ResearchPad - renal-system https://www.researchpad.co Default RSS Feed en-us © 2020 Newgen KnowledgeWorks <![CDATA[Naringenin mitigates autoimmune features in lupus-prone mice by modulation of T-cell subsets and cytokines profile]]> https://www.researchpad.co/article/elastic_article_15753 Naringenin is flavonoid mainly found in citrus fruits which has shown several biological properties. In this work, we evaluated the therapeutic potential of the flavonoid Naringenin. Five-month-old B6.MRL-Faslpr/J lupus-prone mice were administered daily orally with Naringenin for seven months. We showed that Naringenin treatment at 50 or 100 mg/kg inhibited the splenomegaly and decreased the levels of anti-nuclear and anti-dsDNA autoantibodies. Furthermore, a reduction in serum concentration of TNF-α, IFN-γ and IL-6 was observed in the mice provided with Naringenin. Interestingly, serum levels of IL-10 increased. Naringenin decreased the frequency and absolute numbers of splenic effector memory T cells. Additionally, in order to be able to evaluate whether Naringenin prevented kidney damage, twelve-week-old MRL/MpJ-Faslpr/J mice, an accelerated lupus model, were orally administered with Naringenin at 100 mg/kg for six weeks. Surprisingly, Naringenin treatment prevented kidney damage and reduced the development of fibrosis similar to cyclophosphamide group. Moreover, Naringenin treatment increased the percentage of regulatory T cells in this aggressive model of lupus. Together, these results suggest a potential ability of Naringenin to reduce the autoimmunity in lupus-prone mice by modulation of T-cell subsets and cytokines profile that mitigate the development of important lupus clinical manifestations.

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<![CDATA[Influence of total western diet on docosahexaenoic acid suppression of silica-triggered lupus flaring in NZBWF1 mice]]> https://www.researchpad.co/article/elastic_article_14732 Lupus is a debilitating multi-organ autoimmune disease clinically typified by periods of flare and remission. Exposing lupus-prone female NZBWF1 mice to crystalline silica (cSiO2), a known human autoimmune trigger, mimics flaring by inducing interferon-related gene (IRG) expression, inflammation, ectopic lymphoid structure (ELS) development, and autoantibody production in the lung that collectively accelerate glomerulonephritis. cSiO2-triggered flaring in this model can be prevented by supplementing mouse diet with the ω-3 polyunsaturated fatty acid (PUFA) docosahexaenoic acid (DHA). A limitation of previous studies was the use of purified diet that, although optimized for rodent health, does not reflect the high American intake of saturated fatty acid (SFA), ω-6 PUFAs, and total fat. To address this, we employed here a modified Total Western Diet (mTWD) emulating the 50th percentile U.S. macronutrient distribution to discern how DHA supplementation and/or SFA and ω-6 reduction influences cSiO2-triggered lupus flaring in female NZBWF1 mice. Six-week-old mice were fed isocaloric experimental diets for 2 wks, intranasally instilled with cSiO2 or saline vehicle weekly for 4 wks, and tissues assessed for lupus endpoints 11 wks following cSiO2 instillation. In mice fed basal mTWD, cSiO2 induced robust IRG expression, proinflammatory cytokine and chemokine elevation, leukocyte infiltration, ELS neogenesis, and autoantibody production in the lung, as well as early kidney nephritis onset compared to vehicle-treated mice fed mTWD. Consumption of mTWD containing DHA at the caloric equivalent to a human dose of 5 g/day dramatically suppressed induction of all lupus-associated endpoints. While decreasing SFA and ω-6 in mTWD modestly inhibited some disease markers, DHA addition to this diet was required for maximal protection against lupus development. Taken together, DHA supplementation at a translationally relevant dose was highly effective in preventing cSiO2-triggered lupus flaring in NZBWF1 mice, even against the background of a typical Western diet.

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<![CDATA[Odiparcil, a potential glycosaminoglycans clearance therapy in mucopolysaccharidosis VI—Evidence from <i>in vitro</i> and <i>in vivo</i> models]]> https://www.researchpad.co/article/elastic_article_14726 Mucopolysaccharidoses are a class of lysosomal storage diseases, characterized by enzymatic deficiency in the degradation of specific glycosaminoglycans (GAG). Pathological accumulation of excess GAG leads to multiple clinical symptoms with systemic character, most severely affecting bones, muscles and connective tissues. Current therapies include periodic intravenous infusion of supplementary recombinant enzyme (Enzyme Replacement Therapy–ERT) or bone marrow transplantation. However, ERT has limited efficacy due to poor penetration in some organs and tissues. Here, we investigated the potential of the β-D-xyloside derivative odiparcil as an oral GAG clearance therapy for Maroteaux–Lamy syndrome (Mucopolysaccharidosis type VI, MPS VI). In vitro, in bovine aortic endothelial cells, odiparcil stimulated the secretion of sulphated GAG into culture media, mainly of chondroitin sulphate (CS) /dermatan sulphate (DS) type. Efficacy of odiparcil in reducing intracellular GAG content was investigated in skin fibroblasts from MPS VI patients where odiparcil was shown to reduce efficiently the accumulation of intracellular CS with an EC50 in the range of 1 μM. In vivo, in wild type rats, after oral administrations, odiparcil was well distributed, achieving μM concentrations in MPS VI disease-relevant tissues and organs (bone, cartilage, heart and cornea). In MPS VI Arylsulphatase B deficient mice (Arsb-), after chronic oral administration, odiparcil consistently stimulated the urinary excretion of sulphated GAG throughout the treatment period and significantly reduced tissue GAG accumulation in liver and kidney. Furthermore, odiparcil diminished the pathological cartilage thickening observed in trachea and femoral growth plates of MPS VI mice. The therapeutic efficacy of odiparcil was similar in models of early (treatment starting in juvenile, 4 weeks old mice) or established disease (treatment starting in adult, 3 months old mice). Our data demonstrate that odiparcil effectively diverts the synthesis of cellular glycosaminoglycans into secreted soluble species and this effect can be used for reducing cellular and tissue GAG accumulation in MPS VI models. Therefore, our data reveal the potential of odiparcil as an oral GAG clearance therapy for MPS VI patients.

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<![CDATA[Preliminary study: Health and performance assessment in broiler chicks following application of six different hatching egg disinfection protocols]]> https://www.researchpad.co/article/elastic_article_14617 As part of a Germany-wide project that evaluates strategies for the reduction of multi-resistant bacteria along the poultry production chain, the impact of different hatching egg disinfectants on hatchability and health of the broiler chicks was evaluated. Animal trials were conducted with extended-spectrum beta-lactamase- (ESBL) producing Escherichia (E.) coli contaminated hatching eggs and six disinfection protocols that used formaldehyde, hydrogen peroxide, low-energy electron irradiation, peracetic acid and an essential oil preparation. Each protocol was tested on a group of 50 chicks. Equally sized positive and negative control groups were carried along for each trial. Hatchability, mortality and body weight were recorded as performance parameters. During necropsy of half of the animals in each group on day 7 and 14 respectively, macroscopic abnormalities, body weight, weights of liver and gut convolute were recorded and a range of tissue samples for histological examination were collected as part of the health assessment. A decrease in hatchability was recorded for spray application of essential oils. Body weight development was overall comparable, in several groups even superior, to the Ross308 performance objectives, but a reduced performance was seen in the hydrogen peroxide group. Histologically, lymphoid follicles were regularly seen in all sampled organs and no consistent differences were observed between contaminated and non-contaminated groups. Significances were infrequently and inconsistently seen. In conclusion, remarkable findings were a decrease in hatchability caused by the essential oils spray application and a reduced body weight development in the hydrogen peroxide group. Therefore, the essential oils preparation as spray application was deemed inappropriate in practice, while the application of hydrogen peroxide was considered in need of further research. The other trial results indicate that the tested hatching egg disinfectants present a possible alternative to formaldehyde.

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<![CDATA[Long-term outcomes after extracorporeal membrane oxygenation in patients with dialysis-requiring acute kidney injury: A cohort study]]> https://www.researchpad.co/article/5c92b361d5eed0c4843a3f31

Background

Acute kidney injury (AKI) is a common complication of extracorporeal membrane oxygenation (ECMO) treatment. The aim of this study was to elucidate the long-term outcomes of adult patients with AKI who receive ECMO.

Materials and methods

The study analyzed encrypted datasets from Taiwan’s National Health Insurance Research Database. The data of 3251 patients who received first-time ECMO treatment between January 1, 2003, and December 31, 2013, were analyzed. Characteristics and outcomes were compared between patients who required dialysis for AKI (D-AKI) and those who did not in order to evaluate the impact of D-AKI on long-term mortality and major adverse kidney events.

Results

Of the 3251 patients, 54.1% had D-AKI. Compared with the patients without D-AKI, those with D-AKI had higher rates of all-cause mortality (52.3% vs. 33.3%; adjusted hazard ratio [aHR] 1.82, 95% confidence interval [CI] 1.53–2.17), chronic kidney disease (13.7% vs. 8.1%; adjusted subdistribution HR [aSHR] 1.66, 95% CI 1.16–2.38), and end-stage renal disease (5.2% vs. 0.5%; aSHR 14.28, 95% CI 4.67–43.62). The long-term mortality of patients who survived more than 90 days after discharge was 22.0% (153/695), 32.3% (91/282), and 50.0% (10/20) in the patients without D-AKI, with recovery D-AKI, and with nonrecovery D-AKI who required long-term dialysis, respectively, demonstrating a significant trend (Pfor trend <0.001).

Conclusion

AKI is associated with an increased risk of long-term mortality and major adverse kidney events in adult patients who receive ECMO.

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<![CDATA[The natural drug DIAVIT is protective in a type II mouse model of diabetic nephropathy]]> https://www.researchpad.co/article/5c92b34ad5eed0c4843a3d15

There is evidence to suggest that abnormal angiogenesis, inflammation, and fibrosis drive diabetic nephropathy (DN). However, there is no specific treatment to counteract these processes. We aimed to determine whether DIAVIT, a natural Vaccinium myrtillus (blueberry) and Hippophae Rhamnoides (sea buckthorn) extract, is protective in a model of type II DN. Diabetic db/db mice were administered DIAVIT in their drinking water for 14 weeks. We assessed the functional, structural, and ultra-structural phenotype of three experimental groups (lean+vehicle, db/db+vehicle, db/db+DIAVIT). We also investigated the angiogenic and fibrotic pathways involved in the mechanism of action of DIAVIT. Diabetic db/db mice developed hyperglycaemia, albuminuria, and an increased glomerular water permeability; the latter two were prevented by DIAVIT. db/db mice developed fibrotic glomeruli, endothelial insult, and glomerular ultra-structural changes, which were not present in DIAVIT-treated mice. Vascular endothelial growth factor A (VEGF-A) splicing was altered in the db/db kidney cortex, increasing the pro-angiogenic VEGF-A165 relative to the anti-angiogenic VEGF-A165b. This was partially prevented with DIAVIT treatment. Delphinidin, an anthocyanin abundant in DIAVIT, increased the VEGF-A165b expression relative to total VEGF-A165 in cultured podocytes through phosphorylation of the splice factor SRSF6. DIAVIT, in particular delphinidin, alters VEGF-A splicing in type II DN, rescuing the DN phenotype. This study highlights the therapeutic potential of natural drugs in DN through the manipulation of gene splicing and expression.

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<![CDATA[Role of intraoperative oliguria in risk stratification for postoperative acute kidney injury in patients undergoing colorectal surgery with an enhanced recovery protocol: A propensity score matching analysis]]> https://www.researchpad.co/article/N90678846-11a4-456d-84dc-7e3677d2f27e

Background

The enhanced recovery after surgery (ERAS) protocol for colorectal cancer resection recommends balanced perioperative fluid therapy. According to recent guidelines, zero-balance fluid therapy is recommended in low-risk patients, and immediate correction of low urine output during surgery is discouraged. However, several reports have indicated an association of intraoperative oliguria with postoperative acute kidney injury (AKI). We investigated the impact of intraoperative oliguria in the colorectal ERAS setting on the incidence of postoperative AKI.

Patients and methods

From January 2017 to August 2019, a total of 453 patients underwent laparoscopic colorectal cancer resection with the ERAS protocol. Among them, 125 patients met the criteria for oliguria and were propensity score (PS) matched to 328 patients without intraoperative oliguria. After PS matching had been performed, 125 patients from each group were selected and the incidences of AKI were compared between the two groups. Postoperative kidney function and surgical outcomes were also evaluated.

Results

The incidence of AKI was significantly higher in the intraoperative oliguria group than in the non-intraoperative oliguria group (26.4% vs. 11.2%, respectively, P = 0.002). Also, the eGFR reduction on postoperative day 0 was significantly greater in the intraoperative oliguria than non-intraoperative oliguria group (−9.02 vs. −1.24 mL/min/1.73 m2 respectively, P < 0.001). In addition, the surgical complication rate was higher in the intraoperative oliguria group than in the non-intraoperative oliguria group (18.4% vs. 9.6%, respectively, P = 0.045).

Conclusions

Despite the proven benefits of perioperative care with the ERAS protocol, caution is required in patients with intraoperative oliguria to prevent postoperative AKI. Further studies regarding appropriate management of intraoperative oliguria in association with long-term prognosis are needed in the colorectal ERAS setting.

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<![CDATA[Drug induced pancreatitis: A systematic review of case reports to determine potential drug associations]]> https://www.researchpad.co/article/N8c4889da-2d62-467b-8b66-b271dff2cf8d

Objective

A current assessment of case reports of possible drug-induced pancreatitis is needed. We systematically reviewed the case report literature to identify drugs with potential associations with acute pancreatitis and the burden of evidence supporting these associations.

Methods

A protocol was developed a priori (PROSPERO CRD42017060473). We searched MEDLINE, Embase, the Cochrane Library, and additional sources to identify cases of drug-induced pancreatitis that met accepted diagnostic criteria of acute pancreatitis. Cases caused by multiple drugs or combination therapy were excluded. Established systematic review methods were used for screening and data extraction. A classification system for associated drugs was developed a priori based upon the number of cases, re-challenge, exclusion of non-drug causes of acute pancreatitis, and consistency of latency.

Results

Seven-hundred and thirteen cases of potential drug-induced pancreatitis were identified, implicating 213 unique drugs. The evidence base was poor: exclusion of non-drug causes of acute pancreatitis was incomplete or poorly reported in all cases, 47% had at least one underlying condition predisposing to acute pancreatitis, and causality assessment was not conducted in 81%. Forty-five drugs (21%) were classified as having the highest level of evidence regarding their association with acute pancreatitis; causality was deemed to be probable or definite for 19 of these drugs (42%). Fifty-seven drugs (27%) had the lowest level of evidence regarding an association with acute pancreatitis, being implicated in single case reports, without exclusion of other causes of acute pancreatitis.

Discussion

Much of the case report evidence upon which drug-induced pancreatitis associations are based is tenuous. A greater emphasis on exclusion of all non-drug causes of acute pancreatitis and on quality reporting would improve the evidence base. It should be recognized that reviews of case reports, are valuable scoping tools but have limited strength to establish drug-induced pancreatitis associations.

Registration

CRD42017060473.

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<![CDATA[Severe hyperbilirubinemia is associated with higher risk of contrast-related acute kidney injury following contrast-enhanced computed tomography]]> https://www.researchpad.co/article/N624c57d4-8983-4ece-aecc-e0e7860066cf

Introduction

Contrast-induced acute kidney injury (CI-AKI) is associated with high risks of morbidity and mortality. Hyperbilirubinemia might have some renal protection but with no clear cutoff value for protection. Related studies are typically on limited numbers of patients and only in conditions of vascular intervention.

Methods

We performed this study to elucidate CI-AKI in patients after contrast-enhanced computed tomography (CCT). The outcomes were CI-AKI, dialysis and mortality. Patients were divided to three groups based on their serum levels of total bilirubin: ≤1.2 mg/dl, 1.3–2.0 mg/dl, and >2.0 mg/dl.

Results

We enrolled a total of 9,496 patients who had received CCT. Patients with serum total bilirubin >2.0 mg/dl were associated with CI-AKI. Those undergoing dialysis had the highest incidence of PC-AKI (p<0.001). No difference was found between the two groups of total bilirubin ≤1.2 and 1.3–2.0 mg/dl. Patients with total bilirubin >2mg/dl were associated with CI-AKI (OR = 1.89, 1.53–2.33 of 95% CI), dialysis (OR = 1.40, 1.01–1.95 of 95% CI) and mortality (OR = 1.63, 1.38–1.93 of 95% CI) after adjusting for laboratory data and all comorbidities (i.e., cerebrovascular disease, coronary artery disease, peripheral arterial disease, and acute myocardial infarction, diabetes mellitus, hypertension, gastrointestinal bleeding, cirrhosis, peritonitis, ascites, hepatoma, shock lung and colon cancer). We concluded that total bilirubin level >2 mg/dl is an independent risk factor for CI-AKI, dialysis and mortality after CCT. These patients also had high risks for cirrhosis or hepatoma.

Conclusion

This is the first study providing evidence that hyperbilirubinemia (total bilirubin >2.0 mg/dl) being an independent risk factor for CI-AKI, dialysis and mortality after receiving CCT. Most patients with total bilirubin >2.0mg/dl had cirrhosis or hepatoma.

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<![CDATA[The SARS-CoV-2 receptor ACE2 expression of maternal-fetal interface and fetal organs by single-cell transcriptome study]]> https://www.researchpad.co/article/N6fc22072-15f3-4c64-b34f-34474f5cf931

The new type of pneumonia caused by the SARS-CoV-2 (Severe acute respiratory syndrome coronavirus 2) has been declared as a global public health concern by WHO. As of April 3, 2020, more than 1,000,000 human infections have been diagnosed around the world, which exhibited apparent person-to-person transmission characteristics of this virus. The capacity of vertical transmission in SARS-CoV-2 remains controversial recently. Angiotensin-converting enzyme 2 (ACE2) is now confirmed as the receptor of SARS-CoV-2 and plays essential roles in human infection and transmission. In present study, we collected the online available single-cell RNA sequencing (scRNA-seq) data to evaluate the cell specific expression of ACE2 in maternal-fetal interface as well as in multiple fetal organs. Our results revealed that ACE2 was highly expressed in maternal-fetal interface cells including stromal cells and perivascular cells of decidua, and cytotrophoblast and syncytiotrophoblast in placenta. Meanwhile, ACE2 was also expressed in specific cell types of human fetal heart, liver and lung, but not in kidney. And in a study containing series fetal and post-natal mouse lung, we observed ACE2 was dynamically changed over the time, and ACE2 was extremely high in neonatal mice at post-natal day 1~3. In summary, this study revealed that the SARS-CoV-2 receptor was widely spread in specific cell types of maternal-fetal interface and fetal organs. And thus, both the vertical transmission and the placenta dysfunction/abortion caused by SARS-CoV-2 need to be further carefully investigated in clinical practice.

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<![CDATA[Optimization of tissue sampling for Borrelia burgdorferi in white-footed mice (Peromyscus leucopus)]]> https://www.researchpad.co/article/Nff220985-8630-4822-8507-6b577103a931

Peromyscus leucopus (the white-footed mouse) is a known reservoir of the Lyme disease spirochete Borrelia burgdorferi. Sampling of white-footed mice allows for year-round B. burgdorferi surveillance as well as opportunities to establish the diversity of the different variants in a geographic region. This study explores the prevalence of B. burgdorferi infections in the tissues of white-footed mice, investigates the correlations between B. burgdorferi infected tissues, and determines the optimum field methods for surveillance of B. burgdorferi in P. leucopus. A total of 90 mice and 573 tissues (spleen, liver, ear, tongue, tail, heart, and kidney) were screened via nested PCR for B. burgdorferi infections. A large number of infections were found in the 90 mice as well as multiple infections within individual mice. Infections in a single mouse tissue (spleen, liver, ear, tongue and tail) were predictive of concurrent infection in other tissues of the same mouse at a statistically significant level. Ear tissue accounted for 68.4% of detected infections, which increased to 78.9% of the infected mice with the inclusion of tail samples. The use of ear punch or tail snip samples (used individually or in tandem) have multiple advantages over current Lyme disease ecological studies and surveillance methodologies, including lower associated costs, minimization of delays, year-round B. burgdorferi testing opportunities, as well as longitudinal monitoring of B. burgdorferi in defined geographic regions. In the absence of an effective vaccine, personal prevention measures are currently the most effective way to reduce Lyme disease transmission to humans. Thus, the identification and monitoring of environmental reservoirs to inform at-risk populations remains a priority. The sampling methods proposed in this study provide a reasonable estimate of B. burgdorferi in white-footed mice in a timely and cost-effective manner.

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<![CDATA[Acute kidney injury and adverse renal events in patients receiving SGLT2-inhibitors: A systematic review and meta-analysis]]> https://www.researchpad.co/article/N25fa93a0-706a-4469-9476-c6f8ced4ff6a

Background

Sodium-glucose cotransporter-2 inhibitors (SGLT2is) represent a new class of oral hypoglycemic agents used in the treatment of type 2 diabetes mellitus. They have a positive effect on the progression of chronic kidney disease, but there is a concern that they might cause acute kidney injury (AKI).

Methods and findings

We conducted a systematic review and meta-analysis of the effect of SGLT2is on renal adverse events (AEs) in randomized controlled trials and controlled observational studies. PubMed, EMBASE, Cochrane library, and ClinicalTrials.gov were searched without date restriction until 27 September 2019. Data extraction was performed using a standardized data form, and any discrepancies were resolved by consensus. One hundred and twelve randomized trials (n = 96,722) and 4 observational studies with 5 cohorts (n = 83,934) with a minimum follow-up of 12 weeks that provided information on at least 1 adverse renal outcome (AKI, combined renal AE, or hypovolemia-related events) were included. In 30 trials, 410 serious AEs due to AKI were reported. SGLT2is reduced the odds of suffering AKI by 36% (odds ratio [OR] 0.64 [95% confidence interval (CI) 0.53–0.78], p < 0.001). A total of 1,089 AKI events of any severity (AEs and serious AEs [SAEs]) were published in 41 trials (OR 0.75 [95% CI 0.66–0.84], p < 0.001). Empagliflozin, dapagliflozin, and canagliflozin had a comparable benefit on the SAE and AE rate. AEs related to hypovolemia were more commonly reported in SGLT2i-treated patients (OR 1.20 [95% CI 1.10–1.31], p < 0.001). In the observational studies, 777 AKI events were reported. The odds of suffering AKI were reduced in patients receiving SGLT2is (OR 0.40 [95% CI 0.33–0.48], p < 0.001). Limitations of this study are the reliance on nonadjudicated safety endpoints, discrepant inclusion criteria and baseline hypoglycemic therapy between studies, inconsistent definitions of renal AEs and hypovolemia, varying follow-up times in different studies, and a lack of information on the severity of AKI (stages I–III).

Conclusions

SGLT2is reduced the odds of suffering AKI with and without hospitalization in randomized trials and the real-world setting, despite the fact that more AEs related to hypovolemia are reported.

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<![CDATA[Exploit fully automatic low-level segmented PET data for training high-level deep learning algorithms for the corresponding CT data]]> https://www.researchpad.co/article/5c8823d0d5eed0c484639091

We present an approach for fully automatic urinary bladder segmentation in CT images with artificial neural networks in this study. Automatic medical image analysis has become an invaluable tool in the different treatment stages of diseases. Especially medical image segmentation plays a vital role, since segmentation is often the initial step in an image analysis pipeline. Since deep neural networks have made a large impact on the field of image processing in the past years, we use two different deep learning architectures to segment the urinary bladder. Both of these architectures are based on pre-trained classification networks that are adapted to perform semantic segmentation. Since deep neural networks require a large amount of training data, specifically images and corresponding ground truth labels, we furthermore propose a method to generate such a suitable training data set from Positron Emission Tomography/Computed Tomography image data. This is done by applying thresholding to the Positron Emission Tomography data for obtaining a ground truth and by utilizing data augmentation to enlarge the dataset. In this study, we discuss the influence of data augmentation on the segmentation results, and compare and evaluate the proposed architectures in terms of qualitative and quantitative segmentation performance. The results presented in this study allow concluding that deep neural networks can be considered a promising approach to segment the urinary bladder in CT images.

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<![CDATA[Hyperkalemia and renin-angiotensin aldosterone system inhibitor therapy in chronic kidney disease: A general practice-based, observational study]]> https://www.researchpad.co/article/5c8acc87d5eed0c48498f966

Data on hyperkalemia frequency among chronic kidney disease (CKD) patients receiving renin-angiotensin aldosterone system inhibitors (RAASis) and its impact on subsequent RAASi treatment are limited. This population-based cohort study sought to assess the incidence of clinically significant hyperkalemia among adult CKD patients who were prescribed a RAASi and the proportion of patients with RAASi medication change after experiencing incident hyperkalemia. We conducted a retrospective, population-based cohort study (1 January 2013–30 June 2017) using Australian national general practice data from the NPS MedicineWise’s MedicineInsight program. The study included adults aged ≥18 years who received ≥1 RAASi prescription during the study period and had CKD (estimated glomerular filtration rate [eGFR] <60 ml/min/1.73m2). Study outcomes included incident clinically significant hyperkalemia (serum potassium >6 mmol/L or a record of hyperkalemia diagnosis) and among patients who experienced incident hyperkalemia, the proportion who had RAASi medication changes (cessation or dose reduction during the 210-day period after the incident hyperkalemia event). Among 20,184 CKD patients with a median follow-up of 3.9 years, 1,992 (9.9%) patients experienced an episode of hyperkalemia. The overall incidence rate was 3.1 (95% CI: 2.9–3.2) per 100 person-years. Rates progressively increased with worsening eGFR (e.g. 3.5-fold increase in patients with eGFR <15 vs. 45–59 ml/min/1.73m2). Among patients who experienced incident hyperkalemia, 46.6% had changes made to their RAASi treatment regimen following the first occurrence of hyperkalemia (discontinuation: 36.6% and dose reduction: 10.0%). In this analysis of adult RAASi users with CKD, hyperkalemia and subsequent RAASi treatment changes were common. Further assessment of strategies for hyperkalemia management and optimal RAASi use among people with CKD are warranted.

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<![CDATA[Renal injury after uninephrectomy in male and female intrauterine growth-restricted aged rats]]> https://www.researchpad.co/article/5c8acce7d5eed0c48499029e

Epidemiological studies report an inverse association between birth weight and risk for kidney disease that may differ between males and females, but studies investigating this association are limited. This study tested the hypothesis that male intrauterine growth-restricted offspring in a model of low birth weight induced by placental insufficiency in the rat exhibit enhanced renal injury in response to a persistent secondary renal insult while female growth-restricted offspring are protected. For this study, control offspring from sham-operated dams and growth-restricted offspring from reduced uterine perfusion dams underwent uninephrectomy or a sham procedure at 18 months of age. One month later, urinary markers of renal injury, renal function, and histological damage were measured. Results were analyzed using 2-way ANOVA. Male and female offspring were assessed separately. Proteinuria and urinary neutrophil gelatinase-associated lipocalin were significantly elevated in male growth-restricted offspring exposed to uninephrectomy when compared to male uninephrectomized control. Urinary kidney injury marker-1 was elevated in male uninephrectomized growth-restricted offspring relative to male sham growth-restricted but not to male uninephrectomized controls. Likewise, urinary neutrophil gelatinase-associated lipocalin was elevated in female uninephrectomized growth-restricted offspring but only when compared to female sham growth-restricted offspring. Markers of renal function including glomerular filtration rate and serum creatinine were impaired after uninephrectomy in female offspring regardless of birth weight. Histological parameters did not differ between control and growth-restricted offspring. Collectively, these studies suggest that both male and female growth-restricted offspring demonstrate susceptibility to renal injury following uninephrectomy; however, only male growth-restricted offspring exhibited an increase in renal markers of injury in response to uninephrectomy relative to same-sex control counterparts. These findings further suggest that urinary excretion of protein, kidney injury marker-1, and neutrophil gelatinase-associated lipocalin may be early markers of kidney injury in growth-restricted offspring exposed to a secondary renal insult such as reduction in renal mass.

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<![CDATA[Single-cell transcriptomics reveals gene expression dynamics of human fetal kidney development]]> https://www.researchpad.co/article/5c784fb4d5eed0c4840073c4

The current understanding of mammalian kidney development is largely based on mouse models. Recent landmark studies revealed pervasive differences in renal embryogenesis between mouse and human. The scarcity of detailed gene expression data in humans therefore hampers a thorough understanding of human kidney development and the possible developmental origin of kidney diseases. In this paper, we present a single-cell transcriptomics study of the human fetal kidney. We identified 22 cell types and a host of marker genes. Comparison of samples from different developmental ages revealed continuous gene expression changes in podocytes. To demonstrate the usefulness of our data set, we explored the heterogeneity of the nephrogenic niche, localized podocyte precursors, and confirmed disease-associated marker genes. With close to 18,000 renal cells from five different developmental ages, this study provides a rich resource for the elucidation of human kidney development, easily accessible through an interactive web application.

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<![CDATA[A computational model of epithelial solute and water transport along a human nephron]]> https://www.researchpad.co/article/5c7d95f0d5eed0c484734ff2

We have developed the first computational model of solute and water transport from Bowman space to the papillary tip of the nephron of a human kidney. The nephron is represented as a tubule lined by a layer of epithelial cells, with apical and basolateral transporters that vary according to cell type. The model is formulated for steady state, and consists of a large system of coupled ordinary differential equations and algebraic equations. Model solution describes luminal fluid flow, hydrostatic pressure, luminal fluid solute concentrations, cytosolic solute concentrations, epithelial membrane potential, and transcellular and paracellular fluxes. We found that if we assume that the transporter density and permeabilities are taken to be the same between the human and rat nephrons (with the exception of a glucose transporter along the proximal tubule and the H+-pump along the collecting duct), the model yields segmental deliveries and urinary excretion of volume and key solutes that are consistent with human data. The model predicted that the human nephron exhibits glomerulotubular balance, such that proximal tubular Na+ reabsorption varies proportionally to the single-nephron glomerular filtration rate. To simulate the action of a novel diabetic treatment, we inhibited the Na+-glucose cotransporter 2 (SGLT2) along the proximal convoluted tubule. Simulation results predicted that the segment’s Na+ reabsorption decreased significantly, resulting in natriuresis and osmotic diuresis.

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<![CDATA[Real-time adaptive planning method for radiotherapy treatment delivery for prostate cancer patients, based on a library of plans accounting for possible anatomy configuration changes]]> https://www.researchpad.co/article/5c818e8ad5eed0c484cc24c8

Background and purpose

In prostate cancer treatment with external beam radiation therapy (EBRT), prostate motion and internal changes in tissue distribution can lead to a decrease in plan quality. In most currently used planning methods, the uncertainties due to prostate motion are compensated by irradiating a larger treatment volume. However, this could cause underdosage of the treatment volume and overdosage of the organs at risk (OARs). To reduce this problem, in this proof of principle study we developed and evaluated a novel adaptive planning method. The strategy proposed corrects the dose delivered by each beam according to the actual position of the target in order to produce a final dose distribution dosimetrically as similar as possible to the prescribed one.

Material and methods

Our adaptive planning method was tested on a phantom case and on a clinical case. For the first, a pilot study was performed on an in-silico pelvic phantom. A “library” of intensity modulated RT (IMRT) plans corresponding to possible positions of the prostate during a treatment fraction was generated at planning stage. Then a 3D random walk model was used to simulate possible displacements of the prostate during the treatment fraction. At treatment stage, at the end of each beam, based on the current position of the target, the beam from the library of plans, which could reproduce the best approximation of the prescribed dose distribution, was selected and delivered. In the clinical case, the same approach was used on two prostate cancer patients: for the first a tissue deformation was simulated in-silico and for the second a cone beam CT (CBCT) taken during the treatment was used to simulate an intra-fraction change. Then, dosimetric comparisons with the standard treatment plan and, for the second patient, also with an isocenter shift correction, were performed.

Results

For the phantom case, the plan generated using the adaptive planning method was able to meet all the dosimetric requirements and to correct for a misdosage of 13% of the dose prescription on the prostate. For the first clinical case, the standard planning method caused underdosage of the seminal vesicles, respectively by 5% and 4% of the prescribed dose, when the position changes for the target were correctly taken into account. The proposed adaptive planning method corrected any possible missed target coverage, reducing at the same time the dose on the OARs. For the second clinical case, both with the standard planning strategy and with the isocenter shift correction target coverage was significantly worsened (in particular uniformity) and some organs exceeded some toxicity objectives. While with our approach, the most uniform coverage for the target was produced and systematically the lowest toxicity values for the organs at risk were achieved.

Conclusions

In our proof of principle study, the adaptive planning method performed better than the standard planning and the isocenter shift methods for prostate EBRT. It improved the coverage of the treatment volumes and lowered the dose to the OARs. This planning method is particularly promising for hypofractionated IMRT treatments in which a higher precision and control on dose deposition are needed. Further studies will be performed to test more extensively the proposed adaptive planning method and to evaluate it at a full clinical level.

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<![CDATA[Serum amyloid A and Janus kinase 2 in a mouse model of diabetic kidney disease]]> https://www.researchpad.co/article/5c6f149fd5eed0c48467a449

Background

Serum amyloid A (SAA), a potent inflammatory mediator, and Janus kinase 2 (JAK2), an intracellular signaling kinase, are increased by diabetes. The aims were to elucidate: 1) a JAK2-mediated pathway for increased SAA in the kidneys of diabetic mice; 2) a JAK2-SAA pathway for inflammation in podocytes.

Methods

Akita diabetic mice (129S6) with podocyte JAK2 overexpression and angiotensin II infusion (4 weeks) were given a JAK1,2 inhibitor (LY03103801, 3 mg/kg/day orally for the last two weeks). Kidneys were immunostained for SAA isoform 3 (SAA3). SAA3 knockout and control mouse podocytes were exposed to advanced glycation end products (AGE) or exogenous SAA with JAK2 inhibition (Tyrphostin AG 490, 50μM). JAK2 activity (phosphorylation, Western blot, 1 hour) and mRNA for SAA3 and associated inflammatory genes (Cxcl5, Ccl2, and Ccl5) were measured by RT-PCR (20 hours).

Results

SAA3 protein was present throughout the diabetic kidney, and podocyte JAK2 overexpression increased tubulointerstitial SAA3 compared to wild type diabetic controls, 43% versus 14% (p = 0.007); JAK1,2 inhibition attenuated the increase in SAA3 to 15% (p = 0.003). Urine albumin-to-creatinine ratio (r = 0.49, p = 0.03), mesangial index (r = 0.64, p = 0.001), and glomerulosclerosis score (r = 0.51, p = 0.02) were associated with SAA3 immunostaining scores across mouse groups. Exposing podocytes to AGE or exogenous SAA increased JAK2 activity within one hour and mRNA for associated inflammatory genes after 20 hours. JAK2 inhibition reduced SAA3 mRNA expression in podocytes exposed to AGE or SAA. SAA3 knockout podocytes had >85% lower AGE-induced inflammatory genes.

Conclusion

JAK1,2 inhibition reduced SAA and histological features of DKD in podocyte JAK2-overexpressing mice. In podocytes exposed to a diabetes-like condition, JAK2 inhibition reduced expression of SAA, while SAA knockout blocked expression of associated pro-inflammatory mediators. SAA may promote JAK2-dependent inflammation in the diabetic kidney.

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<![CDATA[Sexual dimorphism of acute doxorubicin-induced nephrotoxicity in C57Bl/6 mice]]> https://www.researchpad.co/article/5c76fe23d5eed0c484e5b5ad

Doxorubicin (DOX) is a chemotherapeutic agent that has been reported to cause nephrotoxicity in rodent models and to a lesser degree in cancer patients. Female rodents have been shown to be protected against several features of DOX-induced nephrotoxicity. Nevertheless, the underlying mechanisms of this sexual dimorphism are not fully elucidated. Therefore, in the current study, we investigated the sex and time-dependent changes in pathological lesions as well as apoptotic and fibrotic markers in response to acute DOX-induced nephrotoxicity. We also determined the effect of acute DOX treatment on the renal expression of the sexually dimorphic enzyme, soluble epoxide hydrolase (sEH), since inhibition of sEH has been shown to protect against DOX-induced nephrotoxicity. Acute DOX-induced nephrotoxicity was induced by a single intra-peritoneal injection of 20 mg/kg DOX to male and female adult C57Bl/6 mice. The kidneys were isolated 1, 3 and 6 days after DOX administration. Histopathology assessment, gene expression of the apoptotic marker, BAX, protein expression of the fibrotic marker, transforming growth factor-β (TGF-β), and gene and protein expression of sEH were assessed. DOX administration caused more severe pathological lesions as well as higher induction of the apoptotic and fibrotic markers in kidneys of male than in female mice. Intriguingly, DOX inhibited sEH protein expression in kidneys of male mice sacrificed at 3 and 6 days following administration, suggesting that induction of sEH is not necessary for acute DOX-induced nephrotoxicity. However, DOX-induced inhibition of renal sEH in male mice may protect the kidney from further DOX-induced injury in a negative feedback mechanism. We also observed lower constitutive expressions of TGF-β and sEH in the kidney of female mice which may contribute, at least in part, to sexual dimorphism of DOX-induced nephrotoxicity.

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