Altered Renal Function Research Articles

Establishing a blood fructosamine reference range for the Brazilian population based on data from ELSA – Brasil

ObjectivesThe fructosamine test is used in the monitoring of diabetes mellitus, particularly in cases with restrictions on the use of glycated hemoglobin (mainly in the setting of altered red blood cell lifespan and interference by hemoglobin variants). It could also provide additional information on shorter-term glycemic control. The objective of the study is to establish the reference range of the fructosamine in the Brazilian population. Design and methodsThe reference interval was defined as suggested by the Clinical and Laboratory Standards Institute (CLSI). The study participants were from a Brazilian cohort (The Longitudinal Study of Adult Health – ELSA-Brasil) with baseline data collected between 2008 and 2010. A total of 466 subjects were selected after exclusion of diabetic individuals, and those with altered glycemic markers and renal function tests. ResultsThe reference interval was 186–248 μmol/L for women and 196–269 μmol/L for men. Fructosamine levels were higher in men than in women (p = 0.006) and in the non-white population (p = 0.034) and had a negative correlation with the body mass index (r = −0.117; p = 0.011). ConclusionsThe reference intervals for fructosamine were affected by sex. Reference intervals stratified by sex would be more adequate in the interpretation of the fructosamine test.

Selective abdominal venous congestion induces adverse renal and hepatic morphological and functional alterations despite a preserved cardiac function

Venous congestion is an important contributor to worsening renal function in heart failure and the cardiorenal syndrome. In patients, it is difficult to study the effects of isolated venous congestion on organ function. In this study, the consequences of isolated abdominal venous congestion on morphology and function of the kidneys, liver and heart were studied in a rat model. Twelve sham-operated (SHAM) male Sprague Dawley rats were compared to eleven inferior vena cava-constricted (IVCc) rats for twenty-one weeks. Abdominal venous pressure was significantly higher in the IVCc versus SHAM group (p < 0.0001). Indices of liver and kidney weight, function and morphology, inflammation as well as collagen deposition were significantly increased in the IVCc compared to SHAM group, (p < 0.05). Echocardiographic and hemodynamic parameters were largely unaffected by abdominal venous congestion. In this rat model of isolated abdominal venous congestion, retrogradely conducted glomerular hypertension without a concomitant change in glomerular filtration rate was observed. Adverse short-term hepatic morphological alterations were developed which explain the observed organ function dysfunction. Importantly, cardiac function remained comparable between both groups. This study provides relevant insight in the pathophysiology of abdominal congestion on organ function.

Urinary Exosome-Derived microRNAs Reflecting the Changes in Renal Function in Cats.

Increased incidence of kidney disease (KD) is a common concern in human and companion animals. Cats, in particular, are highly susceptible to KD. Novel KD biomarkers would help to address these problems. Therefore, we are focusing on microRNA, a highly conserved nucleic acid, as a KD biomarker for various animals. We previously reported that altered levels of urinary exosome (UExo)-derived microRNAs indicate renal pathologies in dogs. This study comprehensively examined UExo-derived microRNAs, which reflected the KD status in cats. The examined cats were divided into two groups: normal renal function (NR) and KD. Based on our previous data in dogs and cats, as well as the present data on UExo-derived microRNAs in cats by next-generation sequencing, let-7b, let-7f, miR-10a, miR-10b, miR-21a, miR-22, miR-26a, miR-27b, miR-146a, miR-181a, miR-191, and miR-486a were identified as biomarker candidates. In summary, the levels of UExo-derived let-7b, miR-22, and miR-26a significantly decreased in cats with KD from the early stages of the disease. UExo-derived miRNA levels normalized to urinary creatinine or total RNA of miR-21a was significantly higher in the KD group. Importantly, the ratio of UExo-derived miR-21a to let-7b showed a significant and strongest correlation with serum creatinine (ρ = 0.751), blood urea nitrogen (ρ = 0.754), and urinary creatinine (ρ = −0.421) among all examined indices. Further, the ratio of miR-181a to let-7b or miR-10b significantly correlated with the progression of renal dysfunction in the KD group. Thus, we identified that UExo-derived microRNAs in cats, and their raw and normalized levels could indicate altered renal function.

Cyclooxygenase-2, Asymmetric Dimethylarginine, and the Cardiovascular Hazard From Nonsteroidal Anti-Inflammatory Drugs.

Large-scale, placebo-controlled trials established that nonsteroidal anti-inflammatory drugs confer a cardiovascular hazard: this has been attributed to depression of cardioprotective products of cyclooxygenase (COX)-2, especially prostacyclin. An alternative mechanism by which nonsteroidal anti-inflammatory drugs might constrain cardioprotection is by enhancing the formation of methylarginines in the kidney that would limit the action of nitric oxide throughout the vasculature. Targeted and untargeted metabolomics were used to investigate the effect of COX-2 deletion or inhibition in mice and in osteoarthritis patients exposed to nonsteroidal anti-inflammatory drugs on the l-arginine/nitric oxide pathway. Analysis of the plasma and renal metabolome was performed in postnatal tamoxifen-inducible Cox-2 knockout mice, which exhibit normal renal function and blood pressure. This revealed no changes in arginine and methylarginines compared with their wild-type controls. Moreover, the expression of genes in the l-arginine/nitric oxide pathway was not altered in the renal medulla or cortex of tamoxifen inducible Cox-2 knockout mice. Therapeutic concentrations of the selective COX-2 inhibitors, rofecoxib, celecoxib, and parecoxib, none of which altered basal blood pressure or renal function as reflected by plasma creatinine, failed to elevate plasma arginine and methylarginines in mice. Finally, plasma arginine or methylarginines were not altered in osteoarthritis patients with confirmed exposure to nonsteroidal anti-inflammatory drugs that inhibit COX-1 and COX-2. By contrast, plasma asymmetrical dimethylarginine was increased in mice infused with angiotensin II sufficient to elevate blood pressure and impair renal function. Four weeks later, blood pressure, plasma creatinine, and asymmetrical dimethylarginine were restored to normal levels. The increase in asymmetrical dimethylarginine in response to infusion with angiotensin II in celecoxib-treated mice was also related to transient impairment of renal function. Plasma methylarginines are not altered by COX-2 deletion or inhibition but rather are elevated coincident with renal compromise.

Correction: Cisplatin-Induced Non-Oliguric Acute Kidney Injury in a Pediatric Experimental Animal Model in Piglets.

[This corrects the article DOI: 10.1371/journal.pone.0149013.].

Preterm Birth: Long Term Cardiovascular and Renal Consequences.

Background: Cardiovascular and chronic kidney diseases are a part of non-communicable chronic diseases, the leading causes of premature death worldwide. They are recognized as having early origins through altered developmental programming, due to adverse environmental conditions during development. Preterm birth is such an adverse factor. Rates of preterm birth increased in the last decades, however, with the improvement in perinatal and neonatal care, a growing number of preterm born subjects has now entered adulthood. Clinical and experimental evidence suggests that preterm birth is associated with impaired or arrested structural or functional development of key or-gans/systems making preterm infants vulnerable to cardiovascular and chronic renal diseases at adult-hood. This review analyzes the evidence of such cardiovascular and renal changes, the role of perina-tal and neonatal factors such as antenatal steroids and potential pathogenic mechanisms, including de-velopmental programming and epigenetic alterations.Conclusion: Preterm born subjects are exposed to a significantly increased risk for altered cardio-vascular and renal functions at young adulthood. Adequate, specific follow-up measures remain to be determined. While antenatal steroids have considerably improved preterm birth outcomes, repeated therapy should be considered with caution, as antenatal steroids induce long-term cardio-vascular and metabolic alterations in animals’ models and their involvement in the accelerated cellular senescence observed in human studies cannot be excluded.

58] The effect of β-caryophyllene on renal dysfunction following ischaemia–reperfusion injury

ObjectiveTo investigate the effect of β-caryophyllene (BCP) on renal ischaemia–reperfusion injury (IRI)-induced renal dysfunction, as IRI causes renal functional alterations that might lead to permanent renal impairment and BCP (a natural bicyclic sesquiterpene and constituent of many essential oils and spices) has been shown to exhibit anti-inflammatory, antioxidant, antispasmodic and chemopreventive activities in several organs. BCP is a USA Food and Drug Administration (FDA)-approved food additive and its effect on IRI has not been investigated.

Population pharmacokinetics of daptomycin in critically ill patients with various degrees of renal impairment.

The objective of this study was to characterize the pharmacokinetics of unbound and total concentrations of daptomycin in infected ICU patients with various degrees of renal impairment. From these results, the probability of attaining antimicrobial efficacy and the risks of toxicity were assessed. Twenty-four ICU patients with various renal functions and requiring treatment of complicated skin and soft-tissue infections, bacteraemia, or endocarditis with daptomycin were recruited. Daptomycin (Cubicin®) at 10 mg/kg was administered every 24 h for patients with creatinine clearance (CLCR) ≥30 mL/min and every 48 h for patients with CLCR <30 mL/min. Total and unbound plasma concentrations and urine concentrations of daptomycin were analysed simultaneously following a population pharmacokinetic approach. Simulations were conducted to estimate the probability of attaining efficacy (unbound AUCu/MIC >40 or >80) or toxicity (Cmin >24.3 mg/L) targets. Exposure to unbound daptomycin increased when the renal function decreased, thus increasing the probability of reaching the efficacy targets, but also the risk of toxicity. Modifications of the unbound fraction (fu) of daptomycin did not affect the pharmacokinetics of unbound daptomycin, but did affect the pharmacokinetics of total daptomycin. Daptomycin at 10 mg/kg q24h allowed efficacy pharmacokinetic/pharmacodynamic targets for ICU patients with CLCR ≥30 mL/min to be reached. For patients with CLCR <30 mL/min, halving the rate of drug administration, i.e. 10 mg/kg q48h, was sufficient to reach these targets. No adverse events were observed, but the toxicity of the 10 mg/kg q24h dosing regimen should be further assessed, particularly for patients with altered renal function.

Renal expression and urinary excretion of Na+/dicarboxylate cotransporter 1 (NaDC1) in obstructive nephropathy: a candidate biomarker for this pathology.

Obstructive nephropathy is characterized by alterations in renal function that depends on the degree and type of obstruction. To increase the knowledge about the physiopathological mechanisms involved in the renal damage associated with bilateral ureteral obstruction (BUO), we studied the renal expression and function (as urinary citrate excretion) of sodium-dependent dicarboxylate cotransporter (NaDC1) in rats. In addition, we evaluated the urinary excretion of NaDC1 as a candidate biomarker forthis pathology. Male Wistar rats underwent bilateral ureteral obstruction for 1 (BUO1), 2 (BUO2), 5 (BUO5), and 24 (BUO24) h or sham operation. After 24h of ureteral releasing, traditional parameters of renal function and citrate levels were determined, and NaDC1 levels were evaluated in total renal homogenates, apical plasma membranes, and urine by electrophoresis and Western blotting. Traditional parameters of renal function were only modified in BUO5 and BUO24. The renal expression of NaDC1 was decreased in BUO5 and BUO24, with a concomitant increase in urinary excretion of citrate. Moreover, the urinary excretion of NaDC1 increased after short times of ureteral obstruction (BUO1 and BUO2) and was positively correlated with the time elapsed after obstruction. The results obtained from the renal expression of NaDC1 could explain an adaptive mechanism to prevent the formation of kidney stones by increasing the levels of citrate, a calcium chelator. The urinary excretion of NaDC1 could be postulated as an early biomarker of obstructive nephropathy that also gives information about the duration of the obstruction.

Neurological and Psychological Changes in Hemodialysis Patients Before and After the Treatment.

Neurological, psychological, and cognitive disorders in chronic kidney disease may contribute to poor quality of life in these patients. The aim of this study was to assess the electroencephalographic, psychological, and cognitive changes before and after hemodialysis (HD) compared with healthy controls (HC). Sixteen HD patients and 15 HC were enrolled. Electroencephalogram (EEG), Minnesota multiphasic personality inventory (MMPI-2) Satisfaction profile (SAT-P), and Neuropsychological test Global z-scores (NPZ5) were performed before (T0) and after (T1) HD treatment and in HC. Renal function, inflammatory markers and mineral metabolism indexes were also evaluated. Patients did not show significant differences before and after HD in the absolute and relative power of band of EEG, except in Theta/Alpha index (P < 0.001). At T1, HD patients showed significant differences in Beta, Delta and Theta band, in addition to Theta/alpha index, with respect to HC. Moreover, HD patients showed significant differences in specific MMPI-2 clinical and content scales, SAT-P domains and NPZ5 tests of memory and concentration with respect to HC. We also observed significant correlations between renal function, mineral metabolism, inflammatory markers and psychocognitive alterations. In our sample EEG abnormalities tend to reduce, but not significantly, after HD treatment and differences remain present with respect to HC. In HD patients cognitive and psychological alterations were associated with reduced quality of life and correlated with mineral metabolism and inflammation. Modification in EEG and in psychological and cognitive parameters should be assessed in a larger HD population to confirm our observation.

Clinical relevance of aortic stiffness in end-stage renal disease and diabetes: implication for hypertension management.

: Evidence suggests that aortic stiffness may antedate and contribute initially to the development of hypertension and cardiovascular risk (CVR). In treated hypertensive patients, both diabetes and end-stage renal disease (ESRD) are comorbid conditions associated with increased aortic stiffness and high CVR. Thus, the pathophysiological relationship between aortic stiffness, blood pressure (BP) and CVR may have clinical implication in the management of hypertension. In patients with diabetes or ESRD, aortic stiffness is a significant predictor of CVR, independently of BP control. The hallmark of accelerated aortic stiffening in these patients associates the presence of vascular calcification, which is considered as a time-dependent process. Aortic stiffness represents a marker of structural but also functional arterial damage associated with increased pressure pulsatility. Carotid-femoral pulse wave velocity (cf-PWV), as a marker of aortic stiffness, may provide a readily available information for the effectiveness of risk reduction strategies. SBP, hyperglycemia and progressive alteration of renal function are considered as determinants of accelerated aortic stiffening. These findings suggest that earlier and intensive treatment of glycemia and BP could be important to limit or even reverse stiffening process. In patients with ESRD, more specific and potentially modifiable kidney disease-related parameters such as phosphocalcic disorders and vitamin K deficiency, appear correlated with aortic calcification and cf-PWV. An important and recent finding is that the magnitude of longitudinal increase in cf-PWV may represent a clinically pertinent surrogate for cardiovascular events. Aortic stiffness may be, thus, considered as an intermediate marker to monitor effectiveness of preventive strategies in these high-risk patients.

Tempestività di intervento nella colica renale: aspetti fisiopatologici

Renal colic is one of the most common diagnoses of emergency room access and ureteral stone is one of the most common causes of renal colic due to ureteral obstruction. Ureteral obstruction initially causes an increase of intraureteral pressure, which returns to baseline values after a short time after the reduction in urine production and the progressive increase in the circumference and ureter length. Reduction in urinary flow depends on the renal hemodynamic response, which has three phases: initial vasodilation of the preglomerular afferent artery; vasoconstriction of the postglomerular efferent artery; and, finally, vasoconstriction of the preglomerular afferent artery. Renal parenchyma ischemia is associated with oxidative stress, inflammatory infiltrate and subsequent apoptosis of tubular cells and interstitial fibrosis. This degenerative pathological process tends to continue even after relatively early removal of the obstruction and despite the restoration of renal hemodynamics. Fibrosis progression is associated with alterations in renal function with hyperfiltration in the surviving nephronic population and alterations in tubular function. These pathophysiological aspects have to be considered in the management of patients with renal colic and ureteral obstruction. Expulsive treatment of renal stones should be carefully planned by accurate selection of patients and frequent follow-up controls. When the obstruction is severe or the expulsion time is prolonged, early treatment or temporary urinary diversion with deferred treatment should be considered. The time limit for awaiting spontaneous stone passage is not well defined and varies depending on the degree of obstruction and possible complicating factors, however it may be prudent to not exceed two to three weeks.

Functionality, comorbidity, complication & surgery of hip fracture in older adults by age distribution.

Hip fractures may be the greatest complication secondary to osteoporotic disorder. The objective of this study was to determine the influence of age distribution in the functionality, comorbidity, complications and surgical features of older adults with hip fractures. A prospective cohort study was carried out from 2013 to 2014. A sample of 557 adults over 75 years old with osteoporotic hip fractures was recruited from the Orthogeriatric Unit of the León University Hospital (Spain). Age distributions of 75-84, 85-90 and >90 years old were considered. Firstly, sociodemographic data, fracture type and hospital staying days were collected. Secondly, baseline functionality (Barthel index), ambulation, cognitive impairment and comorbidities were described. Thirdly, surgical intervention, urgency, type, American Association of Anesthesiologists (ASA) scores, non-surgical cause, and baseline pharmacologic treatments were determined. Finally, complications and features at hospital discharge were observed. The age ranges did not show any statistically-significant differences (P<.05; R2=.000-.005) for gender, fracture type, or number of hospital staying days. Statistically-significant differences (P<.05; R2=.011-.247) between age groups were observed for Barthel index, cognitive impairment, dementia, osteoporosis, Parkinson's disease, aortic stenosis, surgery type, ASA-score, non-surgical cause, benzodiazepines, antidementia, anti-osteoporosis, insulin, pharmacologic treatments, renal function alteration, heart failure, destination and ambulation features. All other measurements did not show statistically-significant differences (P>.05; R2=.000-.010). Age distributions greater than 75 years old may determine the functionality, comorbidities, surgical features, baseline pharmacologic treatments, complications and features at hospital discharge for older adults who suffer a hip fracture.

Population pharmacokinetics of oxaliplatin after intraperitoneal administration with hyperthermia in Wistar rats

BackgroundThe evaluation of the efficacy and toxicity of hyperthermic intraoperative peritoneal chemotherapy presents some difficulties, due in part to the lack of information about the pharmacokinetic behavior of the drugs administered in this procedure. The aim of this study was to characterize the population pharmacokinetics of hyperthermic intraoperative peritoneal oxaliplatin in Wistar rats and to evaluate the effect of treatment-related covariates dose, instillation time and temperature on the pharmacokinetic parameters. MethodsOxaliplatin peritoneal and plasma concentrations from 37 rats treated by either intravenous or intraperitoneal oxaliplatin administrations under different instillation times, temperatures and doses were analyzed according to a population pharmacokinetic approach using the software NONMEM V7.3®. ResultsIntraperitoneal (n = 115) and plasma (n = 263) concentrations were successfully described according to a two-compartment model with first order absorption. No significant effect of dose, temperature and instillation time on pharmacokinetic parameters was found. However, an abrupt decrease in the elimination process was observed, reflected in the structural pharmacokinetic model through a modification in clearance. The typical parameters values and the interindividual variability (CV %) in clearance, central and peripheral volume of distribution were 3.25 mL/min (39.1%), 53.6 mL (37.8%) and 54.1 mL (77.3%), respectively. Clearance decreased to 0.151 mL/min (39.1%) when the instillation was still ongoing, at 31.4 min. One of the possible reasons behind the clearance decrease would be an alteration of renal function due to surgery and/or hyperthermia. ConclusionsThis study described the deterioration of the drug elimination process due to the procedure, and estimated the time at which this deterioration is most likely to occur. In addition, dose, instillation time and temperature had no influence in the PK parameters.

Effect of Fructose Overconsumption since Early Age on Renal Function and Sympathetic Nerve Activity

Increased consumption of ready‐to‐eat foods and beverages that contain high fructose content may contribute to the onset of cardiovascular and renal diseases. Moreover, fructose overload in diet since prenatal period may increase the risk of the offspring to diseases later in life. Thus, the objective of this study was to evaluate the effects of increased consumption of fructose since prenatal period until adulthood on: blood pressure, renal function and renal sympathetic nerve activity of the offspring at adulthood.MethodsFemales Wistar rats were randomly assigned to groups: Control (C) and Fructose (F). The C group received food and drinking water ad libitum, and F group received food and D‐fructose solution (20%) for drinking ad libitum. In F, the offer of D‐fructose solution begun 1 week before mating and continued during pregnancy and lactation. After birth, the progeny was limited to 8 offspring and designated as Control Offspring (CO) and Fructose Offspring (FO). At 21st day of life, male offspring were placed in collective cages and received the same treatment of the dams. The experiments were performed at 4 months old rats. Direct measurement of systolic arterial blood pressure and mean arterial blood pressure (SAP and MAP), and the registration of the renal sympathetic nerve activity (RSNA) were performed in 6 animals of each group (CO and FO). The renal function parameters were evaluated in other 6 rats of each group. Renal parameters evaluated: glomerular filtration rate (GFR ‐ inulin clearance), renal plasma flow (RPF ‐ PAH clearance), protein excretion (EProt), urine osmolarity (Uosm), urinary excretion/24 h (V), sodium (ENa+) and potassium (EK+) excretion. The study was approved by the Ethical Research Committee of the Universidade Federal de São Paulo (protocol: 2757270117).ResultsCompared with CO group, FO presented higher values of SAP (FO: 165 ± 5 vs CO: 141 ± 6 mmHg) and MAP (FO: 130 ± 5; CO: 110 ± 4 mmHg). FO had decreased GFR (FO: 5.1 ± 0.7; CO: 8.4 ± 0.5 ml/min/kg), Uosm (FO: 305 ± 60; CO: 1522 ± 81 mosm/l) and potassium excretion (FO: 182 ± 18; CO: 302 ± 28 mM/24 h). The urine excretion and protein excretion were increased in FO compared with CO group (V: FO: 52 ± 1; CO: 14 ± 0.7 ml/24 h; EProt: FO: 10.3 ± 1; CO: 6.4 ± 1 mg/24 h). There were no significant differences between the groups regarding the baseline RSNA (FO: 59 ± 4; CO: 71 ± 14 spikes/s), RPF (FO: 15.0 ± 2; CO: 16.2 ± 1 ml/min/kg) and sodium excretion (FO: 91.2 ± 15; CO: 85.7 ± 15 mM/24 h). Values are presented as mean ± sem, p ≤ 0.05.ConclusionsOur data show that increased consumption of fructose since early age leads to increase in blood pressure and alterations in renal function in the offspring (reduced: GFR, urine osmolarity and potassium excretion; and increased protein excretion).Support or Funding InformationCAPESThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

APOL1‐like gene insertion associated with increased blood pressure in the African Green Monkey

End stage renal disease affects 660,000 adults in the United States and disproportionally affects people of African descent. Studies have identified two alleles in the apolipoprotein L1 (APOL1) gene that are expressed in high frequency in African‐ American populations and may contribute to a 4–5 fold increased incidence of end stage renal disease (ESRD) in this demographic. The African Green Monkey (AGM, Chlorocebus aethiops sabaeus) is an Old World monkey species that develops spontaneous hypertension and is indigenous from the regions of Africa from which the two APOL1 alleles are known to exist in humans. We have recently reported that the AGM exhibits renal glomerular and vascular pathologies in conjunction with significant spontaneous hypertension. Furthermore, we report elsewhere that this spontaneous hypertension in the AGM is associated with significant proteinuria even when the animals are prehypertensive; suggesting that altered renal glomerular and/or tubular function in regulating protein excretion may precede the development of spontaneous hypertension in the AGM. This study hypothesized that gene sequence changes in the APOL1‐like gene region may be expressed in the AGM and are associated with increased blood pressure and altered renal function, similar to the human population. DNA was extracted from whole blood or frozen tissue in 44 adult males and the APOL1‐like gene region was sequenced. Bioinformatic analysis identified a 6 nucleotide insertion at base 329 that was positively associated with increased systolic blood pressures (p&lt;0.05). Within the cohort, 2 animals were found to be homozygous for the sequenced insertion (mean ± SE SBP: 206.6±0.1 mmHg), 10 animals were heterozygous (SBP: 136.6±14.6 mmHg), and 32 animals did not have the insertion (SBP: 135.7± 7 mmHg). This data suggests that the insertion in the APOL1‐like gene may affect blood pressure regulation (and/or kidney function) in the AGM, providing a novel and exciting nonhuman primate model to study the progression of ESRD in a non‐human primate species that expresses variations within the APOL1 gene, which is known to correlate with early onset ESRD in African Americans. Ongoing studies are focused on increasing the AGM cohort size, adding normotensive and hypertensive females to the sequenced cohort, and collection of renal functional data on all sequenced animals to determine the effect of the APOL1‐like insertion on kidney function and blood pressure regulation in the AGM.Support or Funding InformationFunding provided by Biomedical Science Research Group, LLC.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Neutrophil Depletion Influences Renal Outcomes in Male Mice with Chronic Angiotensin II Infusion

Hypertension is the leading cause of morbidity and mortality worldwide; yet the exact cause for many cases remain unknown. Recent research has highlighted the significance of the immune system in the development and progression of HTN in animal models. Much of this research has focused on classical immune pathways involving antigen presenting cells and subsequent activation of the adaptive immune response (primarily CD8+ T‐cells). These activated lymphocytes then support the development of HTN by mediating end‐organ damage in organs tasked with regulating blood pressure and extracellular volume (such as the kidneys). In the current study, we set out to determine the role of neutrophils in a murine model of HTN – the chronic angiotensin II (AngII) infusion model. All animal experiments were performed following animal protocols approved by the Liberty University IACUC and conform to the FASEB Statement of Principles for the use of animals in research and education. Baseline blood pressure was recorded in male C57Bl/6 mice (N=10) for 3 weeks using the CODA‐8 tail cuff volume pressure recording system. Neutrophil depletion was accomplished via intraperitoneal injections of a monoclonal anti‐Ly6G antibody (1A8, n=5), or IgG control (2A3, n=5) every 48 hours (250μg/mouse). 18 hours following the first antibody injection, a mini‐osmotic pump was implanted into the rear flank delivering 500ng/kg*min AngII. 3 days after pump implantation, blood pressure readings resumed and continued for 14 days. After 14 days, mice were individually housed in metabolic cages and urine was collected for quantification of albuminuria. Renal blood flow was estimated in anesthetized mice using contrast‐enhanced ultrasonography. Following renal blood flow estimation, mice were euthanized and blood, kidney, and spleens collected for determination of leukocyte content by flow cytometry. All data were analyzed using general linear models procedures in SPSS. Significant differences in blood pressure were observed periodically during the 14 days of AngII infusion (P≤0.05 for days 8, 12, and 14); however, the overall effect of treatment (1A8 vs. 2A3) did not reach statistical significance (P&lt;0.2). Mice receiving the 1A8 neutrophil depleting antibody also tended (P≤0.07) to have a higher urinary output and albuminuria as compared to mice receiving the isotype control (respectively). No difference in estimated renal blood flow was detected between the treatment groups. Tissue analysis by flow cytometry confirmed the depletion and/or significant reduction of circulating and splenic neutrophils in mice receiving 1A8, but not 2A3, injections after 2 weeks. In the kidneys, mice receiving the 1A8 neutrophil depleting antibody had reduced (P=0.03) CD45+ leukocyte content. Further analysis of renal single cell suspensions revealed a significant reduction (P=0.04) in B‐cells and higher (P=0.03) CD8+ T‐cells in 1A8 treated animals. Taken together, our data suggest that neutrophil depletion alters several renal outcomes in the AngII murine model of HTN, with neutropenic mice tending to have higher blood pressure, greater urinary output and albuminuria as compared to control mice. These effects could be mediated by the significant differences in renal leukocyte content between the treatment groups. Further studies are needed to confirm our results and delineate the molecular mechanisms responsible for altered renal function and inflammation due neutrophil depletion in this animal model.Support or Funding InformationThis work was supported by Liberty University, College of Osteopathic Medicine intramural grant #2016‐07This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Serum Cystatin C Level for Evaluation of Renal Functions in Women with Severe Preeclamptic Toxemia

Abstract Background: Preeclampsia is a complex and serious multisystem disorder of pregnancy with a worldwide incidence of 5-7% and contributes significantly to maternal and perinatal morbidity and mortality. Altered renal function is an essential component of the pathophysiological process in PE, so close monitoring of renal function is important to ensure a timely delivery before serious renal damage occurs. Aim of the Work: To evaluate diagnostic value of cystatin C serum levels as an alternative marker of renal function in women with severe preeclamptic toxemia versus matching cases of normal pregnancy and compare it with the traditional markers of renal function, Creatinine, urea and serum uric acid. Patients and Methods: A case-control study includes 80 Primigravidae with singleton pregnancy and gestation ≥28 weeks and were divided into two groups, Group 1: (40 patients) with severe preeclampsia and Group 2: (40 patients) as a control group (normotensive and nonproteinuric). Markers of kidney function were investigated in two groups of pregnant women and comparison between both groups as regards to cystatin C serum levels, creatinine, blood urea and serum uric acid was done. Results: The difference in the mean serum uric acid level (5.10±0.96 versus 4.70±0.63mg/dl) was significantly higher in preeclampsia (p=0.027), the specificity was 100% and sensitivity of the test was 87.5%, the difference in the mean serum concentration of creatinine (0.94±0.16 versus 0.86± 0.12mg/dl) was significantly higher in preeclampsia (p=0.028), the specificity of the test was 100% and the sensitivity was 82.5%. Serum cystatin C level has a mean (1.26±0.21 versus 0.75±0.05mg/l) which was significantly higher in preeclampsia (p=0.001) with a specificity 100% and sensitivity 96%. Conclusion: It is concluded that among serum creatinine, blood urea, serum uric acid & serum cystatin C, Serum cystatin C is the earliest & a better marker of renal dysfunction in preeclampsia.

Tempol, a superoxide dismutase-mimetic drug, prevents chronic ischemic renal injury in two-kidney, one-clip hypertensive rats

ABSTRACTTempol, a superoxide dismutase-mimetic drug, has been shown to attenuate radical-induced damage, exerting beneficial effects in the animal models of oxidative stress and hypertension. This study evaluated the effect of Tempol on renal structural and functional alterations in two-Kidney, one-Clip hypertensive rats. In this study, young male Wistar rats had the left kidney clipped (2K1C), and sham-operated animals (Sham) were used as controls. Animals received Tempol (1mmol/L in drinking water) or vehicle for 5 weeks. Systolic blood pressure was evaluated once a week. At the end of the experimental protocol, the animals were placed in metabolic cages to collect urine (24h) and then anesthetized with thiopental (70mg/kg i.p.) to collect blood by puncturing the descending aorta for biochemical analysis, and the clipped kidney for morphological and immunohistochemical analyses. The vasodilator effect of Tempol was evaluated in mesenteric arterial bed (MAB) isolated from adult Wistar rats. The chronic treatment with Tempol prevented the development of hypertension and the increased plasma levels of urea, creatinine, and 8-isoprostane in 2K1C animals. Tempol also improved both glomeruli number and kidney volume to normal levels in the 2K1C+Tempol group. In addition, the treatment prevented the increased collagen deposition and immunostaining for renin, caspase-3, and 8-isoprostane in the stenotic kidney of 2K1C animals. Moreover, Tempol induced a dose-dependent vasodilator response in MAB from Wistar rats. These results suggest that Tempol protects the stenotic kidney against chronic ischemic renal injury and prevents renal dysfunction in the 2K1C model, probably through its antioxidant, vasodilator and antihypertensive actions.

Hypoxia: A cause of acute renal failure and alteration of gastrointestinal microbial ecology.

Oxygen is very important to the existence of life. Oxygen deficiency, defined as hypoxia, elicits adaptive responses in cells and tissues. Lower oxygen concentration can cause the alteration of renal function, affects the maintenance of a balance of the body fluids, electrolytes, pH, and blood pressure homeostasis. Impaired fluid regulation could, in addition, contribute to the precipitation of pulmonary edema and exacerbate hypoxemia which may accelerate the progression of chronic kidney disease. In this context, the present study attempted to evaluate the association of renal injury and oxidative stress at different atmospheric pressures (1829, 3657, and 5486 m). Limited fecal analysis of experimental animals was also done to evaluate the impact of hypobaric hypoxia on the composition of dominant gastrointestinal microbiota. The study was performed on 24 male Wister strain rats and divided into four groups (C, HA-I, HA-II, and HA-III), and exposure was carried out for seven days period. In hypoxic exposure rats, plasma urea, creatinine, electrolytes and malonaldehyde level elevated and catalase and superoxide dismutase level diminished significantly compared to the controls. Increase in blood uremia profile, toxicity markers, and lipid peroxidation marker enzymes indicated that hypoxia causes renal failure. Histological structures of the kidney of group HA-II and HA-III animals showed severe disorganization of glomerulus and dilation of renal tubules. These results indicate nephrotoxicity or acute renal failure can occur at hypobaric hypoxia and it also affected the gut microbial population. This alteration was observed significantly above 3000 m.