The advantage of using this waveguide-based approach is that it provides a distributed surface to assess the average impact of conversion coatings on surface resistivity. This average resistivity more closely maps to the RF losses seen by microwave systems. In addition, testing the waveguide test article provides a very repeatable test methodology; waveguide technology is very mature from a manufacturing perspective. Also, the waveguide flanges provide a repeatable way to connect to the test article so long as they are masked or cleaned after any potential environmental exposure. Finally, the rectangular shape of the waveguide can be canonically described by a closed form expression, improving understanding of the specific mechanisms leading to the loss. This talk discusses an experiment where multiple 3-foot pieces of WR-28 were used as test articles. The WR-28 test articles were chosen to assess the impact to performance at Ka-band. The 3-foot sections are convenient articles because they can easily be measured on a workbench while at the same time being electrically long at Ka-band (on the order of 100 wavelengths). This talk discusses three different populations of test articles, each coated with a different type of conversion coating. This talk also discusses how an initial measurement of these test articles before environmental exposure showed little difference between these populations. Finally, this talk will discuss plans for environmental testing and in-process RF measurements to be captured during these tests.


2017 ◽  
Vol 2017 (1) ◽  
pp. 000046-000051 ◽  
Author(s):  
Joshua S. Petko ◽  
Philip A. Lovell ◽  
Jeremy D. Clifton ◽  
Paul H. Cohen ◽  
Karl F. Schoch

Abstract Conversion coatings are used to inhibit corrosion on aluminum structures while maintaining electrical conductivity. The most common type of conversion coatings in aerospace applications (MIL-DTL-5541 Type I), contain hexavalent chromium compounds as the corrosion-inhibiting additive. These Type I conversion coatings have a long pedigree and are highly effective in preventing corrosion; however, the hexavalent chromium compounds in these coatings are carcinogenic and water-soluble. Therefore, the use of these compounds is highly regulated in order to protect both workers and the public leading to high cost in both use and disposal. In addition to these regulations, use of these materials on new designs for DOD is prohibited by DFARS 48 CFR Parts 223 and 252, and is scheduled to be prohibited in Europe in September 2017 by REACH regulations. In response, new more environmentally friendly non-hexavalent chromium-based processes are becoming available. Coatings resulting from these types of processes are referred to as MIL-DTL-5541 Type II conversion coatings. The long term reliability and performance impacts resulting from the use of these coatings are not fully understood and there currently is an effort in the U. S. aerospace industry organized by NASA to fully define these impacts while hardware is still in the design stage. While significant work has been performed to define the corrosion performance of various Type II conversion coatings, there has been minimal work performed to quantify the impact a Type II conversion coating would have on RF electrical assemblies where plated printed wiring boards (PWBs) and aluminum structures come in intimate contact. The primary concern for these assemblies is that these junctions are inherently susceptible to galvanic corrosion; PWBs are clad with copper, which is highly cathodic while aluminum is highly anodic. In order to reduce the potential for galvanic corrosion, PWBs in DOD applications are typically plated with SnPb coating which is less cathodic than the copper. In addition, an immersion bath is used to coat the aluminum with a conversion coating that is less anodic. Changes to the conversion coating could increase the galvanic corrosion occurring at this junction. In addition, RF signals may also be negatively impacted by changes to the electrical resistivity and parasitic capacitances caused by changes to this junction. For this reason, it is highly desirable to create a RF test article that is highly sensitive to the impacts of galvanic corrosion at the junctions of passivated aluminum and plated printed wiring boards. This talk discusses a RF test article that is designed to assess the longitudinal impact of galvanic corrosion on electrical assemblies. The test article features a specialized suspended stripline/microstrip stepped impedance filter that is designed to de-tune in the presence of galvanic corrosion. The design of this filter uses a pair of machined aluminum housings to sandwich a thin two sided printed wiring board. The high-impedance sections of the filter employ cavities above and below the thin PWB to create an effective airstripline transmission line. The low-impedance sections of the filter employ a PWB ground plane to create a microstrip mode. Small aluminum feet are machined in the bottom aluminum housing to create an electrical contact between the aluminum housing and PWB ground plane. These feet are designed to function as sacrificial elements that corrode away in the presence of galvanic corrosion, creating series capacitance in the ground signal path. This talk reviews recent test results that show how the response of this specially designed filter changes in the presence of galvanic corrosion and compares these results with electrical simulations. This talk also discusses how information gained from the filter response can be used to assess the electrical impact of Type II conversion coatings. Finally, this talk will discuss the experimental design needed to quantify the impact of Type II conversion coatings with respect to the current baseline processes.


2012 ◽  
Vol 30 (4_suppl) ◽  
pp. 92-92
Author(s):  
Dean Bogoevski ◽  
Sormeh Mina ◽  
Asad Kutup ◽  
Maximilian Bockhorn ◽  
Matthias Reeh ◽  
...  

92 Background: Due to controversial staging systems, classifying tumors of the esophagogastric junction (EGJ) and the choice of the following surgical therapy remains a delicate affair. Methods: In this study the impact of the preoperative surgical-clinical assessment concerning assorting tumors of the EGJ was evaluated in correlation to the patient’s outcome. We analyzed clinicopathological data from 92 patients who were pre- and intraoperatively classified as distal esophageal cancer (Type I) and thus underwent esophagectomy with gastric tube reconstruction and who afterwards (final histology) in part turned out to be cardia/gastric cancers (Type II). Results: Patients with Type II cancers showed significantly more frequent lymphonodal metastasis (p=0.022) and higher recurrence rates (p=0.01), especially distant metastatic recurrence (p=0.03). Cancer-related death was also significantly higher (p=0.002) and recurrence-free survival was significantly shorter (median: 22 vs. 57 months, p=0.027). Also the thoracoabdominal approach (TA) had a favourable influence on patients’ outcome compared to the transhiatal approach (TH). Conclusions: The correct preoperative assessment of tumors of the EGJ and the appropriate surgical therapy are crucial for the outcome of the patient. Those patients with Type II cancers might experience a survival benefit by undergoing radical combined esophago (-hemi)gastrectomy with colon interposition.


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