bluuebunny/crossref_metadata_2025_split huggingface dataset:
P0143OPPOSING EFFECTS OF P38 MAPK IN PODOCYTES ON ALDOSTERONE-INDUCED GLOMERULAR INJURY IN POD-GC-A CKO MICE
Authors: SUGIOKA SAYAKA , Kato Yukiko , Ishii Akira , Mori Keita , Osaki Keisuke , Tokudome Takeshi , Matsusaka Taiji , Yanagita Motoko , Yokoi Hideki 
Published: June 2020

Abstract

Background and Aims
Previously, we demonstrated that uninephrectomized aldosterone-infused, high salt-fed podocyte-specific guanylyl cyclase-A (natriuretic peptide receptor 1) conditional KO (pod-GC-A cKO) mice exhibited glomerular injury and that pharmacological inhibition of p38 MAPK ameliorates podocyte damage. However, the effects of genetic deletion of p38 MAPK in podocytes of pod-GC-A cKO mice have been unclarified.

Method
We generated p38 MAPK(fl/fl);Nephrin-Cre (pod-p38 MAPK cKO) mice and p38 MAPK(fl/fl);GC-A(fl/fl);Nephrin-Cre (pod-p38MAPK/GC-A DKO) mice. For induction of glomerular injury, we treated them with aldosterone and high salt at 2 months of age for 3 weeks without nephrectomy (B-ALDO). In vitro, we examined the effect of p38 MAPK inhibitor in cultured human podocytes transfected with GC-A siRNA.

Results
B-ALDO-treated pod-p38 MAPK/GC-A DKO mice resulted in significant elevation of serum Cr (0.29 ± 0.04 mg/dl), massive albuminuria (42,660 ± 20,200 μg/mgCr) and severe foot process effacement in addition to intracapillary fibrin thrombi which indicated endothelial damage. Vehicle-treated DKO mice, B-ALDO-treated pod-GC-A cKO mice, and B-ALDO-treated pod-p38 MAPK cKO showed normal serum Cr levels (0.14 ± 0.01, 0.18 ± 0.02, 0.20 ± 0.01 mg/dl, respectively), mild increase of albuminuria (223 ± 6.5, 1,496 ± 592, 649 ± 303 μg/mgCr, respectively) and only segmental foot process effacement. Blood pressure was not elevated in either mutant mice compared with that of B-ALDO control mice. Furthermore, glomerular mRNA expressions of MCP-1, PAI-1, and FN were upregulated and that of VEGF-A was downregulated in DKO mice. In vitro, suppression of GC-A mRNA by siRNA in combination with p38 MAPK inhibitor downregulated VEGF mRNA in human cultured podocytes. Our previous works showed that pharmacological inhibition of p38 MAPK in the whole body ameliorated podocyte damage, whereas our current result showed that genetic deletion of p38 MAPK in podocytes aggravated renal injury. In order to explain the discrepancy in these results, we added an analysis of podocyte specific GC-A fl/fl p38 fl/+ cKO mice. Pod GC-A fl/fl p38 fl/+ cKO mice exhibited considerably milder renal damage than pod GC-A fl/fl p38 fl/fl double cKO mice.

Conclusion
Genetic complete p38 MAPK deletion in GC-A-nul podocytes exacerbated aldosterone-induced glomerular endothelial cell injury as well as podocytes, and resulted in renal dysfunction, probably through VEGF downregulation, whereas partial p38 MAPK inhibition in podocytes ameliorated aldosterone-induced glomerular injury in pod-GC-A cKO mice. These results suggest a certain level of p38 MAPK in podocytes is necessary to protect endothelial and epithelial cells from aldosterone-induced renal injury.
P0144LOW-ENERGY SHOCKWAVE TREATMENT PROMOTES ENDOTHELIAL PROGENITOR CELL HOMING TO THE STENOTIC PIG KIDNEY
Authors: Zhao Yu , Zhang Xiao liang , Liu Bicheng , Lerman Lilach 
Published: June 2020

Abstract

Background and Aims
Endothelial progenitor cells (EPCs) patrol the circulation and contribute to endothelial cell regeneration and tissue revascularization. Atherosclerotic renal artery stenosis (ARAS) induces microvascular loss in the stenotic kidney. A regimen of low–energy shockwave therapy (SW) induces angiogenesis and reduces chronic ischemia, but the mechanism remains unclear. This study tested the hypothesis that SW increases EPCs homing to the stenotic kidney and increases renal capillary regeneration in a unilateral ARAS swine model.

Method
Domestic pigs were randomized to normal control or unilateral ARAS (induced by a local irritant coil in the renal artery and a high-fat diet). ARAS pigs were treated with low-energy SW (0.1 mJ/mm2) or sham (n=6 each group), bi-weekly for 3 consecutive weeks, starting after 3 weeks of ARAS. Blood samples for EPCs (CD34+ and KDR+ by flow cytometry) and the homing factor SDF-1 were collected 4 weeks after completion of SW treatment from the inferior vena cava (IVC) and the stenotic kidney (STK) vein and artery. Urine was collected from the urinary bladder. Kidneys were studied ex vivo for morphology and expression of an endothelial cell marker (CD31) and the pro- angiogenic growth factor angiopoietin (Ang)-1.

Results
In ARAS, tubulointerstitial fibrosis, tubular score, urinary protein, serum creatinine and mean arterial pressure were significantly increased and capillary count (Fig. 1A) decreased (P&lt;0.05 vs. control), but all markedly improved in ARAS+SW (P&lt;0.05 vs. ARAS). EPC number was decreased in the IVC and renal artery of ARAS pigs (Fig. 1B), but improved in ARAS+SW. SDF-1 levels in the IVC, STK vein and artery, and Ang-1 expression in the kidney of ARAS+SW, were all increased (P&lt;0.05 vs. ARAS).

Conclusion
Low-energy shockwave improves ischemic kidney capillary density, which is associated with and may be at least in part mediated by promoting EPC mobilization and homing to the stenotic kidney.
P0145MESENCHYMAL STEM CELLS PROTECT RENAL TUBULAR CELLS VIA TSG-6 REGULATED MACROPHAGE FUNCTION AND PHENOTYPE SWITCHING
Authors: Zhao Yu , Zhang Xiao liang , Liu Bicheng , Lerman Lilach 
Published: June 2020

Abstract

Background and Aims
Tumor necrosis factor-α-induced gene/protein (TSG)-6 is a key factor influencing mesenchymal stem cells (MSCs) immunomodulatory properties, but its renoprotective efficacy is unknown. Using a novel swine model of renal artery stenosis (RAS) complicated by metabolic syndrome (Mets), we assessed the therapeutic effects of adipose tissue-derived MSCs-produced TSG-6 and mechanisms underlying the immunomodulatory properties of MSCs.

Method
Five groups of pigs (n=6 each) were studied after 16 weeks of diet-induced Mets and unilateral RAS (Mets+RAS), either untreated or treated 4 weeks earlier with a single intra-renal delivery of autologous posrcine adipose tissue-derived MSCs (pMSC). Lean, Mets, and RAS shams served as controls. We studied renal function in vivo (using CT imaging) and kidney histopathology and macrophage phenotype ex vivo. In vitro, TSG-6 levels were measured in conditioned media of human MSCs (hMSCs) incubated with or without TNF-α. Additionally, levels of the tubular injury marker LDH were measured in conditioned media after co-culturing macrophages with injured HK-2 cells (achieved by TNF-α and antimycin-A, AMA) with or without addition of TSG-6. The effects of TSG-6 on macrophage phenotype (M1/M2), adhesion, and migration capability were determined.

Results
Mets+RAS pigs showed increased renal M1 macrophages and renal vein TNF-α levels. After p-MSCs delivery, renal vein TSG-6 increased and TNF-α decreased, M1 macrophage switched to M2 (Fig. A),, renal function improved, and fibrosis alleviated. In vitro, TNF-α increased TSG-6 secretion by h-MSCs. TSG-6 decreased LDH release from injured HK-2, induced a macrophage phenotypic switch from M1 to M2 (Fig. B), and reduced M1 macrophage adhesion and migration (Fig. C).

Conclusion
TNF-α-induced TSG-6 release from MSCs in vivo and in vitro may decrease renal tubular cells injury, which is associated with and may be at least in part mediated by regulating macrophage function and phenotype.
P0146MESENCHYMAL STEM CELLS AND THEIR EXTRACELLULAR VESICLES PROGENY DECREASE RENAL INJURY IN EXPERIMENTAL SWINE RENAL ARTERY STENOSIS THROUGH DIFFERENT MECHANISMS
Authors: Zhao Yu , Zhang Xiao liang , Liu Bicheng , Lerman Lilach 
Published: June 2020

Abstract

Background and Aims
Novel therapies are needed to address the increasing prevalence of chronic kidney disease. Mesenchymal stem cells (MSCs) and MSC-derived extracellular vesicles (EVs) augment tissue repair. EVs have practical benefits, but their efficacy relative to MSCs is incompletely understood. We tested the hypothesis that EVs are as effective as MSCs in protecting the stenotic kidney but target different injury pathways.

Method
Pigs were studied after 16 weeks of renal injury achieved by diet-induced metabolic syndrome (Mets) and renal artery stenosis (RAS). Pigs were untreated or treated four weeks earlier with a single intrarenal delivery of autologous adipose tissue-derived MSCs (1 × 107) or EVs (1 × 1010). Lean pigs and sham RAS served as controls (n=6 each). Stenotic kidney function was studied in-vivo using CT. Histopathology and expression of necroptosis markers (RIPK-1 and RIPK-3), inflammatory and growth factors (angiopoeitin-1 and VEGF) was studied ex-vivo.

Results
Stenotic-kidney glomerular filtration rate and blood flow in Mets+RAS were both lower than Mets, increased in Mets+RAS+MSCs, and further improved in Mets+RAS+EV. Both MSCs and EVs improved renal function, hypoxia, and decreased renal fibrosis and apoptosis. MSC were slightly more effective in preserving microvascular density (0.02-0.2mm in diameter), and prominently attenuated renal inflammation. However, EVs more significantly upregulated growth-factor expression and decreased necropotosis.
Conclusion: Adipose tissue-derived MSCs and their EVs both improve stenotic kidney function and decrease tissue injury in Mets+RAS. MSCs more effectively preserve the microcirculation, while EVs bestow better preservation of renal cellular integrity. These findings encourage further exploration of this novel approach to attenuate renal injury.
P0157GENETICALLY DETERMINED HYPOALBUMINEMIA AND THE RISK OF HYPERTENSION: GWAS-BASED INSTRUMENTAL VARIABLE ANALYSIS
Authors: Han Sang-Woong , Yu Mi-yeon , Choi Jong Wook , Yi Joo-Hark , Lee Chang Hwa , Park Joon-Sung 
Published: June 2020

Abstract

Background and Aims
Hypoalbuminemia is a clinical indicator of vascular endothelial dysfunction. However, the genetic association of hypoalbuminemia with hypertension has not yet been clarified. We investigated whether genetic variation(s) associated with decreased serum albumin level is deeply related with increased risk of hypertension.

Method
Mild hypoalbuminemia was defined as a serum albumin concentration of less than 4.0 g/dL. We performed GWAS-based instrumental variable analysis using the population-based cohort data collected from KoGES. Eligible as cases were all native Koreans without significant medical illness and a total 4326 participants were divided in into control (n = 3157) and hypoalbuminemic (n = 1168) according to their serum albumin level.

Results
Our GWAS revealed that 71 susceptibility loci were associated with mild hypoalbuminemia and subsequent two-stage least squares estimation analysis showed that both genetic variations at rs2894536 in LOC107986598 gene and rs10972486 in the ATP8B5P gene were related with systolic blood pressure. In subsequent Cox-proportional hazards model, we found that not only low serum albumin (HR = 0.654, 95% CI = 0.521-0.820), but also polymorphisms of rs2894536 (HR = 1.176, 95% CI = 1.015-1.361) and rs10972486 (HR = 1.152, 95% CI = 1.009-1.316) were significant predictor of hypertension. Our two-stage residual inclusion analysis indicated that candidate genetic variation attenuated the association between serum albumin and hypertension, showing hazard ratios of hypoalbuminemia on development of hypertension were 0.762 (0.659-0.882) for rs2894536 and 0.759 (0.656-0.878) for rs10972486.

Conclusion
These findings support a causal relationship between hypoalbuminemia-associated genetic variation, hypoalbuminemia and development of hypertension.
P0162HEMODIALYSIS AND PERITONEAL DIALYSIS PATIENTS HAVE SEVERELY IMPAIRED ENDOTHELIAL POST-OCCLUSIVE FOREARM VASODILATORY RESPONSE ASSESSED WITH LASER SPECKLE CONTRAST IMAGING
Authors: Alexandrou Maria Eleni , Gkaliagkousi Eugenia , Loutradis Charalampos , Dimitriadis Chrysostomos , Mitsopoulos Eustathios , Lazaridis Antonios , Nikolaidou Varvara , Dolgiras Panagiotis , Papadopoulou Dorothea , Douma Stella , Papagianni Aikaterini , Sarafidis Panteleimon 
Published: June 2020

Abstract

Background and Aims
Endothelial dysfunction is associated with cardiovascular events and mortality in various disease states, including end-stage-renal-disease (ESRD). Novel technological approaches have emerged for real-time assessment of endothelial reactivity. This study examined forearm skin microcirculation using Laser Speckle Contrast Imaging (LSCi) before and after arterial occlusion in ESRD patients undergoing hemodialysis (HD) or peritoneal dialysis (PD)

Method
38 patients undergoing HD were matched in a 1:1 ratio with 38 PD patients (for age, sex and dialysis vintage) and 38 controls (for age and sex). Skin microvascular reactivity parameters assessed with LSCI included baseline perfusion, occlusion perfusion, and peak perfusion during post-occlusive reactive hyperemia (PORH); time to peak perfusion; proportional change from baseline to peak perfusion; baseline and peak cutaneous vascular conductance (CVC); proportional change from baseline to peak CVC; and the amplitude of the PORH response (calculated as the difference between peak and baseline CVC).

Results
Baseline perfusion [HD: 46.97±14.6; PD: 49.32±18.07; controls: 42.02±11.94 Laser-Specle-Perfusion-Units (LSPU), p=0.097] and peak post-occlusion perfusion (104.77±28.68 vs 109.04±40.77 vs 116.96±30.96 LSPU, p=0.238) did not differ between groups. However, the post-occlusive vascular response was completely different, since time to peak response (HD: 7.24±6.99; PD: 10.68±9.45; controls: 11.11±5.1 sec, p=0.003) and the (%) increase from baseline to peak perfusion (HD: 133%±66; PD: 149%±125; controls: 187%±61, p=0.001) was significantly lower in ESRD patients.
ESRD patients had also lower levels of peak CVC, indicating the maximum capillary recruitment (HD: 1.05±0.3; PD: 1.07±0.44; controls: 1.57±0.52 LSPU/mmHg, p&lt;0.001), lower % increase of CVC at peak (p=0.001), and lower amplitude of the PORH response (p=0.001) (a measure of the difference between baseline and maximum capillary recruitment).

Conclusion
Using this novel non-invasive technology endothelial post-occlusive skin vasodilatory response was found to be similar between HD and PD patients and significantly impaired compared to controls. Future studies are needed to assess the prognostic implications of this microcirculatory functional defect.
P0180U-SHAPED RELATIONSHIP BETWEEN SERUM URIC ACID LEVEL AND THE RISK OF END STAGE RENAL DISEASE AND ALL-CAUSE MORTALITY IN MEN
Authors: Go Su-Ryeong , Lee, Hajeong , Heo Nam Ju , CHIN HO JUN , Na Ki Young 
Published: June 2020

Abstract

Background and Aims
High uric acid level was known as a risk factor to incident chronic kidney disease, mortality, or cardiovascular mortality. However, it is obscure which level of uric acid (UA) is safe to prevent end stage renal disease (ESRD) and mortality. We searched the optimal range of UA level to escape the incident ESRD and death in a large cohort of general population.

Method
We enrolled 143,762 adult subjects participated in voluntary health check-up program from three referral hospitals in Korea between 1995 and 2009. We defined 48,147 control subjects (CONTROL) without risk factors of high UA level, to calculate 5, 20, 80, and 95 percentiles of UA level and allocated whole participants into five groups (G1, G2, G3, G4, G5) according to the criteria in each gender. We merged the incident data of ESRD from the Korean ESRD registry by December 2017 and the mortality data from the Ministry of the Interior and Safety by May 2018 based on the identifier of Koreans. This project was approved by institutional review boards of the three hospitals.

Results
The UA levels of 5, 20, 80, 95 percentiles in CONTROL were 2.9 mg/dL, 3.5 mg/dL, 4.9 mg/dL, and 5.7 mg/dL in females, and 4.1 mg/dL, 5.0 mg/dL, 6.8 mg/dL, and 7.8 mg/dL in males. There were 76,784 (53.4%) males and 66,978 (46.6%) females. The age was 50.5 ± 12.2 years and the level of GFR by CKD-EPI equation was 94.3 ± 15.2 ml/min/1.73 m2 at enrollment. Among females, ESRD was developed in 110 subjects (0.2%) and 1,922 subjects (2.9%) were dead during more than 12 years. The level of UA and groups of UA were not independent risk factors to mortality or incident ESRD in females. Among males, there were 162 subjects with ESRD (0.2%) and 4293 subjects (5.6%) were dead. Compared to G3 group (5.0 mg/dL ≤ UA&lt;6.8 mg/dL), other groups showed higher risk of incident ESRD adjusted with related factors by Cox’s hazard proportional model in males (p=0.016). The Hazard ratios (HRs) for incident ESRD in G1 group (&lt;4.1 mg/dL), G4 group (6.8 mg/dL ≤ UA&lt; 7.8 mg/dL), and G5 group (7.8 mg/dL ≤ UA) were 2.409 (95% CI, 1.312-4.423, P=0.005), 1.710 (95% CI, 1.080-2.707, P=0.022), and 1.742 (95% CI, 1.098-2.762, P=0.018), respectively. The HRs for all-cause mortality in G1, G4, and G5 group were 1.203 (95% CI, 1.017-1.346, P=0.001), 1.099 (95% CI, 1.006-1.201, P=0.037), and 1.137 (95% CI, 1.015-1.272, P=0.026), respectively. We found there were 591 subjects died from cardiovascular disease (CVD) among 3,352 deaths with valid cause of death. G1 and G5 group showed higher risk for CVD-mortality compared to G3 group in men (p&lt;0.001).

Conclusion
Serum uric acid level showed U-shaped pattern of HRs for incident ESRD and all-cause mortality in men, only. The appropriate uric acid level might be 4.1-6.7 mg/dL in men.
P0188TOTAL CHOLESTEROL EXCESS DOESN'T AFFECT CORONARY ARTERY CALCIFICATION INDEPENDENTLY OF RENAL FUNCTION
Authors: Kuryata Olexandr , Shatailo Viktor , Nikolaichyk Alina , Semenov Viktor 
Published: June 2020

Abstract

Background and Aims
Coronary artery calcium score (CACS) allows to improve significantly predictive value of traditional tools for cardiovascular risk estimation. Reduced renal function is associated with increase of rates of cardiovascular events. Dyslipidemia is an important factor of cardiovascular system injury in chronic kidney disease. The Aim. To investigate association between glomerular filtration rate (GFR), total cholesterol and CACS.

Method
We performed the study on 170 patients (77 males and 93 females, aged 56 [52;63] years) who underwent CACS at Dnipropetrovsk Mechnikov Regional Hospital, Dnipro, Ukraine, from December 2017 till March 2019. Patients in the study were free of known cardiovascular disease and required reclassification of cardiovascular risk. Patients were subdivided by total cholesterol (TC) level (&lt;5.2 mmol/l, n=83; ≥5.2 mmol/l, n=87) and by GFR (≥90 ml/min, n=64; 60-89 ml/min, n=90; 30-59 ml/min, n=16). CACS was presented in Agatston units (AU).

Results
Median age in groups by TC was comparable (56 [53;63] vs 56 [51;64] years, p=0.51) and elevated significantly with decline of GFR (54 [49;59], 57 [53;65] and 70 [59;77] years for patients with GFR≥90, 60-89 and 30-59 ml/min respectively, p for trend &lt;0.001). We didn’t observe any statistically significant differences of CACS after patients subdivision, though it was higher in TC≥5.2 mmol/l group.

Conclusion
We didn’t find convincing data supporting significant impact of TC excess on coronary artery calcification.
P0192RELATIONSHIP BETWEEN SERUM HEPCIDIN AND THE PROGRESSION OF CHRONIC KIDNEY DISEASE: KOREAN COHORT STUDY FOR OUTCOME IN PATIENTS WITH CHRONIC KIDNEY DISEASE (KNOW-CKD)
Authors: Sung Su Ah , Han Kum Hyun , Lee Jien , Lee Taehee 
Published: June 2020

Abstract

Background and Aims
Hepcidin plays a central role in iron metabolism. However, few studies have evaluated the relationship between serum hepcidin and the progression of chronic kidney disease (CKD). This study aimed to determine the relationship between serum hepcidin levels and the progression of renal diseases in patients with CKD.

Method
We reviewed data of 2,016 patients from a large-scale multicenter, prospective study enrolled between 2011 and 2016, who had data regarding the serum hepcidin level, hemoglobin level, iron indices, usage of erythopoiesis-stimulating agents (ESA) or iron, and follow-up of renal events. Renal events were defined as a &gt;50% decrease in kidney function from the baseline values, doubling of the serum creatinine level, or initiation of renal-replacement treatment.

Results
During a mean 3.6 years, 556 patients developed renal events (27.6%). In multivariate Cox proportional hazard regression analysis adjusted for confounders including kidney function, the hemoglobin level, conventional iron indices, usage of ESA or iron, and other chronic diseases, the hazard of serum hepcidin for renal events was evident in the comparison between only the first and fourth quartiles (hazard ratio 1.603, 95% confidence interval, 1.187-2.163, P = 0.002). In the multivariate penalized spline curve analysis, the relationship between serum hepcidin and renal events was J-shaped, and the renal hazard was particularly evident at a serum hepcidin level ≥60 ng/ml.

Conclusion
Increased serum hepcidin levels independently predict the progression of CKD in non-dialysis patients with CKD. The potential direct renal hazard of serum hepcidin needs to be confirmed in future randomized controlled trials.
P0199ASSESMENT OF FILTRATION RATE IN ONCOLOGICAL PATIENTS
Authors: Klimek Kamila , ALONSO GARCIA FABIOLA , Lara Ruiz Alfonso , AGUDO MARTINEZ ANA , Almenara Tejederas Marina , SALGUIERA LAZO MERCEDES 
Published: June 2020

Abstract

Background and Aims
Accuracy in the estimation of the glomerular filtration rate (GFR) in oncological patients is essential in order to adjust chemotherapy doses accordingly. Finding an appropriate formula for this subgroup of patients is a subject of ongoing debate. The present study introduces a cohort of the aforementioned patients followed in the Onconephrology outpatients clinic, in which different formulas were applied for the calculation of the GFR.

Method
A retrospective study with a cohort of 17 onconephrological patients was conducted. The following variables were evaluated: age, sex, height, weight, body mass index, body surface area and type of tumor. Renal function was estimated with the Cockcroft Gault, the Janowitz-Williams, the CKD-EPI, the adjusted by body surface-CKD-EPI, the MDRD, the adjusted by body surface-MDRD, the CKD-EPI Cystatin C, the adjusted by body surface-CKD-EPI Cystatin C formulas and 24-hour urine creatinine clearance. Every equation was compared with the Cr EDTA clearance which is considered the gold standard. The statistical analysis was carried out by means of the IBM SPSS Statistics software. Concordance between chromatography and the remaining formulas was assessed with the Wilcoxon (null hypothesis of no difference between medians) and Bland-Altman tests.

Results
6 women and 11 men were included in the study, with a mean age of 64.24 years (SD 9.9), a mean BMI of 28.25kg/m2 (SD 7.98), and a mean Cr EDTA clearance was 37.07ml/min (SD 15.45). 15 patients suffered from solid malignancies, whereas the remaining 2 patients suffered from hematological tumors. The most common solid tumor was lung cancer (n=5), followed by rectal carcinoma (n=2).
The null hypothesis was accepted for the adjusted for body surface-CKD-EPI Cystatin C equation (p-0,089) and 24-hour urine creatinine clearance (p 0.955), when compared to 51Cr EDTA clearance. The Bland-Altman test revealed the smallest differences between the 24-hour urine creatinine clearance and 51Cr EDTA clearance (-0.09867), with 95% concordance limits of -36.14 and 34.17, and a non-significant linear regression coefficient (p 0.915).

Conclusion
This study revealed that the 24-hour urine creatinine clearance is the closest formula to the gold standard for the assessment of the GFR in patients with malignancies. However, the small sample size hinders the generalization of these results. Larger sample size studies are mandatory to confirm these findings.