bluuebunny/crossref_metadata_2025_split huggingface dataset:
#5482 CIRCULATING BIOMARKERS OF COLLAGEN REMODELING AS MARKERS FOR DEVELOPMENT OF MICROALBUMINURIA IN TYPE 2 DIABETES: THE PRIORITY TRIAL
Authors: Møller Alexandra Louise , Curovic Viktor Rotbain , Rasmussen Daniel G K , Genovese Federica , Karsdal Morten A , Hansen Tine , Rossing Peter 
Published: June 2023

Abstract

Background and Aims
Kidney disease progression is characterized by extensive deposition of extracellular matrix components such as collagen. Therefore, we assessed the effect of spironolactone on collagen remodeling biomarkers and investigated the association between the markers and development of microalbuminuria in serum of persons with type 2 diabetes and normoalbuminuria.

Method
We measured collagen type III (PRO-C3), VI (PRO-C6; endotrophin), VII (PRO-C7), and XXVIII (PRO-C28) formation, and a fragment of degraded crosslinked collagen type III (CTX-III) in serum of persons with high-risk (stratified by a urinary proteomics classifier, CKD273) for development of microalbuminuria, randomized to either spironolactone 25 mg or placebo. Crude and adjusted Cox models were applied to investigate the association between baseline biomarker levels and development of the primary outcome, persistent microalbuminuria, and development of microalbuminuria in at least one morning void sample, used as a secondary outcome.

Results
In the PRIORITY trial, spironolactone treatment did not prevent progression to microalbuminuria compared to placebo. All biomarkers were measured in 154 participants at baseline and 117 at end-of-study (week 208). Treatment with spironolactone did not affect serum levels of any of the investigated collagen remodeling biomarkers compared to placebo, and there were no differences in delta-biomarker levels between baseline and end-of-study (p ranging 0.277-0.875). In crude analyses, serum endotrophin was associated with both the primary (n = 44) and secondary outcome (n = 74) (HR per two-fold higher level: 1.58, 95% CI: 1.03-2.44, p = 0.037 and 1.62, 1.12-2.35, p = 0.010), whereas serum PRO-C3 was only associated with the secondary outcome (1.89, 1.19-2.99, p = 0.007). After adjustment for sex, baseline age, systolic blood pressure, estimated glomerular filtration rate, urinary albumin-creatinine ratio, and HbA1c, serum endotrophin and PRO-C3 remained significantly associated with the secondary outcome (1.52, 1.03-2.24, p = 0.036 and 1.73, 1.08-2.78, p = 0.022). Levels of PRO-C7, PRO-C28, and CTX-III were not associated with the specified outcomes. Neither baseline levels of serum endotrophin nor PRO-C3 correlated with baseline CKD273 levels (R: 0.00-0.06, p&gt;0.47).

Conclusion
Treatment with spironolactone did not change serum levels of collagen remodeling biomarkers. Serum endotrophin, reflecting collagen type VI formation and the pro-fibrotic molecule endotrophin, and PRO-C3, a marker of collagen type III formation, were associated with development of microalbuminuria in at least one urine sample, suggesting that these biomarkers are relevant risk markers for kidney disease development in type 2 diabetes.
#5490 GENERATIVE ARTIFICIAL INTELLIGENCE FOR CREATION OF SYNTHETIC HYPERTENSION TRIAL DATA
Authors: Jain Chirag , Judge Conor 
Published: June 2023

Abstract

Background and Aims
Synthetic data can be an effective supplement or alternative to real data for the training of machine learning models. Synthetic data may also be used to evaluate new tools, develop educational curricula, or remove undesirable biases in datasets. We aim to evaluate four synthetic data generation methods applied to hypertension randomized clinical trial data.

Method
The Systolic Blood Pressure Intervention Trial (SPRINT) trial showed that intensive BP control to SBP &lt;120 mm Hg results in significant cardiovascular benefits in high-risk patients with hypertension compared with routine BP control to &lt;140 mm Hg. The Synthetic Data Vault (SDV) is a Synthetic Data Generation ecosystem of libraries that allows users to easily generate new Synthetic Data that has the same format and statistical properties as the original dataset. SDV supports multiple types of data, including date-times, discrete-ordinal, categorical, and numerical. SPRINT data was pre-processed to create a single table of 140,000 patient visits with baseline variables (age, sex, race, aspirin use, estimated Glomerular Filtration Rate (eGFR)) and visit level variables (systolic and diastolic blood pressure, heart rate and total number of antihypertensive medications at end of visit). Using the SDV library for python, we used four generative models to create synthetic SPRINT data, 1. Gaussian copula model, 2. Conditional Tabular Generative adversarial network (CTGAN), 3. CopulaGan model, and 4. Tabular Variational Auto-encode (TVAE). We evaluated the results using the SDMetrics library which includes the shapes of the columns (marginal distributions), the pairwise trends between the columns (correlations), reproduce mathematical properties from your original data and new row synthesis. Finally, an overall quality score which represents an amalgamation of the marginal distribution and correlations was computed, where 0 indicates the lowest quality and 1 indicates the highest.

Results
Two hundred thousand synthetic patient visits were created for each method. The overall quality scores in order were 90.67% for Gaussian copula, 86.77% for TVAE, 81.03% for CTGAN’, and 79.7% for CopulaGAN. The column shape score which represents the marginal distribution was highest for Gaussian Copula (94.54%), followed by TVAE (88.44%), CTGAN (82.35%), and Copula GAN (80.27%). The column pair trend which corresponds to correlations was highest for Gaussian Copula (86.8%), followed by TAVE (85.1%), CTGAN (79.72%), and Copula GAN (79.12%).

Conclusion
Gaussian copula created the highest scoring synthetic SPRINT data based on the marginal distribution, correlations, and overall score. The Synthetic Data Vault is a feasible collection of methods for generation of synthetic clinical trial data for training future machine learning and AI models.
#5503 PIOGLITAZONE REVERSES MIR-130A AND MIR-199 DYSREGULATION INDUCED BY TGF-BETA DURING KIDNEY FIBROSIS
Authors: Mozes Miklos , Gantsetseg Garmaa , Manzéger Anna , Kokeny Gabor 
Published: June 2023

Abstract

Background and Aims
The peroxisome proliferator-activated receptor-γ (PPARγ) agonists have been shown to dampen TGF-β signaling and suppress miR-130a in VSMCs and also profibrotic miR-21-5p in the kidney. We have recently demonstrated that pioglitazone ameliorates established renal fibrosis by suppressing STAT3 and EGR1 [1], but its effect on renal miR-130a has not been investigated. Thus, we aimed to study how chronic oral pioglitazone treatment would affect TGF-β–driven renal miRNA dysregulation in mice.

Method
Ten week old male C57Bl6 control (CTL, n = 6) and TGF-β transgenic mice (TGFb, n = 12, having elevated plasma TGF-β1 level) were used. CTL mice and half of TGFb mice received regular chow. The second half of transgenic mice received pioglitazone containing chow (dose: 20mg/kg/day) for 5 weeks (TGFb+Pio, n = 6), when the kidneys were evaluated.

Results
Untreated TGFb mice had a 4.7-fold and 2.8-fold type I and type III collagen mRNA overexpression as compared to controls, respectively. This was accompanied by 3.8-fold pro-fibrotic Egr2 mRNA, 2.9-fold miR-130a, 3.9-fold miR-199 and 3.3-fold miR-21 overexpression. Chronic treatment with the PPARγ agonist pioglitazone reduced the expression of both collagen mRNAs and miRNAs miR-199 and miR-21 to control levels, but miR-130a reached even lower values than in control kidneys. Interestingly, the expression of miR-200a (regulated by TGF-beta and known to ameliorate fibrosis) was similar in all CTL and TGFb groups, regardless of treatment.

Conclusion
Our data indicate that PPARγ agonist pioglitazone not only attenuates the TGF-β induced miR-21 overexpression, but also the renal dysregulation of miR-130a and miR-199, supporting its anti-fibrotic effects.
#5517 IN CHRONIC KIDNEY DISEASE, IRON DEFICIENCY-INDUCED ANEMIA IS ASSOCIATED WITH HIGHER LEVELS OF FGF23 THAT ARE NOT REDUCED BY IRON ADMINISTRATION
Authors: Valdés-Díaz Karen , Lopez-Baltanas Rodrigo , Romero Ana Torralbo , Membrives Cristina , Moreno Julio Manuel Martínez , Dominguez Casimiro Valle , Rodriguez Mariano , Cabrera Maria Sagrario Soriano , Muñoz-Castañeda Juan R , Ortiz Maria Encarnacion Rodriguez , Martin-Malo Alejandro 
Published: June 2023

Abstract

Background and Aims
Iron (Fe) deficiency significantly contributes to anemia in chronic kidney disease (CKD). High FGF23 levels, commonly found in CKD, are related to adverse outcomes in patients. In the normal setting, an association between Fe deficiency and FGF23 has been observed. However, it is unknown whether Fe deficiency-induced anemia might contribute to the excessive FGF23 levels in CKD. Thus, this study was intended to evaluate the interplay between Fe deficiency, CKD, and FGF23.

Method
Male Wistar rats with normal renal function received either standard (40 ppm Fe) or Fe-deficient (4 ppm Fe) diets for 6 weeks to induce anemia. Then, several normal and all the anemic rats were switched to an adenine-enriched (0.6%) diet to induce renal damage. Groups of anemic-uremic animals were treated with oral (ferric citrate, FC and ferrous sulfate, FS) or intravenous (ferric carboxymaltose, FCx) Fe at a dose of 9 mg/kg for 5 weeks. Hematological and mineral metabolism parameters were determined at sacrifice. All experimental protocols were approved by the Ethics Committee for Animal Research of the University of Córdoba.

Results
Plasma and serum biochemistries are shown in Table 1. CKD per se was associated with derangements in hematological parameters. The presence of Fe deficiency-induced anemia further decreased these parameters, being statistically significant in the case of serum Fe (P = 0.003). Iron therapy improved hematocrit, hemoglobin, and Fe levels, although statistical significance for all of them was only reached when FC was administered (P = 0.012, P = 0.038, and P = 0.002, respectively). As expected, CKD rats exhibited disturbances in mineral metabolism. Interestingly, uremic and anemic rats showed higher intact (P = 0.039) and c-terminal (P = 0.048) FGF23 levels when compared with CKD group. Despite normalization of serum Fe, intact FGF23 further increased following administration of FS (P = 0.022), and same trend was observed with all the compounds. However, cFGF23 levels remained unchanged in all the Fe-treated groups.

Conclusion
The presence of Fe-induced anemia in an experimental model of CKD is associated with further increases in the levels of both intact and c-terminal FGF23. Thus, other factors distinct than serum Fe might influence FGF23 levels. Our results support the need for investigating the precise mechanisms underlying the relationship between Fe and FGF23 to optimize the clinical management of anemia, particularly in the context of renal dysfunction.
#5522 USING THE KIDNEY FAILURE RISK EQUATION TO PREDICT END-STAGE KIDNEY DISEASE IN CKD PATIENTS OF SOUTH ASIAN ETHNICITY: AN EXTERNAL VALIDATION STUDY
Authors: Maher Francesca , Teece Lucy , Major Rupert , Brunskill Nigel , Booth Sarah , Gray Laura 
Published: June 2023

Abstract

Background and Aims
The Kidney Failure Risk Equation (KFRE) predicts the 2- and 5-year risk of needing kidney replacement therapy (KRT) using four risk factors – age, sex, urine albumin-to-creatinine ratio (ACR), and creatinine-based estimated glomerular filtration rate (eGFR). Although the KFRE has been recalibrated in a UK cohort, this did not consider minority ethnic groups. Further validation of the KFRE in different ethnicities is a research priority. The KFRE also does not consider the competing risk of death, which may lead to overestimation of KRT risk. This study externally validates the KFRE for patients of South Asian ethnicity and compares methods for accounting for ethnicity and the competing event of death.

Method
Data were gathered from an established UK cohort containing 35,539 individuals diagnosed with chronic kidney disease. The KFRE was externally validated and updated in several ways taking into account ethnicity, using recognised methods for time-to-event data, including the competing risk of death. A clinical impact assessment compared the updated models through consideration of referrals made to secondary care.

Results
The external validation showed risk of KRT differed by ethnicity. Model validation performance improved when incorporating ethnicity and its interactions with ACR and eGFR as additional risk factors. Further, accounting for the competing risk of death improved prediction. Using a criteria of 5 year ≥5% predicted KRT risk, the competing risks model resulted in an extra 3 unnecessary referrals (0.59% increase) but identified an extra 1 KRT case (1.92% decrease) compared to the previous best model. A hybrid criteria of predicted risk using the competing risks model and the previous guidelines should be used in referrals to secondary care.

Conclusion
The accuracy of KFRE prediction improves when updated to consider South Asian ethnicity and to account for the competing risk of death. This may reduce referrals whilst identifying risks of KRT and could further individualise the KFRE and improve its clinical utility. Further research should consider other ethnicities.
#5531 MOLECULAR IMAGING OF PDGFR-β IN KIDNEY FIBROSIS
Authors: Klinkhammer Barbara Mara , Moeckel Diana , Wagner Maike , Kiessling Fabian , Lammers Twan , Boor Peter 
Published: June 2023

Abstract

Background and Aims
Chronic kidney disease affects &gt;10% of the world's population and is associated with high mortality and morbidity. The best predictor of CKD progression is the extent of fibrosis, i.e., pathological deposition of extracellular matrix (ECM) and loss of functional kidney parenchyme. Currently, there are no specific treatment options and invasive biopsies remain the gold standard for diagnosis. Multiple signaling pathways are involved in fibrosis, including platelet-derived growth factor (PDGF) signaling. Mesenchymal stromal cells express both PDGF receptors PDGFR-α and PDGFR-β, whose activation drives proliferation, migration and production of extracellular matrix, i.e., key processes involved in fibrosis initiation and progression. Based on these notions, we set out to study the bicyclic PDGFR-β-binding peptide (BiPPB) for diagnosis, quantitative imaging and treatment monitoring of kidney fibrosis.

Method
The biodistribution and kidney accumulation of Cy7-labeled BiPPB and a scrambled peptide control were visualized and quantified using in vivo computed tomography - fluorescence molecular tomography (CT-FMT), ex vivo fluorescence reflectance imaging (FRI) and microscopy. This was done in three different mouse models of kidney fibrosis: the unilateral ischemia-reperfusion injury (I/R), the adenine-induced nephropathy (Adenine) and a transgenic model with constitutive PDGFR-β activation specifically in renal mesenchymal cells leading to increased PDGFR-β expression and expansion of PDGFR-β+ cells (Mutant). In the latter model, we also monitored pharmacological PDGFR-β inhibition with imatinib. Kidney fibrosis and therapeutic efficacy findings were verified by immunohistochemistry (IHC).

Results
In vivo 3D CT-FMT imaging and ex vivo 2D FRI showed strong accumulation in fibrotic kidneys for Cy7-labeled BiPPB, whereas only moderate amounts accumulated in the contralateral (I/R) and healthy (Adenine) kidney over 48 hours after i.v. injection. The accumulation of the scrambled BiPPB was also significantly lower compared to the specific BiPPB. In transgenic Mutant mice with specific activation of mesenchymal cells and primary renal scaring significantly more Cy7-BiPPB accumulated in the kidneys in comparison to healthy wildtype littermates. In combination with imatinib treatment for three weeks (Mutant imatinib) the accumulation of Cy7-BiPPB was decreased (Fig. 1a-c). This was confirmed ex vivo by significantly increased probe accumulation (2D FRI; Fig. 1d) and PDGFR-β expression (immunohistochemistry (IHC) Fig. 1e) in fibrotic kidneys, which was diminished by imatinib treatment.

Conclusion
Our findings demonstrate the potential of PDGFR-β-based imaging agents for non-invasive and quantitative monitoring of renal fibrosis progression and therapy response.
#5532 COVID-19 INFECTION MODIFIES GLOMERULAR DISEASE EVOLUTION
Authors: Ojeda Felipe Ignacio , Rivera Miguel Giovanni Uriol , Rodenas Estela de Los Angeles Mas , Arias-Camisón Paloma Livianos , Mulet Aina Obrador , Arrufat Gemma , Zamora Maria Gomez , Mendoza Sonia Cleofe Jimenez 
Published: June 2023

Abstract

Background and Aims
A fibrotic effect of the SARS-Cov2 virus (Covid-19) has been described and the risk for acute renal failure in glomerular disease (GD) patients; however, the long-term renal effect in these patients is unknown. We evaluate the impact of the Covid-19 infection on eGFR, the influence of proteinuria, the effect of the drugs used to control glomerulonephritis and the use of Paxlovid (nirmatrelvir/ritonavir) for covid infection control.

Method
We retrospectively evaluate the eGFR (mL/min/1.73m2) at month 12 and 6 before infection (pre-infection period), during infection, 6 months after infection and at the last visit post-infection in renal biopsy-proven glomerulonephritis patients. Patients were included from January/2020 to July/2022. All patients were followed up for six months or more from infection.

Results
Forty-seven patients were included. The mean follow-up was 13 months (min: 6-max = 33). Sex Female 24 (52%), Age (mean[SD]) = 47 (14) years. 39(85%) were vaccinated before infection. At infection time, 31(66%) of the patients presented proteinuria (protein/creatinine ratio &gt; 0,2 mg/mg). 27(54%) received oral steroids, 27(54%) mycophenolate, 24(51%) prednisone, and 27(54%) renin-angiotensin system inhibitors (RASi). Four (8%) started chronic renal replacement therapy during the follow-up, and 12(25%) required hospital admission. During the pre-infection period, eGFR remained stable (mean change (95%CI): -2.2 (-8.2 to 3.7) mL/min/1.73m2, P = 1. Compared with month six before infection, eGFR decreased at the end of the follow-up by 9.1 (95% CI: 0.96 to 17.2) mL/min/1.73m2, P = 0.019. After stratifying by the presence of proteinuria, eGFR decreased only in those with proteinuria 14.5 (95%CI: 3.7 to 25.4) mL/min/1,73m2, while no changes were observed in those without proteinuria. No changes in proteinuria level after infection were observed. No interaction between drugs used, hospitalisation requirements and eGFR evolution was observed. In the sub-group of patients treated with Paxlovid (all previously vaccinated) after six months of follow-up, no patients required hospitalisation; however, eGFR evolution was similar to the whole group, which decreased only in those with proteinuria at baseline.

Conclusion
The Covid-19 infection in proteinuric GD patients changed the renal function evolution dramatically. The medication used (mycophenolate, steroid and RASi), including Paxlovid, did not influence this evolution. At the end of the follow-up, the accelerated renal function deterioration continues. Urgent therapeutic measures for controlling eGFR decline in these patients are needed.
#5535 CALCIUM EXCRETION FRACTION AS AN EMERGING PARAMETER FOR AN ACCURATE DIFFERENTIAL DIAGNOSIS OF ACUTE KIDNEY INJURY
Authors: Aranzábal María Alejandra Cortiñas , Sánchez Loreto Mariscal de Gante , Villanueva Laura Salanova , Ruano Pablo , Quiroga Borja 
Published: June 2023

Abstract

Background and Aims
Urinary parameter determination is an essential tool for differentiating acute kidney injury (AKI) etiology. The most used ion in clinical practice is sodium (and its excretion fraction, NaEF), followed by urea (UreaEF) (that is useful in certain circumstances such as diuretic treatment). However, tubular transport includes other anions and cations that have not been widely studied. In the present study, we aim to evaluate the relation between AKI etiology (i.e. functional vs acute tubular necrosis) and calcium excretion fraction (CaEF).

Method
This is a transversal study including consecutive patients with diagnosis of AKI. Patients with suspicion of non-functional or ATN etiology (such as those with proteinuria, hematuria) were excluded. At admission, we collected epidemiological data, comorbidities and active treatments. AKI etiology was determined based on urinary parameters (sodium, urea) and recovery pattern of kidney function after treatment instauration. We compared CaEF in patients with ATN and functional AKI in the whole sample and among patients with and without previous CKD and diuretic prescription.

Results
We included 94 AKI episodes (55% female, 76±15 years). Forty-five (48%) patients had chronic kidney disease (CKD) at baseline and 56 (60%) were receiving treatment with diuretics. Of the 94 AKI, 78 (83%) presented a functional etiology and 16 (17%) were catalogued as ATN. Median CaEF was 1.09 (0.63-2.58) %. CaEF was associated to the etiology of AKI. In patients with functional AKI, median of CaEF was 0.95 (0.60-1.84) % in contrast to ATN (2.33 [1.22-7.27] %)(p&lt;0.001). CaEF presented a positive and significant correlation to NaEF (ρ 0.574, p&lt;0.001) and UreaEF (ρ 0.409, p&lt;0.001). An adjusted regression model including the presence of CKD at baseline and diuretic treatment showed that CaEF independently predicted ATN (OR per 1% increase 1.42, 95%CI [1.16-1.75), p&lt;0.001]. In patients without CKD, CaEF predicted ATN (OR 1.61, 95%CI [1.13-2.28], p = 0.008), in contrast to the cohort with CKD where only a trend was demonstrated (OR 1.29, 95%CI [0.99-1.69], p = 0.057) (Figure 1). CaEF also predicted ATN irrespective of the diuretic prescription at baseline (OR 1.35, 95%CI [1.05-1.74], p = 0.018 for diuretic users and OR 1.57, 95%CI [1.06-2.32], p = 0.025 for non-diuretic users) (Figure 1). Receiving operator curves (ROC) demonstrated a 0,712 area under the curve (AUC) of CaEF &gt;1.6% for ATN, that was the best value for diagnosis in terms of sensitivity and specificity. CaEF&gt;1,6% predicted ATN (OR 8.09, 95%CI [2.32-28.2], p = 0.001) after adjusting for the presence of CKD at baseline and diuretic treatment.

Conclusion
CaEF could help in the identification of the AKI etiology as higher values (i.e. &gt;1.6%) are independently associated with ATN.