bluuebunny/crossref_metadata_2025_split huggingface dataset:
#187 Vasorin (VASN) commands podocyte quiescence and glomerular homeostasis. A novel FSGS mechanism?
Authors: Tharaux Pierre-Louis , Dang Julien , Mahtal Nassim , Chaba Anis , Krautzberger Anja Michaela , Siegerist Florian , Kliewe Felix , Delbet Jean-Daniel , Karras Alexandre , Endlich Nicole , Schrewe Heinrich , Lenoir Olivia 
Published: May 2024

Abstract

Background and Aims
Podocyte dysfunction and loss of quiescence contribute to focal segmental glomerulosclerosis (FSGS) and crescentic glomerulonephritis (CGN). Here, we characterized the role of Vasorin (VASN) in podocytes.

Method
We combined laser capture microdissection and deep RNA sequencing of human glomeruli, RNAscope-based in situ hybridization, immunostaining and mouse models with Vasn-driven fluorescent reporter, targeted Vasn gene deletion in podocytes and cultures of human podocytes.

Results
VASN mRNA is strongly expressed in healthy human and mouse glomeruli with a podocyte-specific pattern. Both global and podocyte-specific, constitutive or inducible gene deletion of Vasn in mice induced a nephrotic syndrome and kidney failure after day 14, with podocyte dedifferentiation and loss and severe FSGS lesions, indicating a fundamental and non-developmental role of VASN in podocyte homeostasis. Furthermore, we measured markedly decreased VASN expression in podocytes of patients with FSGS and ANCA-associated CGN but not with Minimal Change Disease (MCD) and Membranous Nephropathy (MN). We thus wondered whether VASN abundance could be a disease modifier for glomerulopathies.
Mice with podocyte-specific partial heterozygous deletion of Vasn showed no evident baseline renal abnormalities. Still, they showed significantly more podocyte loss, albuminuria and kidney failure than wild-type mice when challenged by type 1 diabetes with glomerular hyperfiltration or CGN experimental models.
Human podocytes transduced with lentiviral VASN-targeting shRNA (shVASN) displayed increased focal adhesion dynamics, resistance to oscillating mechanical stretches, enhanced migratory capacity and epithelial-mesenchymal transition (EMT) markers. Moreover, shVASN podocytes had a higher proliferative capacity, increased cell-cycle reentry and a relative S-phase slow-down. Likewise, transcriptomics analysis found the up-regulation of genes involved in cell metabolism, adhesion and EMT and the down-regulation of genes involved in the S to G2/M phase transition. In vivo, we confirmed that VASN deficiency increased podocyte proliferation in situ and urinary shedding.

Conclusion
These findings highlight the novel role of VASN as an essential master protein that maintains podocyte quiescence and homeostasis during health and kidney diseases while offering a potential new therapeutic target. VASN control mechanisms driving podocyte cell-cycle reentry and detachment and FSGS. Precise mechanisms of VASN functions in podocytes need further insights into VASN molecular partners.
#83 Cardiovascular outcomes in home hemodialysis and peritoneal dialysis patients
Authors: Shah Silvi , Weinhandl Eric , Gupta Nupur , Leonard Anthony , Christianson Annette , Thakar Charuhas 
Published: May 2024

Abstract

Background and Aims
Cardiovascular disease is the leading cause of morbidity and mortality in patients with end-stage kidney disease. Little is known about differences in cardiovascular outcomes between home hemodialysis (HHD) and peritoneal dialysis (PD).

Methods
We evaluated 68 645 patients who initiated home dialysis between 1/1/2005 and 12/31/2018 using the United States Renal Data System with linked Medicare claims. Rates for incident cardiovascular events of acute coronary syndrome, heart failure, and stroke hospitalizations were determined. Using adjusted time-to-event models, the associations of type of home dialysis modality with the outcomes of incident cardiovascular events, cardiovascular death, and all-cause death were examined.

Results
The mean age of patients in the study cohort was 64 ± 15 years, and 42.3% were women. Mean time of follow up was 1.8 ± 1.6 years. The unadjusted cardiovascular event rate was 95.1 per thousand person-years [PTPY] (95% CI, 93.6-96.8), with a higher rate in patients on HHD than on PD (127.8 PTPY; 95% CI, 118.9-137.2 vs. 93.3 PTPY; 95% CI, 91.5-95.1). However, HHD was associated with a slightly lower adjusted risk of cardiovascular events than PD (HR, 0.92; 95% CI, 0.85 to 0.997). Compared to PD patients, HHD patients had 42% lower adjusted risk of stroke (HR, 0.58; 95% CI, 0.48-0.71), 17% lower adjusted risk of acute coronary syndrome (HR, 0.83; 95% CI, 0.72-0.95), and no difference in risk of heart failure (HR, 1.05; 95% CI, 0.94-1.16). HHD was associated with 22% lower adjusted risk of cardiovascular death (HR, 0.78; 95% CI, 0.71-0.86) and 8% lower adjusted risk of all-cause death (HR, 0.92; 95% CI, 0.87-0.97) as compared to PD.

Conclusion
Relative to PD, HHD is associated with decreased risk of stroke, acute coronary syndrome, cardiovascular death, and all-cause death. Further studies are needed to better understand the factors associated with differences in cardiovascular outcomes by type of home dialysis modality in patients with kidney failure.
#2129 Tacrolimus-extended-release versus tacrolimus LCPT: preliminary data
Authors: van Schijndel Emma , Manson Nienke , van Assema Hidde , Standaar Theodora , Vogt Liffert , Mathot Ron , Marquet Pierre , Hilhorst Marc , Bemelman Frederike 
Published: May 2024

Abstract

Background and Aims
To prevent rejection kidney transplant recipients are treated with immunosuppressive drugs, like tacrolimus. The dosage needed to reach therapeutic trough levels of tacrolimus greatly varies between patients. Currently, there are two tacrolimus extended-release variants on the market. Tacrolimus-extended release (Tac-ER/Advagraf) and tacrolimus LCPT (Tac-LCPT/Envarsus). Tac-LCPT was developed using Meltdose technology to improve absorption. Studies suggest that with Tac-LCPT therapeutic levels can be reached with a lower total dose as compared to Tac-ER. We aim to investigate if the dose needed to reach therapeutic trough levels of tacrolimus can be reduced when using Tac-LCPT as compared to Tac-ER in patients who need a relatively high dose.

Method
A prospective open-label switch design study was performed in patients 6 months up to 5 years after receiving a kidney transplant, who received Tac-ER, with therapeutic trough levels, and a concentration/dosage ratio (CDR) &lt;1.05 ng/mlx1/mg. Patients were switched from Tac-ER to Tac-LCPT with a dose reduction of 30% for 3 weeks. After these 3 weeks, they were switched back to their original dose of Tac-ER. Total follow-up was 6 weeks with weekly visits for adjustment of the dosage. The primary outcome was the dose of Tac-LCPT needed to reach therapeutic trough levels as compared to Tac-ER. Secondary outcomes were side effects and pill burden.

Results
For this preliminary analysis, 8 kidney transplant recipients were included. At baseline, the median age was 52.5 (IQR 44.5, 57.0) years old, 75% of patients were male, and the median number of months after transplantation was 14.2 (IQR 11.50, 16.08). The median dose of Tac-ER needed at baseline was 9.0 mg (IQR 8.0, 11.25) with a CDR of 0.89 (IQR 0.68, 0.92). The tacrolimus dosage needed to reach therapeutic trough levels was significantly lower with Tac-LCPT compared to Tac-ER (5.5 mg vs. 9.5 mg, p = 0.03). However, the patients experiencing side effects and the pill burden did not change between the formulations. The Cmax of Tac-ER and Tac-LCPT varied between patients, with no significant difference between formulations (Fig. 1). At the end of the study, two patients preferred to continue Tac-LCPT, one patient preferred Tac-ER and the remaining patients had no preference.

Conclusion
In conclusion, the total needed dosage of tacrolimus to obtain therapeutic trough levels with Tac-LCPT is smaller than with Tac-ER. However, this smaller dosage administered did not translate to fewer side effects, a smaller pill burden, or a lower peak concentration. When inclusion is completed, additional pharmacokinetics will be calculated as well as the determination of CYP3A5 polymorphisms.
#1130 Biopsy-based transcript diagnostics identify early antibody-mediated rejection phenotypes in biopsies with subclinical donor-specific antibodies
Authors: Baumgartner Annina , Schmid Nicolas , Weidmann Lukas , Bortel Nicolà , Lopez Kai Castrezana , Korach Raphael , Harmacek Dusan , Rho Elena , George Britta , Von Moos Seraina , Schachtner Thomas 
Published: May 2024

Abstract

Background and Aims
Biopsy based transcript diagnostics using the molecular microscope diagnostic system (MMDx) have the potential to add diagnostic clarification in the antibody mediated rejection (AMR) continuum. While de novo donor specific antibody (dnDSA) or preformed DSA accompanied by allograft function deterioration are accepted indications for allograft biopsy with therapeutic implications, management strategy for subclinical DSA lacks consensus. MMDx might show clinical utility in this controverse scenario by helping with therapeutic decisions.

Method
In this single-center cohort of 326 indication kidney transplant biopsies assessed by histology and MMDx at the University Hospital Zurich, we analyzed 58 cases with subclinical DSA as biopsy indication. Cases with (n = 44) and without (n = 14) histopathologic features of AMR according to Banff 2022 were compared for molecular AMR rejection transcripts.

Results
When biopsied for subclinical DSA, all 14 cases without histopathologic features of AMR showed absence of molecular AMR. In contrast, molecular AMR was detected in 6/19 (32%) cases with histopathologic diagnosis of AMR and 2/25 (8%) with probable AMR (p = 0.059), Fig. 1. Microvascular inflammation below threshold with C4d negativity was significantly associated with absence of molecular AMR (p &lt; 0.0001). Higher number of calculated epitope mismatch load for HLA class II as measured by PIRCHE II Score was significantly associated with molecular AMR (p = 0.01). In cases with molecular AMR, early AMR scores predominated (R4 vs R6, 0.0002 and R4 vs R5 0.051).

Conclusion
No molecular AMR was observed in absence of histopathologic AMR. Yet, in cases with histopathologic features of AMR, only 8/44 showed molecular AMR. Predominance of early AMR rejection phenotype in cases with molecular AMR transcripts allows hope for MMDx to identify treatment amenable cases with subclinical DSA. Discrepant cases call for re-biopsy to guide therapeutic decisions.
#67 Is Sodium bicarbonate a better alternative in kidney transplantation for better early renal function? A systematic review and meta-analysis
Authors: Abdelshafi Abdelrahman , Hamdallah Aboalmagd , Kedwany Ahmed M , Barakat Ahmed , Sayad Reem , Abdelazeem Basel 
Published: May 2024

Abstract

Background and Aims
Kidney transplantation is a choice treatment for end-stage renal disease. It is the most cost-effective treatment and significantly improves the quality of life. However, metabolic acidosis increased following the transplantation. It can lead to several undesirable effects, such as disturbing the protein balance, resulting in a negative nitrogen equilibrium, increased protein degradation and essential amino acid oxidation, reduced physical functioning, and consequently decreased quality of life. The intraoperative crystalloid used may have significant effects on early function and acid-base balance. Also, sodium bicarbonate may enhance early graft function. This study aims to compare the effect of sodium bicarbonate in enhancing early graft function post-renal transplantation.

Method
We conducted a comprehensive search on multiple databases, including PubMed, MEDLINE, Embase, Scopus, WOS, and the Central Cochrane Registry. We included randomized controlled trials (RCTs) that compared sodium bicarbonate to normal saline during intraoperative kidney transplantation.

Results
Our search retrieved three RCTs, with 246 patients eligible for our criteria. We used either fixed- or random-effects models in the quantitative synthesis of the eligible studies accounting for clinical heterogeneity. Pooled data revealed that the sodium bicarbonate group was associated with a significantly improve in PH level (MD = 0.1; 95% CI: 0.06, 0.13; P &lt; 0.01), Base Excess level (MD = 4.60 mEq/L; 95% CI: 3.43, 5.77; P = 0.003), and urine volume (MD = 2.59 L; 95% CI: 0.88, 4.29; P &lt; 0.01). However, there was no significant difference between two groups in decreasing creatinine level after first day (MD = −0.46 mg/dl; 95% CI: −1.68, 0.76; P = 0.46), but the creatinine level significantly decreases after 2nd day (MD = −1.11 mg/dl; 95% CI: −1.96, −0.26; P = 0.01), and 3rd day (MD = −1 mg/dl; 95% CI: −1.17, −0.72; P &lt; 0.01).

Conclusion
Our study suggests a potential advantage of sodium bicarbonate over the normal saline solution as an intraoperative fluid in improving metabolic acidosis during kidney transplantation.
#762 Hyperkalemia and discontinuation of RAS blockade after initiating SGLT-2i vs. DPP-4i in patients with type 2 diabetes; a population-based cohort study
Authors: Bosi Alessandro , Xu Yang , Fu Edouard L , Faucon Anne-Laure , Sjölander Arvid , Carrero Juan-Jesus 
Published: May 2024

Abstract

Rate of hyperkalemia and discontinuation of renin-angiotensin system blockade after initiating SGLT-2 inhibitors vs. DPP-4 inhibitors in patients with type 2 diabetes; a population-based cohort study

Background and Aims
Post-hoc analyses of clinical trials have suggested that sodium-glucose cotransporter-2 inhibitors (SGLT-2i) lower the rate of hyperkalemia and facilitate the use of renin-angiotensin system inhibitors (RASi) in people with type 2 diabetes and CKD. Whether these effects are generalizable to patients treated in routine clinical practice is unclear. Here, we evaluated the comparative effects of SGLT-2i and dipeptidyl peptidase-4 inhibitors (DPP-4i) on the rate of hyperkalemia and RASi discontinuation.

Method
We conducted a population-based active-comparator, new-user cohort study using data from the Stockholm CREAtinine Measurements (SCREAM) project of people with type 2 diabetes who newly initiated SGLT-2i or DPP-4i between January 2014 and December 2021. The primary outcomes were time to first outpatient hyperkalemia (plasma potassium &gt;5.0 mmol/L) occurrence and recurrent hyperkalemia. The secondary outcomes were mild (potassium &gt;5-≤5.5 mmol/L) and moderate-severe (potassium &gt;5.5 mmol/L) hyperkalemias. Among RASi users, we also studied time to RASi discontinuation through evaluation of pharmacy fills. Cox regression with inverse probability of treatment weighting was used to estimate hazard ratios (HRs) and rate differences for time to first hyperkalemia. Weighted Poisson regression was used to estimate incidence rate ratios (IRRs) for hyperkalemia recurrence.

Results
We included 24 417 individuals (of which 14 470 initiated SGLT-2i and 9, 947 DPP-4i therapy), followed for median 2.0 (Q1-Q3 0.8-3.7) years. Mean age was 67 years and 37% were women. Compared with DPP-4i, initiation of SGLT-2i was associated with a lower rate of first hyperkalemia (adjusted hazard ratio [HR] 0.83; 95% CI 0.72-0.96) and recurrent hyperkalemia (incidence rate ratio [IRR] 0.75; 0.64-0.85). Similar findings were observed among people with eGFR ≥60 (HR 0.73; 95% CI 0.63-0.86) and &lt;60 (HR 0.87; 95% CI 0.63-1.16) ml/min/1.73 m2, as well as for mild (HR 0.82; 95% CI 0.71-0.95) and moderate-severe (HR 0.67; 95% CI 0.52-0.84) hyperkalemias. Out of 15 746 participants that were prevalent RASi users, 17% discontinued RASi therapy during 2.0 (IQR 0.8-3.7) years of follow-up. Initiation of SGLT-2i vs. DPP-4i was not associated with the rate of RASi discontinuation (HR: 1.00; 0.91-1.11).

Conclusion
In patients with type 2 diabetes managed in routine clinical care, the use of SGLT-2i was associated with a lower rate of first and recurrent hyperkalemia compared with DPP-4i. However, this was not accompanied by higher persistence on RASi therapy.
#1225 Lactate aggravates mitochondrial dysfunction via ALDH2 lactylation in acute kidney injury
Authors: Li Jiaying , Shi Xiaoxiao , Hou Fangxing , Luan Xiaodong , Chen Limeng 
Published: May 2024

Abstract

Background and Aims
Elevated lactate levels have been recognized as an independent risk factor in acute kidney injury (AKI) contributed by mitochondrial dysfunction. We previously proved the crucial role of acetaldehyde dehydrogenase 2 (ALDH2) in AKI but not focused on the lactate and lactylation of ALDH2.

Method
We first established a maleic acid (MA) induced AKI model (MA-AKI) in C57BL/6J mice, administrating 2-DG i.p. (a glycolysis inhibitor) or oxamate (a lactate dehydrogenase A inhibitor) to suppress the lactate production. We measured the renal function, mitochondrial function, and lactate in serum and urine, then evaluated the ALDH2 lactylation by co-immunoprecipitation assays, and identified the specific lactation site by mass spectrum. The role of ALDH2 lactylation was explored through point mutation in HEK293 cells. Furthermore, an ALDH2 lactylation eraser was identified, and its function was elucidated in mice and HK-2 cells.

Results
The elevated lactate in the kidney, serum, and urine showed a significant positive correlation to the serum creatinine (Scr, R2 = 0.83, P &lt; 0.0001) in MA-induced mice. Both 2-DG and oxamate partly abolished the Scr increasing and the proximal tubular histopathological injuries. Increased pan-lactylation in AKI mice was effectively inhibited by oxamate, parallel with increased ALDH2 lactylation in MA-stimulated HK-2 cells. Mass spectrometry identified a single lactylate lysine residue in ALDH2 (K52). The introduction of a point mutation (K52 to R) in ALDH2, mimicking the delactylated state, led to partial recovery of ALDH2 activity (1.11 ± 0.07 vs. 0.68 ± 0.15, P = 0.0029) and mitochondrial function in MA-stimulated HK-2 cells. Additionally, sirt3 was identified as an ALDH2 lactylation eraser, and Honokiol (a sirt3 activator) demonstrated enhanced renal function and mitigation of mitochondrial dysfunction in both MA-induced mice and HK-2 cells.

Conclusion
Lactate played a crucial role in mitochondrial dysfunction in AKI partly via induction of ALDH2 lactylation, which shed light on the potential target for the therapy.
#1416 Extracorporeal removal of per- and polyfluoroalkyl substances (PFAS) by hemoadsorption: in vitro kinetic model
Authors: Lorenzin Anna , Perin Natascha , de Cal Massimo , Brendolan Alessandra , Zanella Monica , Ronco Claudio 
Published: May 2024

Abstract

Background and Aims
Per- and polyfluoroalkyl substances (PFAS) are known water pollutants leading to potential public health consequences. High blood levels of PFAS have been associated with several pathological conditions including testicular and kidney cancer. Classic extracorporeal therapies have demonstrated limited efficiency and new approaches should be explored. In this study we studied the possible role of hemoadsorption to achieve a fast, safe and effective removal of PFAS from blood in patients with high blood levels.

Method
We developed an in vitro model of hemoadsorption to test the potential of PFAS removal by extracorporeal treatment. We recirculated a highly polluted batch of water (4 liters) through HA380 sorbent cartridge (Jafron Medical, Zuhai, China) for 120 minutes at a flow of 150 mL/min in a closed loop configuration (Fig. 1). We collected samples at different time points and analyzed 39 different PFAS compounds.

Results
For the PFAS compounds with concentrations significantly above normal, we observed a removal ratio close to 90% already within the first 60 minutes of circulation leading to almost complete elimination of all pollutants at 120 minutes (Fig. 2). RR is remarkably high already in the very early moments of the adsorption process. This is likely dependent on the interaction of the different solutes with the molecular structure of the sorbent.

Conclusion
The in vitro model of hemoadsorption suggests the possible application in vivo of this technique to reduce/normalize the concentrations of PFAS in patients exposed to water or environmental pollution.
#736 The short-term and long-term impact of COVID-19 on the kidney disorders: an observational and Mendelian randomization study
Authors: Chunyang Li , Zhang Chao , Chen Jie , Zeng Xiaoxi 
Published: May 2024

Abstract

Background and Aims
The impact of “long COVID-19” on “short-term” or “long-term” influence on kidney function change remains unknown. We aimed to investigate the causal association between COVID-19 and subsequent kidney outcomes.

Method
10121 participants exposed to COVID-19 were matched up to 3 unexposed controls by age, sex, Townsend deprive index and severity of COVID-19 from UK Biobank. Using conditional and time-varying Cox proportional hazard regression, we first investigated the association between the SARS-CoV-2 infection and incidence of acute kidney disorder and chronic kidney disease (CKD). One-sample mendelian randomization (MR) using polygenetic risk score (PRS) of COVID-19 as instrumental variable was performed. Then, we extended the finding with two-sample MR analyses using GWAS summary statistics from UKB as outcomes, and GWAS of COVID-19 severity, hospitalization and susceptibility from the COVID-19 Host Genetics Initiative (r7) database as exposures.

Results
In observational study, we observed time-varying effects of COVID-19 on the risk of acute kidney disorder incidence, with the highest hazard effect in the second week (HR 12.77, 95% CI: 5.93-27.70) and disappearing in the fourth week (HR 2.28, 95% CI: 0.75-6.93). In subgroup analysis, this time-varying effects were only found in patients with moderate and severe COVID-19, but not mild COVID-19 patients. No association was observed between SARS-CoV-2 infection and the risk of incident CKD. Subsequent individual-level MR showed that COVID-19 severity, hospitalization and susceptibility were significantly associated with increased risk of acute kidney disorder, but not CKD. Two-sample MR indicated that none of the COVID-19 phenotypes were associated with these two diseases nor other kidney traits.

Conclusion
COVID-19 had “short-term” effects on the risk of subsequent acute kidney disorder incidence, and the hazard effects were only observed in moderate or severe but not mild COVID-19 patients.