bluuebunny/crossref_metadata_2025_split huggingface dataset:
MO251HIGHLY SENSITIVE FLOW CYTOMETRIC DETECTION OF RESIDUAL B-CELLS AFTER RITUXIMAB IN ANTI-NEUTROPHIL CYTOPLASMIC ANTIBODY-ASSOCIATED VASCULITIS PATIENTS*
Authors: Teng Y K O , Van Dam L , Oskam Jelle , Kamerling S W A , Arends E J , Bredewold Edwin , Berkowska@lumc.nl M A , Van Dongen J J M , Rabelink T J , Van Kooten Cees 
Published: May 2021

Abstract

Background and Aims
B-cell depletion with rituximab (RTX) is an effective treatment for anti-neutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV) patients. Nevertheless, relapses are frequent after RTX, often preceded by B-cell repopulation suggesting that residual autoreactive B-cells persist despite therapy. Therefore, this study aimed to identify minimal residual autoimmunity (MRA) in the B-cell compartment of AAV patients treated with RTX.

Method
EuroFlow-based highly-sensitive flow cytometry (HSFC) was employed to study B-cell and plasma cell (PC) subsets in-depth in AAV patients before and after RTX treatment. Additionally, peripheral blood mononuclear cells (PBMCs) of these RTX-treated AAV patients were cultured and in vitro stimulated with CpG, IL-2, and IL-21 to induce antibody-secreting cells (ASC). (ANCA)-IgG was measured in these supernatants by ELISA.

Results
By employing EuroFlow-based HSFC, we detected circulating CD19+ B-cells at all timepoints after RTX treatment, in contrast to conventional low-sensitive flow cytometry. Pre-germinal center (Pre-GC) B-cells, memory B-cells and CD20+CD138− plasmablasts (PBs) were rapidly and strongly reduced, while CD20−CD138− PrePC and CD20-CD138+ mature (m)PCs were reduced slower and remained detectable. Both memory B-cells and CD20− PCs remained detectable after RTX. Serum ANCA-IgG decreased significantly upon RTX. Changes in ANCA levels strongly correlated with changes in naive, switched CD27+ and CD27− (double-negative) memory B-cells, but not with plasma cells. Lastly, we demonstrated in vitro ANCA production by AAV PBMCs, 24 and 48 weeks after RTX treatment reflecting MRA in the memory compartment of AAV patients.

Conclusion
We demonstrated that RTX induced strong reductions in circulating B-cells, but never resulted in complete B-cell depletion. Despite strongly reduced B-cell numbers after RTX, ANCA-specific memory B-cells were still detectable in AAV patients. Thus, MRA is identifiable in AAV and can provide a potential novel approach in personalizing RTX treatment in AAV patients.
MO1030THE FIRST CASE OF ATYPICAL HEMOLYTIC UREMIC SYNDROME (AHUS) FEATURES IN AN EXPERIMENTAL MODEL
Authors: Gembillo Guido , Bellinghieri Guido , Savica Vincenzo , Siligato Rossella , Santoro Domenico 
Published: May 2021

Abstract

Background and Aims
Thrombotic Microangiopathies (TM) are three distinct clinical syndromes presenting the same histological renal pattern: typical and atypical Hemolytic Uremic Syndrome (SEU- aSEU) and Thrombotic Thrombocytopenic Purpura (TTP).
So far, the first report of a TM has been generally attributed to Eli Moschowitz. In 1922 he described the case of a 16 years old girl who died after acute onset of fever with petechial lesions and autoptic findings of hyaline thrombosis of terminal arterioles and capillaries, thus profiling the first case of TTP.
Only in the 1955, Conrad Gasser described the first medical record of HUS, describing the case of a patient with a manifestation of bilateral necrosis of the renal cortex.
We describe the first reported case of a Thrombotic Microangiopathy, in particular an experimentally induced aHUS by Richard M. Pearce in 1909. In this case, the trigger leading to aHUS was represented by snake venom injection in an experimental rabbit model.

Method
Pearce described acute glomerular lesions produced in the rabbit using dried venom of rattlesnake Crotalus Adamanteus. It was dissolved in salt solution in the proportion of 0.25 of a milligram to one cubic centimeter, rising gradually to two milligrams, and then followed by doses of 0.5 of a milligram of fresh venom at various intervals. The intervals between injections depended on the general condition of the animal and the amount of albuminuria.

Results
Rabbit kidneys showed well marked hemorrhagic and exudative lesions in the glomeruli; hyaline, granular, blood, and hemoglobin casts in both convoluted and collecting tubules; and granular degeneration of the epithelium of the convoluted tubules and loops of Henle. Pearce also described a “penetration of the cells of the compressed glomerular tuft into the mass of hemorrhage lying either in the tuft itself or in the capsular space” (Figure 1).
In animals surviving 20-30 days after the first injection of the venom, the acute lesions were demonstrated to subside at the microscopic examination and their earlier presence was marked by “occasional casts and compressed masses of red cells in the glomerular spaces and tufts”. At the same time other models also showed “extensive granular degeneration of the convoluted tubules and many casts”. The renal autoptic findings presented the features of a vascular nephritis with severe endothelial changes.

Conclusion
Glomerular and tubular lesions of rabbits’ kidneys induced by crotalus’s venom showed typical features of what is today defined as aHUS. In this first experiment, the author described a glomerular tuft as “more analogous to the organization of a red thrombus than it is to any form of glomerular lesion known in man”, so we can affirm that Pearce described, ante litteram TMA histological features many years before other scientists.
MO092THE ROLE OF CALCIUM IN UROMODULIN EXPRESSION AND SECRETION FROM RENAL MEDULLARY EPITHELIAL CELLS OF HYPERTENSIVE AND NORMOTENSIVE RATS
Authors: Boder Philipp , Mary Sheon , Graham Lesley , Delles Christian 
Published: May 2021

Abstract

Background and Aims
Uromodulin (UMOD) is the most abundantly secreted protein found within the urine, primarily produced by medullary thick ascending limb (mTAL) epithelial cells of the kidneys. There is accruing genetic evidence implicating UMOD in blood pressure regulation and consequently hypertension. The molecular signaling induced by calcium in the kidney and its influence on blood pressure are not well understood. The aim of this study was to investigate the potential role of extracellular calcium and the calcium-sensing receptor (CaSR) in mTAL on UMOD production and secretion in TAL cells with the hope of defining novel clinical targets for the treatment of hypertension.

Method
Kidneys were harvested from normotensive Wistar-Kyoto (WKY) and stroke-prone spontaneously hypertensive (SHRSP) female rats. To determine the effect of extracellular calcium on UMOD secretion, mTAL tubules were incubated in media with and without 1mM calcium, nifedipine (10µM), NPS2143 (1 or 5 µM) and spermine (2mM). Extracellular and intracellular UMOD protein levels were detected by Western blot. Gene expression of Umod was determined by qRT-PCR.

Results
Calcium increased mTAL tubule UMOD secretion in WKY and SHRSP. Nifedipine slightly decreased UMOD secretion in WKY without calcium. In both strains, NPS2143 increased calcium-induced UMOD secretion, with an enhanced effect in SHRSP. Stimulation of CaSR with spermine decreased UMOD secretion in WKY. Analysis of intracellular UMOD levels in these conditions demonstrated increased accumulation when extracellular secretion was low, and vice versa. Incubation of primary mTAL cells with calcium confirmed increased localisation of UMOD at the membrane compared to the cytosol, without any major differences in cell morphology. The Umod mRNA level changes were not statistically significant among conditions.

Conclusion
Trafficking of UMOD in the mTAL is influenced by the type of CaSR ligand and the biased nature of G-protein coupled CaSR signalling. Unravelling the signalling events post-calcium will be necessary for identification of key regulators of UMOD secretion and provide new sites for therapeutic intervention in hypertension.
MO101ASSESSING EARLY RENAL INVOLVEMENT IN ESSENTIAL HYPERTENSION BY MEASURING URINARY ALBUMIN AND UROMODULIN EXCRETION
Authors: Morshed Raquib , Alam Kazi Shahnoor , Alam Babrul , Banerjee Sajal Krishna , Hassan M Z , Chaudhury S R , Chowdhury Maa , Iqbal Md M 
Published: May 2021

Abstract

Background and Aims
Kidneys are target organs in hypertension. Hypertensive damage results in glomerular as well as tubular dysfunction. Albuminuria is a known marker of glomerular damage. Whereas, urinary uromodulin is increasingly considered as potential biomarker of early tubular dysfunction. The aim of this study was to identify the pattern of early renal involvement based on glomerular and tubular function assessment by measuring urinary albumin and uromodulin in hypertensive patients

Method
In this cross-sectional study 122 hypertensive subjects with age&gt;30 years, duration of hypertension &lt;5years, without accelerated or malignant BP, absence of dipstick proteinuria and eGFR&gt;60ml/min. Subjects with possibility of secondary hypertension were excluded. There were also 33 normotensive volunteers included as healthy referents. Morning spot urine for albumin-creatinine ratio (ACR mg/g), urine uromodulin-creatinine ratio (urUMODµg/g), urinary sodium-creatinine ratio (mEq/g) and potassium-creatinine ratio (mEq/g) were measured in single urine sample. Urine uromodulin was measured by ELISA method.

Results
The hypertensive and healthy subjects were matched for age 48±11 vs. 47±11, years (P=NS). The systolic BP was 145±15 vs. 112±12 mmHg and diastolic BP 86±9 vs. 70±8 mmHg; (p&lt;0.001) and the mean ACR was 29±65 vs. 5.6±2.7 mg/g, (p&lt;0.001) respectively. Around 20% hypertensives had albuminuria. Urinary potassium excretion was lower in hypertensives (51±31 vs. 69±31, mEq/g; p&lt;0.02). The median urUMOD in hypertensive subjects was 3.38 (1.73-9.06) and in normotensives 3.85(2.28-5.69) µg/g (P=NS).Multivariate analysis showed significant inverse association between diastolic blood pressure and urinary uromodulin excretion. An urURMOD cut-off of 2.9 (25th percentile in normotensives) showed eGFR, urinary sodium & potassium excretions were significantly lower at low uromodulin cut-off and this was seen in38%subjects.

Conclusion
The glomerular involvement was found in 20% hypertensives as evidenced by albuminuria. In general urinary uromodulin level was not different between hypertensive and normotensive subjects. Association of low uromodulin cut-off with lower eGFR, Na+ and K+ excretion indicates simultaneous tubule glomerular involvement in 38%.
MO102LUNG ULTRASOUND-GUIDED DRY-WEIGHT REDUCTION DECREASES AMBULATORY BLOOD PRESSURE LEVELS IN HYPERTENSIVE HEMODIALYSIS PATIENTS: LONG-TERM ANALYSIS OF A LUST SUB-STUDY*
Authors: Loutradis Charalampos , Sarafidis Pantelis , Ekart Robert , Tsouchnikas Ioannis , Papadopoulos Christodoulos , Kamperidis Vasileios , Alexandrou Maria Eleni , Ferro Charles , Papagianni Aikaterini , London Gérard , Mallamaci Francesca , Zoccali Carmine 
Published: May 2021

Abstract

Background and Aims
Hypertension is highly prevalent and independently associated with adverse outcomes in patients undergoing hemodialysis. The main mechanism leading to BP elevation in these individuals is their inability to maintain water homeostasis. This study examines the long-term effects of dry-weight reduction with a standardized lung-ultrasound-guided strategy on ambulatory BP in hypertensive hemodialysis patients.

Method
This is the report of the 12-month trial phase of a randomized controlled trial in 71 clinically euvolemic, hemodialysis patients with hypertension. Patients were randomized (1:1 ratio) in the active group (23 male and 12 female), following dry-weight reduction guided by the total number of US-B lines prior to a mid-week dialysis session and the control group (24 male and 12 female), following standard-of-care treatment. A 48-hour ABPM was performed in all study participants at baseline and after 12 months.

Results
During follow-up more patients in the active compared to control group had dry weight reduction (71.4% vs 22.2%; p&lt;0.001). US-B lines -4.83±13.73 vs 5.53±16.01; p=0.005) and dry-weight (-1.68±2.38 vs 0.54±2.32; p&lt;0.001) decreased in the active and slightly increased in the control group. At 12 months, 48-hour SBP (136.19±14.78 vs 130.31±13.57; p=0.034) and DBP (80.72±9.83 vs 76.82±8.97; p=0.008) were lower compared to baseline in the active but similar in the control group. Changes in 48-hour SBP (-7.78±13.29 vs -0.10±14.75; p=0.021) were significantly greater in the active compared to the control group. Comparisons for intradialytic, 44-hour, Day-1, Day-2 and day- and night-time BP were to the same direction. The proportion of patients experiencing at least one episode of intradialytic hypotension was numerically lower in the active group (71.4% vs 88.9%, p=0.065).

Conclusion
A lung-ultrasound-guided strategy for dry-weight reduction can effectively and safely decrease ambulatory BP levels during a 12-month follow-up period This method is a simple treatment approach to improve hypertension management in hemodialysis patients.
MO104RISK OF END-STAGE RENAL DISEASE: PREDICTION USING CUMULATIVE NUMBER OF HYPERTENSION DIAGNOSES
Authors: Kim Chang Seong , Choi Hong Sang , Oh Tae Ryom , Bae Eun hui , Kim Soo Wan 
Published: May 2021

Abstract

Background and Aims
Hypertension is the leading risk factor for end-stage renal disease (ESRD). However, the association between repeated measurements of high blood pressure and ESRD is not well-established. This study investigated whether the cumulative number of diagnoses of hypertension is a substantial risk factor for ESRD.

Method
The incidence of ESRD among 2,144,801 participants, identified from the Korean National Health Insurance Service database, who did not have a history of antihypertensive therapy and had documented blood pressure assessments for 4 consecutive years was determined retrospectively. Data were extracted from the database where events of hypertension were defined as systolic blood pressure ≥140 mmHg or diastolic blood pressure ≥90 mmHg.

Results
Over a median follow-up of 7.2 years, ESRD was identified in 1758 of the 2,144,801 participants. In a multivariable Cox model adjusted for age, sex, smoking, alcohol consumption, exercise, and history of diabetes and chronic kidney disease, a positive dose-dependent relationship between the cumulative number of diagnoses of hypertension and ESRD was found (adjusted hazard ratio for ESRD, 2.70 in 4 cumulative number of diagnoses of hypertension compared to no history of hypertension). This association was maintained for the cumulative number of diagnoses of both systolic and diastolic hypertension.

Conclusion
The cumulative number of diagnoses of systolic or diastolic hypertension increases the risk of ESRD. Therefore, preventive treatment to avoid repetitive events of systolic or diastolic hypertension may be important to lower the risk of ESRD in this clinical population.
MO105TELEMEDICAL SURVEILLANCE AND OPTIMIZED TREATMENT OF BLOOD PRESSURE IN KIDNEY TRANSPLANT RECIPIENTS
Authors: Duettmann Wiebke , Naik Marcel , Zukunft Bianca , Schmidt Danilo , Glander Petra , Osmanodja Bilgin , Mayrdorfer Manuel , Choi Mira , Bachmann Friederike , Weber Ulrike , Graf Verena , Dürr Michael , Halleck Fabian , Budde Klemens 
Published: May 2021

Abstract

Background and Aims
Patients with chronic kidney disease suffer often from cardiovascular diseases, especially high blood pressure and its complications such as stroke and heart attack. After kidney transplantation, this condition persists and can in addition harm the graft. However, outpatient care surveillance is not ideal to treat high blood pressure sufficiently. mHealth solutions such as remote vital signs seem to have the potential to fill in this gap.

Method
To optimize the monitoring of kidney transplant recipients (KTR), the MACCS (Medical Assistant for Chronic Care Solution)-project offers participants an intensified control of home-measured vital signs via a smartphone app. Additionally, well-being and medical adherence can be forwarded. A telemedicine team reviews daily incoming data and takes action, if necessary. A self-programed telemedicine dashboard visualizes the data. KTR receive their updated medication plan and medical support. The pilot phase of project started in February 2020 and is ongoing. A randomized controlled trial will start in March 2021. The concept sticks to General Data Protection Regulation (GDPR) of European Union.

Results
Currently, 335 KTR participate in the project with 26 (7.76%) dropouts since beginning. Including the 26 dropouts, we received in total 15 973 blood pressure (BP) values (mmHg) (systolic BP [SBP] mean 128.56, standard deviation [SD] ±103.7, maximum (max) 220, minimum (min) 60; diastolic BP [DBP] mean 78.51, SD ±9.97, max 120, min 60) and 27 481 heart rate (HR) values in beats per minutes (bpm) (mean 70, SD ±14, max 200, min 40). For 278 times, an adaption of antihypertensive therapy took place. In total, 170/335 KTR were hospitalized, which made up for 338 hospitalizations (1.99 cases per patient, max 6, min 1), which led to 3 8547 days in hospital (mean 9.34, SD ±11.43, max 89, min 1). In 331 cases, the diagnosis (main or secondary diagnosis) was related to hypertension, and 196 cases the diagnosis may be a hypertension-related complication, e.g. myocardial infarct. Evaluation regarding significance is in process and requires further data.

Conclusion
mHealth solutions including remote vital signs and telemedicine personnel for regular evaluation have the potential to optimize blood pressure treatment. Acute onset of hypertensive crisis can be handled sufficiently at home and thus reduce treatment at emergency rooms. Since severe complications of high blood pressure levels manifest after years, long-term results are required to conduct conclusions.
MO093CLARIFICATION OF BIOSYNTHESIS OF ANGIOPROTECTIN
Authors: Lellig Michaela , Muñoz-Castañeda Juan R , Hermann Juliane , Rodriguez Mariano , Jankowski Joachim , Jankowski Vera 
Published: May 2021

Abstract

Background and Aims
The renin-angiotensin-aldosterone system (RAAS) is involved in the regulation of the blood pressure, water- and electrolyte balance. Pathophysiologically, this system is essential for the development and pathogenesis of both cardiovascular and renal diseases. Recently, the angiotensin peptide ´angioprotectin´ was identified as an antagonist of the contractile effect of angiotensin II. The amino acid sequence of angioprotectin (pro-glu-val-tyr-ile-his-pro-phe) compared to the amino acid sequence of angiotensin II (asp-arg-val-tyr-ile-his-pro-phe) differs in the n-terminal amino acids asp1 and arg2, which are transformed to pro1 and glu2 by endothelial cells (Jankowski et al., 2011). The aim of the study is the identification of the underlying mechanism of the transformation of angiotensin II to angioprotectin.

Method
To clarify the transformation of angioprotectin diverse angiotensin peptides were incubated with enzymes like glutamic oxaloacetic transaminase (GOT), cofactors like pyridoxal-5’-phosphate (PLP) and other substances like vitamin B6-derivates. Aliquots were collected time-dependently and analyzed by matrix-assisted laser desorption/ionization time of flight mass spectrometry (MALDI-TOF). To investigate the impact of angioprotectin on the organism, rats were treated with angiotensin II in the absence and presence of PLP. The blood pressure was used as read-out of the effect of the treatment.

Results
The incubation of angiotensin II with pyridoxal-5’-phosphate in vitro caused in increased amount of angioprotectin. Since the first two amino acids aspartic acid and arginine of further peptides like angiotensin I, angiotensin (1-6) and cortistatin-17 were also metabolized to proline and glutamic acid, the underlying mechanism is not specific for angiotensin II, but for aspartic acid and arginine. In accordance with this, the blood pressure of spontaneously hypertensive rats (SHR) treated with PLP decreases after three days. The blood pressure of Wistar Kyoto rats (WKY) treated with angiotensin II increases, whereas the blood pressure of WKY rats treated with angiotensin II and PLP decreases to normal level.

Conclusion
Angiotensin II is obviously metabolized by pyridoxal-5’-phosphate (PLP) to angioprotectin. PLP decreases the blood pressure in spontaneously hypertensive rats and in Wistar Kyoto rats. The first two amino acids aspartic acid and arginine are also metabolized to proline and glutamic acid in other peptides.
MO094SALT INFLUENCES UROMODULIN EXCRETION INDEPENDENT OF BLOOD PRESSURE
Authors: Mary Sheon , Boder Philipp , Rossitto Giacomo , Graham Lesley , Scott Kayley , Flynn Arun , Kipgen David , Graham Delyth , Delles Christian 
Published: May 2021

Abstract

Background and Aims
Uromodulin (UMOD) is the most abundant renal protein secreted into urine by the thick ascending epithelial (TAL) cells of the loop of Henle. Genetic studies have demonstrated an association between UMOD risk variants and hypertension. Studies on UMOD overexpressing transgenic mice have shown that UMOD increases the tubular salt reabsorption via enhanced NKCC2 activity. We aimed to dissect the effect of salt-loading and blood pressure on the excretion of UMOD.

Method
Wistar-Kyoto (WKY) and stroke-prone spontaneously hypertensive (SHRSP) rats (n=8/sex/strain) were maintained on 1% NaCl for three weeks. Salt-loaded SHRSP were treated with nifedipine. Tubule isolation and ex vivo incubation with nifedipine were used to assess its direct effect on TAL.

Results
Urinary UMOD excretion was significantly reduced after salt loading in both strains (figure). In salt-loaded SHRSP, nifedipine treatment reduced blood pressure and urinary UMOD excretion. The reductions in urinary UMOD excretion were dissociated from unchanged kidney UMOD protein and mRNA levels, however, were associated with UMOD endoplasmic reticulum accumulation, thus suggesting secretion as a key regulatory step. Ex vivo experiments with TAL tubules showed that nifedipine did not have a direct effect on UMOD secretion.

Conclusion
Our data suggest a direct effect of salt on UMOD secretion independent of blood pressure and a potential role of endoplasmic reticulum stress on the control of UMOD secretion. The role of UMOD as a cardiovascular risk marker deserves mechanistic reappraisal and further investigations based on our findings.