bluuebunny/crossref_metadata_2025_split huggingface dataset:
SO040ROLE OF INTRACELLULAR CA2+ IN THE REGULATION OF THE RENAL CHLORIDE CHANNEL CLC-KA
Authors: Gerbino Andrea , De Zio Roberta , Russo Daniela , Milella Luigi , Milano Serena , Procino Giuseppe , Pusch Michael , Svelto Maria , Carmosino Monica 
Published: June 2020

Abstract

Background and Aims
It has been recognized that the physiological role of ClC-Ka and its mouse homolog ClC-K1 in the nephron is to confer high Cl- permeability in the thin Ascending Limb of loop of Henle (tAL), which in turn is essential for establishing the high osmolarity of the renal medulla in the countercurrent system. Accordingly ClC-K1 KO mice display a severe polyuria resembling a Nephrogenic Diabetes Insipidus (NDI) phenotype. Thus, ClC-Ka in human nephron could be an interesting target for diuretic and anti-hypertensive drugs. Unfortunately the regulation of ClC-Ka in and its electrophysiological properties are still not completely known.

Method
We analyzed, by whole-cell voltage-clamp, Cl- currents in HEK293 cells co-expressing GFP-ClC-Ka and the accessory m-Cherry-tagged barttin subunit, upon intracellular Ca2+ mobilization. The patch clamp protocol consists of a holding potential from 0 mV, which is stepped to various test potentials from -195 and +125 mV for 150 ms. Pulses ended with a tail pulse to -125 mV for 20 ms. Concomitantly we monitored by live confocal microscopy, the membrane expression of either GFP-ClC-Ka or barttin-mCherry.

Results
In control conditions we found a linear current/voltage relationship over a broad range of membrane voltages except of hyperpolarization below -100 mV, where the channel open probability was reduced, providing the well-known hook-shaped appearance of the I-V curve for ClC-Ka channel. Interestingly, both 100 µM ATP and 400 µg/ml of dandelion root extract (DRE), both increasing intracellular Ca2+ in HEK293, significantly inhibited Cl- currents in a time dependent way. Pre-treatment of cells with either the Ca2+ chelator BAPTA-AM or the PCK inhibitor Calphostin C, reverted the inhibitory effects of both ATP and DRE. Interestingly, 1µM of phorbol meristate acetate (PMA), a specific PKC activator, mimicked the inhibitory effect of ATP and DRE on Cl- currents. We finally demonstrated that 30 µM Heclin, an inhibitor of E3 ubiquitin ligase, did not revert the DRE- and ATP- induced Cl- currents inhibition, thus suggesting that the ClC-Ka inhibition is independent of channel ubiquitination. Accordingly, live confocal analysis showed that all the Ca2+ mobilizing compounds tested did not induced neither ClC-Ka nor Barttin internalization. We hypothesized that phosphorylation in the putative PKC consensus sites present in ClC-Ka amino acidic sequence may be involved in the inhibition of channel activity.

Conclusion
In conclusion, we demonstrated for the first time that the activity of ClC-Ka in renal cells could by inhibited by either receptor agonists or natural molecules able to activate an intracellular Ca2+/PKC pathway, thus opening venues for the development of new diuretic drugs.
SO041THE EFFECT AND MECAHNISM OF THE LOX IN AT1R/Β-ARRESTIN BIASED PATHWAY INDUCED RENAL INTERSTITIAL FIBROSIS
Authors: Zhang Xiaoqin , Yu Chen 
Published: June 2020

Abstract

Background and Aims
We studied the downstream and mechanism of β-arrestins signaling in renal fibrosis process and the role of lysyl oxidase (LOX) in the AT1R-β-arrestins pathway.

Method
The mechanism of β-arrestins signaling was studied in normal rat kidney tubule epithelial cells (NRK-52E) treated with SII in vitro. BAPN or placebo was administered during ischemia reperfusion (IR)-induced fibrosis progression. Collagen crosslinking and fibrosis progression were assessed histologically and biochemically.

Results
The mRNA and protein levels of β-arrestin-1 and β-arrestin-2 were significantly upregulated in renal fibrosis model both in vitro and in vivo. SII activated the ERK-STAT3 PY705 but not STAT3-Try727 in nucleus of NRK-52E cells, which effects were abolished when transfection of siRNA targeting β-arrestin-1 and β-arrestin-2 or pretreated with PD98059 (MEK inhibitor). LOX was strongly induced in fibrotic kidney and NRK-52E cells treated with SII. Active LOX significantly increased collagen crosslinking. In established IR-28d renal fibrosis, LOX inhibition promoted fibrosis reversal and with a 25% decrease insoluble collagen. Gene silencing of β-arrestin-1 + 2 or STAT3 apparently inhibited SII-induced LOX expression in vitro. Besides, chromatin immunoprecipitation (ChIP) assay clearly demonstrating the interaction between STAT3 and the LOX promoter, which indicated LOX is a direct target gene of SII-β-arrestins-STAT3 signaling.

Conclusion
The ERK/STAT3 was downstream of AT1R-β-arrestins, ERK entered the nucleus and activated STAT3-PY705. LOX mediates collagen crosslinking and fibrotic matrix stabilization during renal fibrosis via the AT1R-β-arrestins-ERK-STAT3-PY705 signaling. By blocking this profibrotic pathway, therapeutic LOX inhibition attenuates the fibrosis and suggesting target the LOX has significant potency for the treatment of patients with fibrotic kidney disorders.
SO043MALNUTRITION-INFLAMMATION IS A RISK FACTOR FOR BRAIN ATROPHY RELATIVE COGNITIVE IMPAIRMENT IN MAINTENANCE DIALYSIS PATIENTS
Authors: Qian Yujun , Zheng Ke , Lin Tianye , Feng Feng , Han Fei , Zhu Yicheng , Li Xuemei 
Published: June 2020

Abstract

Background and Aims
Cognitive impairment (CI) are prevalent and devastating in dialysis patients, whereas the pathophysiology is not very clear. Brain atrophy may involve in the process of CI. To explore the correlation between brain atrophy and cognitive impairment, as well as the risk factors of brain atrophy, we used the voxel based morphometry (VBM) method to evaluate the changes of brain multi-component volume in maintenance dialysis patients, and analyzed it relationship with detailed cognitive function.

Method
From July 2013 to July 2014, 181 maintenance dialysis patients in our hospital were enrolled for 3.0T MRI examination and cognitive function evaluation. The statistical parameter map (SPM) 8 software package was used for VBM analysis, and the Monte Carlo simulation method (alphasim method) in the functional neural image analysis software package (AFNI) was used for multiple comparison correction at the cluster level to extract the volume of brain multi-component. Cognitive function was evaluated with MMSE, MoCA, Philadelphia word learning test, Boston Naming Test, semantic fluency test and trial making test. The risk factors for brain volume were explored, and the correlation between brain volume and CI was investigated by regression analysis.

Results
This study enrolled 181 dialysis patients, including 119 cases of maintenance hemodialysis and 62 cases of peritoneal dialysis. According to MMSE and MoCA, the incidence of cognitive impairment was 22.7% and 66.3% respectively. The mean values gray matter volume and white matter volume were 575.4mm3 and 457.8mm3, respectively. The volume of gray matter, white matter, amygdala, caudate nucleus and hippocampus were positively correlated with the scores of specific cognitive functions such as total, memory, language and execution. Among them, amygdala volume atrophy was significantly related to the decrease of cognitive function such as MMSE (β = 2.81, P = 0.005), MoCA (β = 6.26, P &lt; 0.001). Serum albumin is the risk factor of gray matter volume (β = 5.0, 95% CI = 3.1 to 6.9, P &lt; 0.001) and white matter volume (β = 3.6, 95% CI = 1.7 to 5.5, P &lt; 0.001); Serum Hypersensitive C-reactive protein is the risk factor of gray matter volume (β = -0.9, 95% CI = -1.7 to - 0.1, P = 0.037).

Conclusion
Brain atrophy in maintenance dialysis patients is closely related to multiple cognitive impairment, and malnutrition - microinflammation may be a risk factor for multi-component brain atrophy.
SO046REGULATION OF GUT MICROBIOTA AND HOST CO-METABOLISM BY POTASSIUM HOMEOSTASIS IN PATIENTS ON HEMODIALYSIS
Authors: Raj Dominic , Gao Bei , Barrows Elizabeth , Jagadeesan Muralidharan , Amdur Richard , Collins Ashte , Regunathan-Shenk Renu , Kincaid Danielle , Omar Badryah , Siddiqi Muhammad 
Published: June 2020

Abstract

Background and Aims
Gut microbiota composition is dysregulated in hemodialysis patients. However, the impact of potassium homeostasis on the gut microbiota and their metabolites has not been studied. Patiromer is a potassium binding polymer that exchanges calcium for potassium in the gastrointestinal (GI) tract, thereby increasing fecal potassium excretion and reducing serum potassium levels.

Method
In this non-randomized, open label, 3-period crossover trial with repeated measures within each period, we investigated the effect of 12 weeks of treatment with patiromer on the microbiome profile and microbiota-related metabolites in 27 hemodialysis patients using multi-omics integration of data from shotgun metagenomic sequencing and untargeted and targeted metabolomic profiling. Data from hemodialysis patients at baseline was first compared with individuals without kidney disease (n=20).

Results
We found that 18 bacterial species and 49 plasma chemical clusters were significantly different between patients and controls. Serum potassium decreased significantly from baseline (5.62±0.65 mEq/L) with patiromer treatment (4.80±0.46 meq/L) and increased during the post-treatment phase (5.45 ± 0.67 meq/L), (p&lt;0.001). Three bacterial species and one bacterial pathway were altered by patiromer. We identified 52 serum metabolites, which were significantly different in patients at baseline compared with controls, and were partially reversed with patiromer treatment. Specifically, the serum levels of polyphenols such as vanillic acid, gallic acid and benzoic acid, and other microbiota-related metabolites such as 2,6-diaminopimelic acid, 2-ketogluconic acid, indole-3-carboxaldehyde and 3-hydroxyphenylacetic acid were reduced by patiromer treatment.

Conclusion
Our study suggests that control of hyperkalemia by patiromer alters the gut microbial composition and host co-metabolism in hemodialysis patients.
SO047HEMODIAFILTRATION DECREASES RISE OF LEPTIN AND RESISTIN IN PROTEIN ENERGY WASTING (PEW) WITHOUT HARMFULL EFFECT ON ALBUMIN CONCENTRATION
Authors: Hory Bernard , Robino Christophe 
Published: June 2020

Abstract

Background and Aims
The role of adipocytokines (ADCK), and particularly of anorectic leptin and of resistin in the mortality of PEW is strongly suspected. Convective techniques (ol-HDF) decrease leptin concentrations but induce a concomitant albumin loss which could be potentially harmful in malnourished patients. The aim of the prospective multicentric randomized study performed in France by the NUTRIPEPA GROUP is to compare one year evolution of 4 ADCK and seric albumin using HDF or HD and membranes with different cut-off.

Method
47 patients responding to both criteria of albumin &lt;35 g/l (mean of 3 dosages) and prognostic inflammatory and nutritional index (PINI)≥ 1 were randomized to be treated using either polyester polyarylate (PEPA Nikkiso Japan) or polysufone, polyethersulfone dialyser (control) and followed for one year. Treatment consists in 3*4 hours HD session or in 3 HDF sessions with more than 20 liters reinjection/session. 24 patients were treated with HDF (HDF gr) : 11 with PEPA, 13 with control, and 23 with HD (HD gr) : 13 with PEPA, 10 with control. Oral nutritional supplementation was systematic, eventually completed by intradialytic parenteral nutrition. Albumin, leptin, adiponectin, ghrelin and resistin concentrations were determined at M0, M6, M9, M12. Delta concentration M0-M12 of albumin and of the 4 ADCK were compared with Wilcoxon test.

Results
At 12 months, decrease of leptin and of resistin was significantly higher in HDF group compare to HD group. There was no significant variation of adiponectin, ghrelin and albumin concentrations regardless of the technic or of dialyser cut-off.

Conclusion
In PEW, on a one year practice and regardless of the cut-off of the dialyser, HDF decreases both the anorexigenic adipokine leptin and resistin, adipokine implicated in insulin resistance, without harmfull incidence on seric albumin concentration. The decrease of concentrations of leptin and resistin obtained using ol-HDF could explain, at least in part, the reduction of one year mortality that we reported last year in preliminary results of NUTRIPEPA study.
SO056THE CLINICAL AND IMMUNOLOGICAL IMPACT OF LOW DOSE RITUXIMAB IN CLINICAL NEPHROLOGY
Authors: Alex Sunu 
Published: June 2020

Abstract

Background and Aims
Currently, the dose of rituximab used in nephrology practice is mostly extrapolated from the dose used in lymphoproliferative disorders. It is possible that a lesser dose may suffice when treating a non-neoplastic disorder. We conducted this study to study the clinical response and CD19 B cell suppression with a single dose of 100mg rituximab in nephrology practice

Method
This was a single center prospective study of role of 100mg rituximab as initial dose in steroid dependent (SDNS), frequently relapsing nephrotic syndrome (FRNS), idiopathic membranous nephropathy (MN) and high immunologic risk kidney transplantation with subsequent doses based on CD19 B cell reconstitution.

Results
Following 100mg rituximab in 42 patients, CD19 B cell percentage decreased from 16.3+7.6 to 0.3±0.3, 1.9±1.7 and 4.0±4.5 by 30, 90 and 180 days respectively. At 30th day, 40(95.2%) had CD19 B cell count &lt;1%. Of the 30 patients with SDNS and FRNS followed up for one year, 29(96.7%) went into remission at day 30. Remission was sustained in 23(76.6%) at day 180 and 21(70%) at 1 year. There was significant decrease [P &lt;0.001] in the dose of steroids needed to maintain remission at 180 days following rituximab (0.27±0.02mg/Kg to 0.02±0.00mg/Kg). Of the five patients with MN, four patients achieved remission by 6 months. Remission was sustained in three patients by 1 year. Of the 7 kidney transplant recipients, 2 had antibody mediated rejections though CD19 B cells were suppressed even at one year.

Conclusion
Low dose of 100 mg rituximab is sufficient to deplete CD19 B cells for up to 90days and is effective in inducing remission in SDNS and FRNS and MN. Targeting subsequent doses depending on CD19 B cell reconstitution may prevent relapses, limit toxicity and be cost effective.
SO060MONOCYTE-TO-LYMPHOCYTE RATIO, AN INDEPENDENT RISK FACTOR OF SURVIVAL IN HEMODIALYSIS PATIENTS: RESULTS FROM THE INTERNATIONAL MONDO CONSORTIUM
Authors: Bright Rupert , Ye Xiaoling , Woollard Kevin , Pusey Charles Dickson , Kotanko Peter , Duncan Neill 
Published: June 2020

Abstract

Background and Aims
Patients with end-stage kidney disease have a high prevalence of chronic inflammation and a higher risk of death. Previous work by our group has indicated a positive relationship between neutrophil counts and neutrophil-to-lymphocyte ratio (NLR) and mortality in a large and ethnically diverse dialysis population. Monocytes also have a crucial inflammatory role, but there has been limited study to date, an association between monocyte-to-lymphocyte ration (MLR) was reported in a small Chinese haemodialysis cohort. The aim of this analysis was to study the independent relationship between MLR and all-cause mortality in a large and ethnically diverse haemodialysis population.

Method
Four cohorts were described by phases of haemodialysis exposure: 1) acute phase cohort- first 90 days on HD as the baseline period with the subsequent 9 months as the follow-up period, 2) early-stable phase cohort- 91 days to the end of 1st year as the baseline followed with 1 year’s follow-up period, 3) mid-stable phase cohort- 2nd year as the baseline and the following 1 year as the follow-up, and 4) late-stable phase cohort- 3rd year as the baseline followed by a 7 year follow-up period. All-cause mortality was recorded during the 4 phases. Kaplan-Meier (KM) curves were applied to explore the association between MLR quartiles with mortality in the 4 cohorts. Cox proportional hazards models with spline terms (adjusted for age, gender, race, body mass index, diabetic (DM) and congestive heart failure (CHF)) were applied to explore the association between MLR levels and all-cause mortality in the cohorts.

Results
A total of 20,848 patients were included in acute phase cohort; 19,575 in the early-stable phase cohort, 16,515 patients in the mid-stable cohort, and 13,708 patients in the late-stable phase cohort. Notably, patients with higher baseline MLR by quartile tended to be older, male and with a higher percentage of DM and CHF as comorbidities. Lower lymphocyte count and higher neutrophil count, NLR, CRP were associated with higher MLR quartile (Table 1), consistent with the observed association with other markers of inflammation and malnutrition: lower albumin, phosphate and higher ferritin. Adjusted all-cause mortality was observed to be higher in patients with higher MLR quartile both in the KM and spline analyses (Figure 1 a & b) in all phase cohorts (data not shown).

Conclusion
There is a positive relationship between higher levels of MLR and adjusted all-cause mortality across all phase cohorts, including long-term follow-up in this large and ethnically diverse haemodialysis population. Higher levels of MLR are seen in patients with DM and CHF and are consistently observed with other markers of inflammation and malnutrition. This work supports the findings made previously in a more a restricted cohort and warrants further mechanistic investigation.
SO061SEX DIFFERENCES IN MORTALITY AMONG PEOPLE WITH END-STAGE KIDNEY DISEASE: DO WOMEN ALWAYS LIVE LONGER?
Authors: De La Mata Nicole , Macleod Grace , Kelly Patrick , Rosales Brenda , Masson Philip , Morton Rachael , Webster Angela 
Published: June 2020

Abstract

Background and Aims
Female life expectancies consistently exceed males in the general population. Yet, this survival advantage may not persist in the presence of a chronic disease due to sex-based differences or healthcare inequities. We aimed to explore sex differences in survival among people with end-stage kidney disease (ESKD) compared to the general population.

Method
We included the entire ESKD population in Australia, 1980-2013 and New Zealand, 1988-2012 from the Australian and New Zealand Dialysis and Transplant Registry. These were linked to national death registers to ascertain deaths and their causes. We estimated relative measures of survival, including standardized mortality ratios (SMR), cumulative relative survival and expected life years lost, using general population data (adjusting for country, age, sex and calendar year) to account for background mortality.

Results
Of the 60,823 ESKD patients, there were 25,042 females (41%) and 35,781 males (59%). Overall 34,417 deaths occurred over the 368,719 person-years of follow-up where a similar proportion of females (57%) and males (56%) died. While mortality sex differences within the ESKD population were minor, once compared to the general population female ESKD patients had greater excess deaths, worse relative survival and greater life years lost compared to male ESKD patients. Female ESKD patients had 12 times (SMR:11.5; 95%CI:11.3-11.7) and males had 7 times (SMR:6.7; 95%CI:6.7-6.8) the expected deaths, with the greatest sex disparity among younger ages and from cardiovascular disease. Relative survival was consistently lower in females (0.57, 95%CI:0.57-0.58 in males vs 0.54, 95%CI:0.54-0.55 in females at 5 years), where the excess mortality was 9% higher (95%CI:7-12%) in female ESKD patients (Fig 1A), adjusting for year and age. The average life years lost for female ESKD patients was 4-5 years greater than male ESKD patients (Average life years lost 25.9 years, 95%CI:25.1-26.7 in males and 31.4 years, 95%CI:30.5-32.1 in females aged 15 years at ESKD) (Fig 1B). Kidney transplantation reduced the sex differences in excess mortality, with similar relative survival (p=0.42; Fig 1C) and average life years lost reduced to 3-4 years for females (Fig 1D).

Conclusion
The impact of ESKD is more profound for women than men with greater excess mortality, however kidney transplantation attenuates these differences. Our findings show that chronic diseases and sex can compound to produce worse outcomes where women lose their survival advantage in the presence of ESKD.
SO066IS OXYGEN-PULSE A GOOD SURROGATE MARKER OF STROKE VOLUME DURING PEAK EXERCISE IN CHRONIC KIDNEY DISEASE?
Authors: Chinnappa Shanmugakumar , Mooney Andrew 
Published: June 2020

Abstract

Background and Aims
As there is growing interest in the benefits of exercise training in chronic kidney disease (CKD), it is important to understand the utility of conventional exercise test parameters in quantifying the cardiopulmonary fitness of patients with CKD. Merely extrapolating information from studies of healthy volunteers and heart failure (HF) patients would not suffice. In the present study we evaluated one such parameter, the peak O2-pulse [the rate of peak O2 consumption (VO2max) to peak heart rate (HR)] which is widely used as a surrogate for peak stroke volume (SV) in HF. We tested the hypothesis that peak O2-pulse is a good surrogate marker for peak stroke volume in CKD.

Method
A cross sectional study of 70 asymptomatic male non-diabetic CKD patients [CKD stages 2-5 (pre dialysis)] without primary cardiac disease. Data from 35 healthy volunteers & 25 HF patients was used for comparison. Specialised cardiopulmonary exercise (CPX) test with CO2 rebreathing technique was utilised to measure peak cardiac output (Qt) and peak SV non-invasively. VO2max was simultaneously measured. Peak O2-pulse was calculated as VO2max/Peak HR. Peripheral O2 extraction [C(a-v)O2] was derived using Fick’s equation, VO2 = Qt x C(a-v)O2. Pearson’s correlation, univariate and multivariate analyses were applied. Results are presented as mean±SD. P&lt;0.05 is considered as significant.

Results
CKD patients had a mean age of 48.4±12.6 years and a mean eGFR of 33.8±25.5 ml/min. Whereas there was a very strong correlation between peak O2-pulse and peak SV in HF (R2= 0.81), the correlation was less robust in CKD (R2 = 0.49) (Fig 1). On multivariate analysis, in HF, peak SV was the major determinant of O2 pulse (β=1.03). The β for peak C(a-v)O2 was 0.44, both P &lt; 10-3. However, in CKD both peak SV (β =0.76, P&lt;10-3) and peak C(a-v)O2 (β=0.70, P&lt;10-3) were significant determinants of O2-pulse rendering O2-pulse a poor surrogate of SV in CKD.

Conclusion
Based on the above results we reject the hypothesis that peak O2-pulse is a good surrogate marker of peak SV in CKD. The results highlight the pitfalls in the application of conventional CPX parameters in evaluating cardiopulmonary fitness in CKD. In view of the unique pathophysiology of the uraemic state further CKD-specific studies evaluating the central and peripheral determinants of aerobic exercise capacity are required.