bluuebunny/crossref_metadata_2025 huggingface dataset:
MO311THE ASSOCIATION BETWEEN NEPHROTIC-RANGE PROTEINURIA AND OXALATE METABOLISM VIOLATION IN PATIENTS WITH PRIMARY GLOMERULONEPHRITIS
Authors: Stepanova Natalia , Snisar Lyudmyla , Lebid Larysa , Savchenko Svitlana
Published: May 2021

Background and Aims

There is a general lack of scientific research on oxalate metabolism in primary glomerulonephritis (PGN) patients. The present study aimed to evaluate plasma oxalic acid (POx) concentration and urinary oxalate (UOx) excretion in PGN patients and determine the role of nephrotic syndrome in oxalate metabolism, which has never before been reported.

Method

A total of 100 participants were enrolled in this cross-sectional single-center study, including 76 PGN patients aged 41 ± 1.83 years and 24 healthy volunteers on a free-choice diet who served as a control reference group to evaluate POx concentration. Among the patients were 53 (69.7 %) patients with nephrotic syndrome (NS) and biopsy-proven PGN and 23 (30.3 %) patients with a clinical diagnosis of PGN. All patients were treated according to KDIGO Clinical Practice Guidelines for Glomerulonephritis.

In addition to routine hematological and biochemical tests, POx concentration and UOx excretion were found in all study participants. POx was measured spectrophotometrically using a commercially available kit (MAK315, Sigma, Spain). Daily UOx excretion was determined using an oxalate oxidase/peroxidase reagent (BioSystems, Spain). Urine protein excretion (UPE) was measured in a 24-h urine collection. The glomerular filtration rate (GFR) was calculated using the CKD-EPI formula.

The data were presented as the median and the interquartile ranges [Me (Q25-Q75)] and compared using the Mann-Whitney test. The Spearman correlation test and the partial correlation coefficient were used to evaluate the association between the examined markers.

Results

POx concentration was significantly higher in the patients with PGN compared with the healthy volunteers: 29.9 (14.9-51.7) vs 18.9 (16.2-23.8) µmol/L, p = 0.01. Although the patients with NS demonstrated a statistically higher GFR level compared with the patients with mild proteinuria [70.5 (47-87) vs 50 (22-76.2) mL/min/1.73 m2, p = 0.01], these patients also had the highest POx level (Fig. 1). Moreover, POx concentration was significantly associated with GFR (r = -0.27, p = 0.005), serum phosphate (r = 0.26, p = 0.007) and UPE (Fig. 2) levels. No significant differences were found in UOx excretions between the groups. However, the higher level of UPE was, the higher level of UOx was observed in the PGN patients with NS (Fig. 3). The partial correlation analysis confirmed a strong association between UPE and POx concentration independently of the patients’ age, gender, GFR and serum phosphate levels (r = 0.22, p = 0.04).

Conclusion

Nephrotic-range proteinuria was significantly associated with the elevation of POx concentration and UOx excretion in the PGN patients. More research with a larger cohort is needed to confirm this preliminary evidence and validate NS as a risk factor for oxalate metabolism violation in PGN patients.
MO314ANA POSITIVITY IN IGA NEPHROPATHY: IS SYSTEMIC LUPUS ERYTHEMATOSUS COMING UP?
Authors: Catapano Fausta , Fabbrizio Benedetta , Mancini Elena
Published: May 2021

Background and Aim.

IgA nephropathy (IgAN) is the most common chronic primary glomerulonephritis leading to progressive renal failure in 1/3 of patients. Although it is a limited non-systemic renal disease, many systemic diseases, such as Systemic Lupus Erythematosus (SLE), are sporadically associated with mesangial IgA deposits. We investigate frequency and meaning of ANA positivity in IgAN.

Methods.

All biopsy-proven IgAN patients followed in our Unit with ANA positivity were selected. Data are compared by non parametric test (Wilcoxon signed-rank test).

Results.

15/68 (22%) IgAN patients resulted ANA+ during a 9-year median follow-up. 10 were females and five were male. Mean age was low. Renal function was normal in 9/15. 24 h Proteinuria was non nephrotic in 15/16. In 10 patients there was low C3. Patient characteristics are summarized in Table 1. At follow-up, renal function did not change significantly (p=NS), however mean 24h-Uprot reduced (p=0.075) Table 2. One male developed SLE, one female a lupus-like Mixed Connective Tissue Disease.

Conclusions.

Our data suggest that 1) in 22% of IgAN patients ANA positivity could be detected; 2) ANA+ IgAN patients are mostly women with normal renal function and non nephrotic proteinuria; 3) after a median 9-year follow-up, ANA+ IgAN patients, on therapy, presented a stable renal function and a reduced proteinuria; 4) ANA+ IgAN patients could develop SLE. More clinical observations and studies are needed for supporting the hypothesis that IgAN+ANA positivity could be part of a new clinical entity of SLE patients.
MO317DETERMINANTS OF LENGHT OF HOSPITAL STAY (LOS) IN NEPHROTIC SYNDROME PATIENTS
Authors: Accarino Simone , Colucci Marco , Pasquinucci Ettore , Sileno Giuseppe , Esposito Vittoria , ARAZZI MARTA , Cristini Eleonora , Esposito Ciro
Published: May 2021

Background and Aims

Generalized edema, non responsive to oral diuretics, is one of the main causes of hospital admission for nephrotic syndrome patients. Although hospital length of stay (LOS) may vary widely, in 2017 the average LOS in acute-care hospitals was lower than 8 days in OECD countries. The aim of the present study was to determine the factors commonly associated with a longer LOS in patients admitted for edema due to nephrotic syndrome in the Nephrology Unit of ICS Maugeri, Pavia, Italy

Method

In this retrospective study we reviewed the medical records of all patients admitted for nephrotic syndrome between 2012-2020 in the Nephrology Unit of ICS Maugeri. Inclusion criteria were the following: age between 18-85 years of age; severe edema non responsive to oral, low dose diuretics; patients with heart failure, serum creatinine > 3.5 g/dl or on dialysis treatment were excluded from the study. Patients were divided into two groups according to the length of stay: ≤ 7 days or ≥ 8 days. Age, gender, serum protein concentration, creatinine, and hemoglobin; serum cholesterol and tryglicerides, urinary protein excretion rate; types of glomerular disease, weight loss were recorded. Student T tests and one-way Anova were performed to evaluate the differences between the means.

Results

60 patients (42 male, 18 female) with a total number of hospital accesses of 93 were enrolled in the study. Mean age was 66.8 ± 13.07 years. Average LOS was 9.02 ± 7.4 days. Protein excretion rate was 6.7 ± 3.6 g/24 hours at the admission and was not statistically changed at discharge. Mean total serum protein and creatinine concentration at the admission were 4.7 ± 0.8 g/dl and 1.8 ± 1.1 mg/dl respectively. Patients with LOS < 7 days were younger (64 ± 11.9 vs 69 ± 13.6 years, p <0.05), had a lower serum creatinine (1.55 ± 0.92 vs 2.08 ± 1.2 mg/dl, p>0.001) and a significantly higher total serum protein concentration (5.02 ± 0.77 vs 4.65 ± 0.76 g/dl, p< 0.001) and haemoglobin (12.6 ± 1.8 vs 11.4 ± 1.8 g/dl, p< 0.05) compared to patients with longer LOS. Proteinuria was not significantly different between the two groups (6.27 ± 3.36 vs 7.1 ± 3.9 g/24 hours, p= NS). While serum cholesterol and tryglicerides were higher in the group of patients with longer LOS, weight loss was similar in the two groups at discharge. Although the difference was not significant, the group with longer hospitalization had a greater number of patients with a diagnosis of focal segmental glomerulosclerosis (FSGS)

Conclusion

Our results demonstrate that age, total serum protein concentration, serum creatinine, higher lipids and probably the diagnosis of FSGS may affect the hospital length of stay of patients with nephrotic syndrome admitted for severe edema. A more aggressive diuretic treatment may be needed in elderly nephrotic syndrome patients with lower GFR and total serum protein concentration.
MO318END-STAGE RENAL DISEASE RELATED FACTORS IN ANCA-ASSOCIATED VASCULITIS
Authors: Ferrer García Guillermo , Moral Berrio Esperanza , Castro Fernández Maria Paz , Piccone Saponara Luis Guillermo , Carreño Parrilla Agustín , Martínez Calero Alberto , Arambarri Segura Minerva , Sidel Tambo Diego , Sanchez Escudero Patricia , Vozmediano Poyatos Carmen
Published: May 2021

Background and Aims

Management of ANCA-Associated Vasculitis (AAV) is in constant update. The aim of the study is to describe our experience as a territorial reference center with this systemic disease and to analyze which factors have a significant influence on the development of end-stage renal disease (ESRD).

Method

Retrospective observational study. All the patients who developed AAV in our center between 2010 and 2019 were included. Demographic variables (age, sex), renal function, other vasculitis related symptoms, induction and maintenance therapy, response degree and follow-up were collected. Categorical variables are expressed as percentages and compared using Chi2 test. Quantitative variables are expressed as mean ± standard deviation and compared using Mann-Whitney U test. Cox regression was performed to determine independent predictors of ESRD. Kaplan-Meier was used to estimate ESRD-free survival. Statistical significance for a value of p< 0,05. Statistical analysis was performed with SPSS 25.0.

Results

45 patients were analyzed, with an average age of 70 ± 11 years. 62.2% were men. Mean time of follow-up 36 ± 31.6 months. 37.8% presented c-ANCA autoantibodies and 57.8% p-ANCA. Mean baseline serum creatinine level was 5.51 ± 3.65 mg/dl and proteinuria 2.82 ± 2.48 g/24h. 77.8% received cyclophosphamide as induction immunosuppressive treatment whereas 13.3% rituximab. 50% received azathioprine, 36.1% mycophenolate and 13.9% rituximab as maintenance treatment. 37.8% patients underwent plasma exchange therapy and 44.4% hemodialysis. Complete remission was achieved by 13.3% of patients, while 57.8% partial remission. 28.9% had absence of remission. 28.9% achieved ESRD. ESRD was associated with undergoing hemodialysis (69.2% vs 30.8% p=0.033), to the type of response (complete 7.7% vs partial 23.1% vs no response 69.2%), baseline creatinine level (8.36 ± 5.44 vs 4.35 ± 1.64 mg/dl p=0.011), creatinine 6 months after induction treatment (4.3 ± 2.05 vs 2.04 ± 0.77 mg/dl p=0.001) and at the end of follow-up (6.33 ± 2.47 mg/dl vs 2.2 ± 1.29 mg/dl p=0.001) and also to baseline proteinuria (4.21 ± 3.12 vs 2.25 ± 1.96 p=0.003), proteinuria 6 months after induction treatment (1.4 ± 1.46 vs 0.58 ± 0.73 g/24h p=0.014) and at the end of follow-up (2.48 ± 1.9 vs 1.12 ± 1.64 p=0.001). Logistic regression only showed end of follow up serum creatinine level as an independent risk factor of ESRD (OR3.74 IC 95% 1.01-13.75 p=0.047). ESRD-free survival chance after 5 of follow-up was 67%.

Conclusion

Only serum creatinine level at the end of follow-up could be found as an associated factor with ESRD. Greater number of patients would be needed in order to obtain other factors leading to ESRD in patients with AAV.
MO320LUPUS FLARE MIMICKING COVID-19 INFECTION: A CASE REPORT
Authors: Sabah Meryem , Jabrane Fatimzahra , El oury Hiba , Khalfaoui Mohamed Amine , Chehab Nasreddine , Medkouri Ghizlaine
Published: May 2021

Background and Aims

The world is in midst of the coronavirus disease 2019 (COVID-19) pandemic.

Method

Studies of the COVID-19 pathophysiology show that its defining character is an overt inflammatory response, similar to cytokine release syndrome, causing a dysregulated immune response. Systemic lupus erythematosus (SLE) is also a disease of immune dysregulation contributing to multisystem compromise. There is very little literature to suggest that COVID-19 could potentially mimick SLE presentation. We describe the case of a female patient who presented with typical Covid19 clinical features, later diagnosed as a new-onset SLE.

Results

A 51-year-old female presented with fever, dyspnea, cough and desaturation at the emergency room. Chest computed tomography scan showed bilateral areas of ground-glass opacities in a peripheral distribution. She was admitted in a Covid-19 ICU. She then progressed to severe acute respiratory distress syndrome, and worsening renal function with proteinuria and hematuria. Further investigations showed bilateral pleural effusions, ascites, leukopenia and thrombocytopenia, positive antinuclear and anti-double-stranded DNA antibodies, and low levels of C3 and C4. SARS-Cov-2 PCR was negative twice. After the establishment of the diagnosis, the patient was transferred to the internal medicine department where she received decongestive therapy, intravenous (IV) pulses of methylprednisolone, along with hydroxychloroquine. She improved sustainably and was discharged after two weeks.

Conclusion

A patient with new-onset lupus presented with clinical features typically seen in COVID-19 patients. The adequate management of the patient was delayed due to the misguided diagnosis.
MO321THE USE OF INTRAVENOUS CYCLOPHOSPHAMIDE AND ORAL STEROIDS IN PRIMARY MEMBRANOUS NEPHROPATHY WITH ADVANCED KIDNEY DISEASE
Authors: Ragy Omar , Hamilton Patrick , Kanigicherla Durga
Published: May 2021

Background and Aims

International guidelines do not recommend specific use of immunosuppression treatment in membranous nephropathy patients presenting with an estimated glomerular filtration rate of <30ml/min/1.73m2. This is due to the scant published evidence of effectiveness and uncertainty around toxic effects at this stage. In this study, we sought to examine the safety and effectiveness of combined cyclophosphamide and steroids in primary membranous nephropathy with advanced kidney disease.

Method

This is a retrospective study of 18 patients with a biopsy confirmed membranous nephropathy who received combination therapy between 2004 and 2019. The mean age was 66.5 with a 5:1 male: female ratio. The immunosuppression regime included monthly intravenous pulse cyclophosphamide and daily oral steroids. All patients had an initial eGFR of < or = 30 ml/min/1.73 m2 at time of treatment. Clinical parameters are serially monitored as part of clinical care and anti-PLA2R antibody levels were measured at the time of and 1-year post immunosuppression treatment where available.

The primary outcome was the achievement of partial remission as per standard criteria. Secondary outcomes were immunological response defined by following the anti-PLA2R antibody levels at the time of presentation and 1-year post, need for renal replacement therapy, outcomes including hospital admission, infections, malignancy, and death.

Results

Partial Remission was achieved in 16 out of 18 (88%) patients.7 patients (39%) reached complete remission, with none of them requiring dialysis over an average follow-up of 5 years. The average increase in eGFR was 12.5 ml/min/1.73m2 from the time of immunosuppression till the latest follow up.

2 out of 18 (11%) patients were refractory to treatment and required initiation of dialysis 1 and 8 years post immunosuppression. Results for the anti-PLA2R antibody test were available for 12 (66.6%) patients at presentation all shown to be positive. Of these, 7 (58%) achieved both immunological and clinical remission. 4 patients developed 4 different cancers (Bladder, mesothelioma, skin SCC and sigmoid) during follow-up; 2 patients required hospital admission for episodes of infections. Both were managed with antibiotics, and patients were discharged home safely. 5 patients died at the end of the follow-up period (27.7%).

Conclusion

Here we show that the combination of intravenous pulse cyclophosphamide and steroid is well tolerated and effective in achieving remission in primary membranous nephropathy with advanced renal disease. Both immunological and clinical responses could be achieved in this cohort. Longer-term risk in such patients includes malignancy and infections. This study provides reassurance that this cohort of patients can be considered for immunosuppressive treatment, although prospective studies are required to provide further robust evidence.
MO323MEDICATION INDUCED RELAPSE OF FGSG
Authors: Anvari Evamaria , Barnes Julie
Published: May 2021

Background and Aims

31-year-old female with past medical history of Multiple Sclerosis diagnosed with Minimal Change Disease (MCD) in 2011. At diagnosis she had proteinuria that exceeded 7 g per day. She was treated with steroids and went into complete remission. In 2017 presented again with nephrotic syndrome and on repeat biopsy she was diagnosed with Focal Segmental Glomerulosclerosis (FSGS). She was restarted on steroids and had some improvement but despite 20 weeks of high dose steroids did not achieve remission. After every attempt of tapering, she would relapse.

Method

Other treatments tried without success were tacrolimus, cyclophosphamide and rituximab. Mild improvement with tacrolimus but stopped after a grand mal seizure. The lowest achievable steroid dose was 20mg daily. She was started on combination therapy tacrolimus and mycophenolate mofetil and was able to come off steroids and went into remission.

Results

After a few months of remission, she began to relapse. It was noted after extensive investigation that she had been placed on cabergolin for hyperprolactinemia by her endocrinologist at the time she began to relapse. Cabergolin was stopped and she went into remission again. We present the first case of FSGS relapse due to cabergolin.

Conclusion

Cabergoline is metabolized by hydrolysis and has limited cytochrome P450 (CYP) metabolism. Despite limited CYP metabolism, cabergoline does have an interaction with clarithromycin, a known inhibitor of CYP and p-glycoprotein. One rat study suggest that mycophenolate is a substrate for p-glycoprotein, so it is possible that there is some competitive inhibition. This would explain why the patient relapsed while on cabergoline and in remission after stopping it.
MO326CORTICOSTEROIDS FOR THE TREATMENT OF AUTOIMMUNE DISEASE: A SYSTEMATIC REVIEW AND META-ANALYSIS OF REPORTED ADVERSE EVENTS IN RANDOMISED CONTROLLED TRIALS
Authors: Major Rupert , Grant Robert , Nockels Keith , Das Mrinal , Floege Jürgen , Barratt Jonathan
Published: May 2021

Background and Aims

Systemic corticosteroids are commonly used to treat autoimmune diseases such as immunoglobulin A (IgA) nephropathy. Corticosteroids are associated with increased risk of adverse events such as weight gain, hyperglycaemia, hypertension, infection and bone fracture occur frequently and affect safe long-term use. Adverse events of corticosteroids in clinical trials may have been historically under-reported. We aimed to perform a systematic review and meta-analysis of reported adverse events of corticosteroids in autoimmune diseases, with a particular focus on kidney pathologies.

Method

Pre-registered protocol systematic review (Prospero ID: CRD42020206650). The following databases were searched from 1980 to 2020:

Placebo-controlled trials in adults with any form of autoimmune disease receiving intravenous or oral corticosteroids were included in the systematic review. Trial protocol major adverse events and all-cause mortality were included as the current study’s main outcome.

Results

After exclusion of duplicates between databases, 4490 OVID MEDLINE and 4987 Cochrane abstracts were reviewed. In total, 110 published clinical trials were identified for inclusion in the study: 14 clinical trials were in kidney autoimmune diseases, including 8 in IgA nephropathy. Results of their published adverse events, including where appropriate meta-analysis, will be presented. Specific results of those studies of kidney pathologies such as IgA nephropathy will be presented.

Conclusion

This systematic review with a pre-registered protocol identified 110 clinical trials examining systemic corticosteroid use versus placebo in autoimmune diseases. These results will help to understand whether the risks of systemic corticosteroids for autoimmune disease has been historically under-reported in the medical literature and whether a clear risk and benefit profile of corticosteroids in autoimmune disease can be assessed.
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

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

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

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

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>30 years, duration of hypertension <5years, without accelerated or malignant BP, absence of dipstick proteinuria and eGFR>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<0.001) and the mean ACR was 29±65 vs. 5.6±2.7 mg/g, (p<0.001) respectively. Around 20% hypertensives had albuminuria. Urinary potassium excretion was lower in hypertensives (51±31 vs. 69±31, mEq/g; p<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

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<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<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

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

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

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

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.
MO098HUMAN STOOL METABOLOME DIFFERS UPON 24-HOUR BLOOD PRESSURE LEVELS AND THE NON-DIPPING BLOOD PRESSURE PROFILE
Authors: Huart Justine , Cirillo Arianna , Taminiau Bernard , Descy Julie , Saint-Remy Annie , Daube Georges , Krzesinski Jean-Marie , Melin Pierrette , De Tullio Pascal , Jouret François
Published: May 2021

Background and Aims

Dysbiosis of gut microbiota (GM) has been involved in the pathophysiology of arterial hypertension (HT), via a putative role of food-derived short chain fatty acids (SCFAs). Among the clinical manifestations of HT, the absence of a significant drop in blood pressure (BP) overnight (i.e. non-dipping BP profile) has been associated with poor cardiovascular outcomes. The link between GM and non-dipping BP profile is unknown.

Method

After informed consent, 16 male patients and their female partners (n=10) were subjected to 24-hours ambulatory BP monitoring and were categorized in 2 groups: HT (n=7; 6 men) and normotension (NT) (n=19). According to the conventional night–day systolic BP ratio >0.9, 15 individuals (8 men and 7 women) were categorized as non-dippers. Metabolomics using Nuclear Magnetic Resonance was performed on stool samples, including the quantification of the 3 main SCFAs (i.e. acetate, propionate and butyrate).

Results

Multivariate analysis (principal component analyses (PCA) and partial least squares (PLS-DA)) of stool metabolomics were not able to statistically separate HT versus NT groups. However, this approach discriminated dippers versus non-dippers groups in both male and female cohorts (Q²=0.87 and 0.98, respectively), as well as in the entire cohort (Q²=0.68). As previously described, fecal amounts of acetate, propionate and butyrate were higher in HT patients than in NT patients in the entire cohort (p=0.027; p=0.015 and p=0.015, respectively). Fecal amounts of acetate, propionate and butyrate were also significantly higher in non-dippers versus dippers in the entire cohort (p=0.027; p=0.038 and p=0.036, respectively). Significant correlations between stool metabolomes and the 24h-mean BP levels were found in male and female cohorts (R²=0.63 and 0.79 respectively) as well as in the entire cohort (R²=0.54).

Conclusion

In conclusion, this 26-patient cohort highlights significant correlations between stool metabolome and (i) BP levels and (ii) non-dipping BP profile in both men and women.
MO100WNT/Β-CATENIN SIGNALING PATHWAY IS ASSOCIATED WITH HYPERTENSIVE CARDIAC AND RENAL FIBROSIS
Authors: Bogdanova Evdokia , Semenova Natalia , Galkina Olga , Zubina Irina , Beresneva Olga , Ivanova Galina , Parastaeva Marina , Dobronravov Vladimir
Published: May 2021

Background and Aims

Arterial hypertension (AH) causes a cardiac remodeling and renal fibrosis which considered to be mediated by reactivation of fetal and pro-fibrotic signaling pathways. Signal transduction of canonical Wnt (β-catenin expression) evaluation in the settings of heart and kidney hypertensive alterations was the subject of the study.

Method

Systolic blood pressure (BP), serum and urinary creatinine (Cr), proteinuria (uTP), inorganic phosphate (sPi), intact parathyroid hormone (PTH), intact fibroblast growth factor 23 (FGF23), Klotho protein, were estimated in spontaneously hypertensive rats after 1 (SHR1, n=6), 2 (SHR2, n=6), 4 (SHR4, n=6) и 6 (SHR6, n=6) months of exposure. Perivascular and interstitial fibrosis (Masson's trichrome), and β-catenin expression (IHC) were analyzed by light microscopy of myocardium and kidney tissues and calculated quantitatively. Statistical comparisons among groups were performed using Mann–Whitney U-test and Kruskal-Wallis H-test. The association between biochemical and morphological variables was estimated by Spearman’s correlation.

Results

In all groups BP increased compared to baseline values (p = 0.011). The decline of renal function was obvious in SHR6 (vs SHR2, p=0.001). Klotho level decreased in SHR2 vs SHR1 (p = 0.026) and in SHR4-6 vs SHR2 (p < 0.013). There were no differences in sPi (p = 0.50), PTH (p = 0.63), FGF23 (p = 0.62) between experimental groups. Perivascular myocardial fibrosis was already increased in SHR2 (vs SHR1, p=0.026, Figure 1a), renal interstitial fibrosis - since 6mo exposure (p = 0.012, Figure 2a). Both cardiac and renal fibrosis were associated with redistribution of β-catenin in cardiomyocytes and tubular epithelial cells (Figure 1a, 2a: decrease in membrane and increase in cytoplasm) without significant changes in tissue β-catenin expression. In heart β-catenin expression correlated with to perivascular fibrosis (Figure 1 b). Renal β-catenin expression correlated with interstitial fibrosis (Figure 2b), but not with sCr (r=-0.03, p>0.05) и uTP (r=0.04, p>0.05).

Conclusion

Reactivation of Wnt/ β-catenin signal transduction is possibly a basic molecular mechanism of cardiac and renal fibrosis in arterial hypertension. The data suggests involvement of Klotho decline mediated activation of canonical Wnt. Targeting these signaling molecules is promising therapeutic strategy for protecting both organs in cardiorenal pathology and requires further research.