University Medical Center Research Articles

Liver histology is associated with long-term clinical outcomes in patients with metabolic dysfunction-associated steatohepatitis.

Few studies have examined the risk of long-term clinical outcomes in patients with metabolic dysfunction-associated steatohepatitis in relation to liver histology. We aimed to study this using a real-world cohort. Adults (N = 702) recorded on Vanderbilt University Medical Center's Synthetic Derivative database (1984-2021) with evidence of metabolic dysfunction-associated steatohepatitis on liver biopsy were followed from the first biopsy until the first clinical event or last database entry (median: 4.7y). Risks of cirrhosis (N = 650), other noncirrhotic liver-related (N = 702) and cardiovascular-related outcomes (N = 660), and mortality due to liver, cardiovascular, or cancer events (N = 660) were determined as a function of baseline histology (fibrosis stage [F], lobular inflammation grade [LI], hepatocyte ballooning grade [HB], and steatosis score) adjusting for sex, age, diabetes, and weight-loss surgery. Cirrhosis risk was reduced for lower versus higher fibrosis stage (HR: F0-1 vs. F3: 0.22 [95% CI: 0.12-0.42]), LI1 versus LI2-3 (0.42 [0.19-0.97]), and HB1 versus HB2 (0.20 [0.08-0.50]). Lower fibrosis stage was associated with significantly lower risks of liver-related outcomes versus F4 cirrhosis (eg, F0-1: 0.12 [0.05-0.25]), whereas no differences were seen across baseline lobular inflammation, hepatocyte ballooning, and steatosis grades/scores. Lower versus higher lobular inflammation grade was associated with lower risks for liver-related outcomes in patients with weight-loss surgery. There was a trend for lower risks for cardiovascular-related and any long-term outcomes with lower versus higher fibrosis stage. Fibrosis stage and lobular inflammation and hepatocyte ballooning grades predict the risk of long-term outcomes, supporting the use of these histological features as potential surrogate markers of disease progression or clinical outcomes.

The Effect of Artificial Intelligence on Patient-Physician Trust: Cross-Sectional Vignette Study.

Clinical decision support systems (CDSSs) based on routine care data, using artificial intelligence (AI), are increasingly being developed. Previous studies focused largely on the technical aspects of using AI, but the acceptability of these technologies by patients remains unclear. We aimed to investigate whether patient-physician trust is affected when medical decision-making is supported by a CDSS. We conducted a vignette study among the patient panel (N=860) of the University Medical Center Utrecht, the Netherlands. Patients were randomly assigned into 4 groups-either the intervention or control groups of the high-risk or low-risk cases. In both the high-risk and low-risk case groups, a physician made a treatment decision with (intervention groups) or without (control groups) the support of a CDSS. Using a questionnaire with a 7-point Likert scale, with 1 indicating "strongly disagree" and 7 indicating "strongly agree," we collected data on patient-physician trust in 3 dimensions: competence, integrity, and benevolence. We assessed differences in patient-physician trust between the control and intervention groups per case using Mann-Whitney U tests and potential effect modification by the participant's sex, age, education level, general trust in health care, and general trust in technology using multivariate analyses of (co)variance. In total, 398 patients participated. In the high-risk case, median perceived competence and integrity were lower in the intervention group compared to the control group but not statistically significant (5.8 vs 5.6; P=.16 and 6.3 vs 6.0; P=.06, respectively). However, the effect of a CDSS application on the perceived competence of the physician depended on the participant's sex (P=.03). Although no between-group differences were found in men, in women, the perception of the physician's competence and integrity was significantly lower in the intervention compared to the control group (P=.009 and P=.01, respectively). In the low-risk case, no differences in trust between the groups were found. However, increased trust in technology positively influenced the perceived benevolence and integrity in the low-risk case (P=.009 and P=.04, respectively). We found that, in general, patient-physician trust was high. However, our findings indicate a potentially negative effect of AI applications on the patient-physician relationship, especially among women and in high-risk situations. Trust in technology, in general, might increase the likelihood of embracing the use of CDSSs by treating professionals.

Termination without global capture: electrocardiographic and anatomical characteristics using 3D-electroanatomical mapping system in reentrant ventricular tachycardia

Abstract Background Termination without global capture (TWGC) is the phenomenon which a pacing stimulus applied during ventricular tachycardia (VT) terminates the tachycardia without generating a QRS complex, and is considered as an indicator for the critical component of the circuit. The details of the electrocardiographic and anatomical characteristics of the site using a 3D-electroanatomical mapping system (3D-EAM) remain unknown. Purpose This study aimed to retrospectively analyze the cases that showed TWGC during VT mapping and ablation, and to investigate the electrocardiographic characteristics and relationship with the substrate identified by 3D-EAM. Methods Of 632 cases of VT associated with structural heart disease from July, 2019 to July, 2023 at a university hospital and a university medical center, cases with TWGC were analyzed. Results TWGC was observed in 10 patients (median age 61 years, 9 males, 5 ischemic cardiomyopathy, median LVEF 31%) at least once (12 times) in 11 locations. Local capture was observed in 6. The QRS morphology generated by continued pacing after TWGC matched the clinical VT in only 5 VTs (42%). Five showed decremental conduction of stimulus to QRS interval following the TWGC. In 11 locations, 4 corresponded to scar area (<0.1 mV) in the voltage map, 6 to border zone (0.1-1.5 mV), and 1 had no information on 3D-EAM. Of 12 times of TWGC, 3 were at the entrance, 1 at the central isthmus, and 1 at the exit. Acute elimination of clinical VT was successful in 7 of 10. Conclusions More than half of the sites with TWGC were located at the border zone in 3D-EAM. TWGC also occurred in the central or exit area, and local capture was observed frequently.Termination without global capture

Feasibility and diagnostic yield of a photoplethysmography-based arrhythmia screening and integrated management pathway in a chronic obstructive pulmonary disease outpatient clinic

Abstract Background Guidelines recommend opportunistic screening for atrial fibrillation (AF) in high-risk populations, including chronic obstructive pulmonary disease (COPD) patients. Purpose We aimed to assess the feasibility and yield of a photoplethysmography (PPG) smartphone app-based pathway for AF detection within a COPD outpatient clinic. Methods Ninety-nine eligible patients from the COPD outpatient clinic at the Maastricht University Medical Center+ underwent a 14-days PPG app-based AF screening. PPG-based AF detection triggered an electrocardiogram (ECG) for AF diagnosis and initiation of a comprehensive AF management. Patients’ adherence and system usability were assessed. Results Patient onboarding was easy, and patients demonstrated good adherence to the protocol (101% [82%-123%]). The usability of the PPG app was satisfactory with a high score in the System Usability Score questionnaire (80.0 [55.0-92.5]). Among 99 patients (mean age 66±9 years; 54% female), 8% had a prior AF diagnosis. Premature beats were common, with 96% of patients showing isolated premature beats (<6 in 960 PPG recordings) and 32% frequent premature beats (≥6 in 210 PPG recordings). The PPG algorithm suspected paroxysmal AF in 6 new cases. AF could be confirmed in 2 patients through resting 12-lead ECG and 1-lead handheld ECG device. One patient who was lost to follow-up. In the remaining 3 patients with suspected AF PPG recordings, analysis of 24-hour, 48-hour and 7-day Holter recordings revealed high burden premature (supra)ventricular beats. Two of these patients manifested self-terminating short episodes of supraventricular tachycardia. Conclusion 14-days opportunistic PPG app-based screening is feasible in COPD outpatient care and results in the detection of new AF cases and premature beats. This novel digital approach offers a practical method to implement recommended AF screening in COPD patients.

Electrophysiology-guided algorithm for patients with conduction abnormalities post TAVR: one-year follow-up

Abstract Introduction Transcatheter aortic valve replacement (TAVR) revolutionized the treatment of aortic stenosis [1]. Although TAVR is an effective treatment for AS patients, it is associated with high incidence of new-onset conduction disturbances and pacemaker implantations. The two most common conduction disturbances after TAVR are new onset left bundle branch block (LBBB) and high-degree atrioventricular block (HDAVB) [2]. While patients with HDAVB require a permanent pacemaker implantation (PPM), the management of LBBB is not completely established yet. According to the ESC 2021 guidelines, a PPM is indicated in patients with persistent HDAVB or new onset alternating BBB after TAVR. Yet, the recommendations regarding other conduction abnormalities are not well defined. In patients with persistent new onset LBBB, ambulatory continuous ECG monitoring or electrophysiology study (EPS) are recommended [3]. Purpose To evaluate the clinical outcomes of patients with conduction disorders after TAVR who were managed according to electrophysiology-guided algorithm (Figure 1), including mortality, late pacemaker’s implantations, and heart failure hospitalizations. Predictors of periprocedural LBBB and HDAVB were also assessed. Methods Retrospective population-based cohort study including all patients who developed new onset LBBB after TAVR at a tertiary University Medical Center from October 1, 2018, to December 31, 2022, and were managed according to specific electrophysiology-guided algorithm. Results The study cohort included 230 consecutive patients who underwent TAVR. Mean age was 80.3 and 56.5% were females (Figure 2). Twenty patients (8.7%) developed HDAVB and required a PPM, whereas 40 patients (17.4%) developed persistent LBBB. According to the algorithm, 8 patients (20%) with a QRS<130ms were discharged without PPM [group A], 20 patients (50%) with a QRS of 130-160ms underwent EPS, and 12 patients (30%) with a QRS>160ms [Group C] received a PPM. Among the EPS group: 9 patients (22.5%) with HV>65ms underwent PPM [group B2], while 11 patients with HV<65ms (27.5%) were discharged without PPM [group B1]. During a one-year follow-up only one patient required late PPM [group B1]. Mortality was higher among the subgroups with PPM [B2 and C] compared to the subgroups without a PPM [A and B1]: 4 vs. 1 patient accordingly. Conclusions The presented electrophysiology-guided algorithm for patients with persistent LBBB after TAVR appears safe and efficient, with a modest incidence of PPM (17.6% of the total cohort) during hospitalization and a minimal need for late PPM at one year follow-up. Importantly, there was no excess of mortality among patients who were discharged without a pacemaker implantation. Thus, we suggest that the presented algorithm may serve as a reliable strategy to distinguish between individuals with new onset persistent LBBB after TAVR who require PPM compared to those in whom a PPM can be safely avoided.

#1920 The impact of kidney function on cardiac diastolic dysfunction trajectories: insights from a longitudinal study

Abstract Background and Aims Although the association between kidney dysfunction and cardiac diastolic dysfunction has been investigated in cross-sectional studies, we currently lack a complete understanding of how the diastolic dysfunction changes over time in individuals with different kidney functions. Exploring the diastolic dysfunction trajectories is crucial as it can provide valuable insights into how kidney function influences cardiac health and which patients are at the highest cardiovascular risk. E/e’ is an echocardiography measure that estimates left ventricular filling pressure and diastolic dysfunction. This study evaluates how kidney function impacts changes in E/e′ over time. Method We identified patients from the Utrecht Patient Oriented Database (UPOD) who visited the outpatient clinic of Utrecht University Medical Center between January 2012 and April 2022. Patients who had received at least three echocardiography reports with a minimum of 12 months between them and had recorded serum creatinine measurements in their electronic health records were included. The estimated glomerular filtration rate (eGFR [mL/min/1.73 m2]) was calculated using the CKD-EPI 2021 creatinine formula without ethnicity and categorized as follows: eGFR ≥ 90, eGFR ≥ 60 - <90, eGFR < 60. Linear mixed-effect models were utilized to determine the impact of kidney function on changes in E/e′ over time. Results A total of 436 patients were included of whom 34.7% were women. The total number of echocardiography examination was 1308. Overall, the median eGFR for all patients was 78.2 mL/min/1.73 m2 [IQR: 61.9, 90.7]. Among them, 26.6%, 51.4%, and 22.0%, had an eGFR ≥ 90, eGFR ≥ 60 - < 90, and eGFR < 60, respectively. Patients with an eGFR < 60 had a higher prevalence of hypertension (64.6%) and cardiovascular disease (84.4%) compared to those with an eGFR ≥ 90, where the prevalence of hypertension and cardiovascular disease was 49.1% and 67.2%, respectively. Additionally, patients with an eGFR < 60 had the lowest mean ejection fraction of 44.9% ± 18.5% and the highest median E/e′ of 12.84 [10.10, 16.16]. The linear mixed model analysis showed that the estimated change in E/e′ per year depended on the level of kidney function. For patients with eGFR ≥ 60 - <90, E/e′ did not significantly change per year (p-value: 0.927). However, for patients with eGFR < 60, a statistically significant (p = 0.014) increase in the E/e′ of 0.45 (0.09, 0.81) was observed per year. Hypertension, diabetes mellitus, and cardiovascular disease were found to affect the change in E/e′, with estimates of 0.95 (0.41, 1.49), 1.82 (0.82, 2.89), and 1.25 (0.54, 1.97), respectively. Conclusion The trajectory of changes in E/e′ over time was significantly affected by varying levels of kidney function. Patients with impaired kidney function (eGFR < 60) have a higher E/e’ compared to those with normal kidney function (eGFR ≥ 90) and presented a significant increase of E/e’ per year.

#2514 Clinical impact of the CKD-EPI 2021 versus the CKD-EPI 2012 formula on GFR estimation and CKD prevalence: results from a Dutch routine-care cohort

Abstract Background and Aims Quantifying the kidney function is crucial for diagnosing and monitoring kidney disorders in clinical practice. Recently, the CKD-EPI 2021 formula was developed for estimating glomerular filtration rate (eGFR), excluding the ethnicity variable. In this study, we aimed to analyze the impact in a Dutch routine-care cohort of introducing the new serum creatinine-based CKD-EPI 2021 formula on glomerular kidney function estimation and the prevalence of chronic kidney disease (CKD), compared to the now used CKD-EPI 2012 formula. Method All patients of 18 years and older of whom serum creatinine was measured between January 2013 and December 2023 at the University Medical Center Utrecht in the Netherlands, were included. Differences in the eGFR measured with the CKD-EPI 2012 formula and the new CKD-EPI 2021 formula were defined as median difference, stratified by gender, age categories, and CKD stages. Results 251.960 patients with 2.312.313 serum creatinine measurements were included in our analysis. Our findings indicate that the CKD-EPI 2021 formula results in a higher eGFR compared to the CKD-EPI 2012 formula (median +3.6 (Inter quartile range (IQR) 2.4 to 4.5) ml/min/1.73 m2 in men, and median +3.1 (IQR 2.0 to 4.0) ml/min/1.73 m2 in women). In total, 21.1% of the patients with CKD stage 2-5 according to the CKD-EPI 2012 formula were classified as having a better CKD stage using the new CKD-EPI 2021 formula; 26.1%, 20.5%, and 15.1% of the patients classified as having CKD stage 3A, 3B, and 4 were classified as having CKD stage 2, 3A, and 3B, respectively (Table 1). Conclusion The introduction of the CKD-EPI 2021 formula would have significant implications for kidney function estimation in the Dutch clinical setting. It is crucial to consider these differences when interpreting kidney function data and making clinical decisions, especially given the potential impact on diagnosing CKD and dosing medication.

#2586 Time to event prediction of new-onset diabetes after transplantation in kidney transplant recipients using machine learning models

Abstract Background and Aims New-onset diabetes after transplantation (NODAT) is a common and serious complication of kidney transplantation that contributes to long-term morbidity and mortality after the transplant procedure. Conventional methods may predict the risk of, but not time to developing NODAT. We aimed to develop a machine learning model that predicts the time to NODAT in kidney transplant recipients (KTR). Method Two large prospective cohort studies of stable KTR (inclusion >1 year after transplantation) from the University Medical Center Groningen were combined. Data collection took place between 2001 and 2003 for cohort A, and between 2008 and 2011 for cohort B, resulting in the inclusion of 750 KTR free of NODAT at baseline. To predict absolute time to NODAT, a bootstrap aggregating (bagging) approach was utilized which consisted of several extreme gradient boosting (XGBoost) models with the accelerated failure time (AFT) objective. The performance of the resulting bagging model was internally evaluated by assessing the concordance index (c-index) in 20% of the dataset not used for training. Results From the 750 KTR included, 76 (10.1%) developed NODAT during a median (interquartile range [IQR]) follow-up of 5.8 (4.7 to 9.2) years. The median (IQR) age was 51.2 (40.5 to 60.7) years and 342 (45.6%) of the KTR were female. During feature engineering, 18 features from 53 were selected. After hyperparameter tuning, model performance during internal validation was 0.84. Furthermore, SHapley Additive exPlanations (SHAP) values were used to estimate feature importance, which revealed that glucose, HbA1c, mean arterial pressure, cyclosporine concentrations and daily vegetable intake were the most important features. Conclusion The developed machine learning model shows good discriminative ability of time to NODAT prediction. Due to the methodology used, the model allows for flexible incremental learning, meaning that the bagging model can be retrained with additional data without compromising on performance.

#1250 Measurement of ionized calcium with a point-of-care ionometer during treatment with etelcalcetide

Abstract Background and Aims Etelcalcetide is an intravenous calcimimetic indicated for the treatment of mineral and bone disorders in hemodialysis patients by lowering parathyroid hormone (PTH), calcium and phosphorus. The assessment of ionized calcium versus total calcium has not yet been studied during treatment with etelcalcetide, and there are no real data on the occurrence of hypocalcemia as measured by ionized calcium in the pre- and post-hemodialysis period during treatment with etelcalcetide. The aim of this study was to describe the time course of ionized and total serum calcium levels during chronic treatment with etelcalcetide and to assess the occurrence of hypocalcemia in patients treated with etelcalcetide by measuring ionized calcium levels. Method This was an observational, non-interventional, prospective, single-arm phase IV study. A total of 20 chronic hemodialysis patients (15 men and 5 women) aged 55.9 ± 18.2 years undergoing dialysis for 5.5 ± 4.3 years in two hemodialysis centers of the University Medical Centre Ljubljana were enrolled in the study between January 2020 and March 2021. All patients received etelcalcetide as a bolus injection into the venous line of the dialysis circuit three times a week, immediately after each hemodialysis session. Ionized calcium levels were determined using a point-of-care ionometer (GEM Premier 3000) before starting treatment with etelcalcetide prior to dialysis, then during treatment in the first week before and after dialysis, then once a week until the maintenance phase was reached and at least once a month thereafter. Hypocalcemia was defined by a pre-dialysis ionized calcium concentration below 0.90 mmol/L. The corrected total calcium values was measured prior to dialysis at least once a month according to routine clinical practice. The data of all these patients were included in the analysis, except for one, who underwent a kidney transplantation after receiving only 4 doses of etelcalcetide. Results We demonstrated that both corrected total calcium and ionized calcium before dialysis decreased over time during treatment with etelcalcetide. Of 240 measurements of ionized calcium with a point-of-care ionometer at the bedside, the concentration of ionized calcium was below 0.90 mmol/L three times in two patients (0.81, 0.84, 0.85). In one patient, we increased a calcium level in the dialysate from 1.50 to 1.75 mmol/L and in the other from 1.25 to 1.50 mmol/L. In addition, we observed 2 further measurements of ionized calcium of 0.90 mmol/L and 18 measurements between 0.91 and 0.96 mmol/L. However, this corresponds to 1.25% of hypocalcemias with ionized calcium below 0.90 mmol/L and 8.3% of those with calcium between 0.90 and 0.96 mmol/L. As calcium concentration in the bath increased, the pre-dialysis calcium concentrations also appeared to increase. At the beginning of the study, the calcium concentration in the dialysate was 1.5 mmol/L in 16 of 20 patients. 2 patients were treated with a calcium concentration in the dialysate of 1.75 mmol/L and 2 others with 1.25 mmol/L. The proportion of patients using higher dialysate calcium concentration was higher at the end of the study, as two patients switched to 1.75 mmol/L, and one from 1.25 to 1.50 mmol/L. This probably indicates a co-intervention triggered by a reduction in serum calcium levels prior to dialysis during treatment with etelcalcetide. Visual comparisons of the time course of ionized and corrected calcium concentrations before dialysis during chronic treatment with etelcalcetide in 19 patients showed a good correlation between point-of-care ionized calcium and routinely measured total calcium. Conclusion A point-of-care ionometer for the determination of ionized calcium at the bedside has the potential to guide etelcalcetide therapy by optimizing serum calcium levels and also to prevent potentially threatening hypocalcemia.

#2978 Formative usability test of a novel device for peritoneal dialysis (WEAKID)

Abstract Background and Aims Chronic kidney disease is a growing problem worldwide with a growing number of patients requiring kidney replacement therapy. In recent years we have developed a novel device for peritoneal dialysis (PD), the WEarable Artificial KIDney (WEAKID); composed of a wearable device connected to a dialysate reservoir. WEAKID uses both sorbent technology and continuous flow PD to improve dialysis efficacy. Formative usability testing aids to the identification of design issues that may interfere with a device's safe and effective use and thus may influence decisions made in the design process. Here, we present the results of an international, multicentre, formative usability study of WEAKID among nurses and patients. Method This study used a mixed-methods design and was conducted in hospitals in Italy (Modena University Hospital), Spain (La Paz University Hospital, Madrid), and the Netherlands (University Medical Center Utrecht) between November 2021 and December 2022. An individual, formative usability testing session was conducted with each participant (nurse or patient) under the conditions of simulated use. Participants were asked to perform basic operational procedures (i.e. turning the device on/off, input of dialysis settings, handling an alarm) with the device according to a usability task list. Their performance was observed and use errors (i.e., something that a participant does or fails to do that results in an unexpected or unintended outcome) were noted. Furthermore, participants were asked for feedback, both verbally and by means of completing the system usability scale (SUS), reflecting perceived usability on a scale from 0 (worst) to 100 (best). Results We included 14 participants (n = 6 nurses, n = 8 patients) in three participating centres. All nurses were female and had a median experience with PD of 20.5 years (range 0.5-32). Patients were generally highly educated (n = 5, 63%). In total, 22 use errors occurred, 10 in nurses and 12 in patients. These use errors included factors not related to the device, e.g. not taking appropriate hygiene measures. In particular, use errors occurred during the priming/connection of catheter and handling the alarm. Participants’ feedback mainly concerned the small screen (and thus font) size, user interface (e.g. lack of colour-coded soft buttons), and (short) length of the patient line. The mean SUS score was 70 (range 57.5–85) for nurses, and 71.9 (range 55–87.5) for patients. Conclusion Despite the slightly above-average perceived usability of the device's current design stage, participants made a lot of suggestions for improvements, and usability must be improved to make the device ready for market introduction.

#2361 The influence of glucose biocompatible solutions to the clinical outcomes of patients treated with continuous ambulatory peritoneal dialysis

Abstract Background and Aims The use of biocompatible glucose solutions is associated with longer preservation of residual renal function and less frequent occurrence of complications in patients on peritoneal dialysis. The aim of this study was to examine the influence of conventional and biocompatible glucose solutions to laboratory parameters and clinical outcomes of PD patients during a four-year period at Zvezdara University Medical Center. Method This retrospective study included 25 incident patients treated with continuous ambulatory peritoneal dialysis (CAPD) during the follow up period from 2018 to 2022. During 2018/2019 these patients used conventional solutions (Dianeal PD4) containing lactate as a buffer, while due to the change in solution production technology in 2020/2021, all patients were transferred to a biocompatible solution (Physioneal 40) with lactate and bicarbonate as a buffer. Clinical outcomes were compared in relation to the administered solution: pain during infusion (measured by a Visual Analogue Scale—VAS), correction of anaemia and bicarbonate, average annual 24h diuresis and 24h ultrafiltration, occurrence of CAPD peritonitis. The statistical significance of the differences between the two periods was checked using the SPSS. Results The average age of 25 patients was 61 ± 14 years, of which 59.1% were male and 40.9% female. The average BMI was 28.5 ± 5.30 kg/m2, and the most common comorbidities were HTA and DM. No statistically significant difference was found for the values of Le, albumin, Hb, PTH, bicarbonate, and K (p ˃ 0.05). During the use of biocompatible solutions, patients had statistically significantly lower Na values (138.84 ± 2.63 vs 137.17 ± 2.41 mmol/l, p = 0.0116, 95% CI 137.15– 138.84) and lower CRP values (15.3 ± 3.3 mg/l vs 7.7 ± 3.2, p = 0.0003, 95% CI 18.60-4.50). Although the dialysis exposure was longer, the rate of peritonitis was lower during the use of biocompatible solutions, but without a statistically significant difference (0.40 episodes per patient-year, vs 0.31 episodes per patient-year, p ˃ 0.05). No statistical significance was found in 24h diuresis value (900 ml vs 750 ml, p = 0.167.95% CI 686.90–1203.31) but the value is expected to be lower due to dialysis duration. Conclusion Our study showed that patients treated with the CAPD method while using a biocompatible solution have statistically significantly higher values of 24h ultrafiltration, lower Na and CRP values and less occurrence of pain during infusion, which significantly affects the quality of life. Although this may indicate better preservation of the peritoneal membrane, a prospective and randomized study is needed to clarify these potential differences.

#3022 Rationale and design of the CORDIAL first-in-human clinical trial: a system for sorbent-assisted continuous flow peritoneal dialysis

Abstract Background and Aims Peritoneal dialysis has important disadvantages, including low plasma clearance and a limited technique survival. A new device for sorbent-assisted continuous flow peritoneal dialysis has been designed (Wearable Artificial KIDney, WEAKID) that is based on continuous recirculation (rapid cycling) of peritoneal dialysate via a single-lumen peritoneal catheter with regeneration of dialysate using sorbents. Anticipated benefits are a better plasma clearance a higher mass transfer area coefficient with continuous flow of dialysate and enhanced diffusion due to a higher time-averaged plasma-dialysate concentration gradient with sorbent-based dialysate regeneration, and a prolonged technique survival thanks to lower peritonitis risk (less (dis)connections) and a lower glucose exposure. Method This is a first-in-human, prospective, open-label, non-randomized, single-arm, multicenter study, that will be performed at the University Medical Center Utrecht (Utrecht, The Netherlands), Università degli studi di Modena e Reggio Emilia (Italy), and Instituto de Investigación Hospital Universitario La Paz, Servicio Madrileño de Salud (Spain). We aim to include 12 stable, adult PD patients. In the first week, blood, urine, and dialysate samples will be collected over three separate days to assess the efficacy of the patient's standard PD schedule. The WEAKID system will then be tested in a clinical setting on 6 days over a period of 2 weeks (three consecutive days per week). During the first week, participants will be treated with WEAKID without sorbents for 4h (first day) or 8h (second and third day). The second week, treatment will consist of WEAKID with sorbents for 4h (first day) or 8h (second and third day). This way, exposure to new components of the system is incremental and the effectiveness of continuous recirculation of dialysate and that the added effect of sorbent-based dialysate regeneration can be analyzed separately. Outcomes The primary aim of this first-in-human clinical trial is to evaluate the (short term) clinical safety and performance of WEAKID treatment in a clinical setting. The primary safety objective will be assessed by describing and examining the incidence of: Key secondary objectives include an evaluation of efficacy in terms of plasma clearance, ultrafiltration, net base release, and patient tolerance. Planning Inclusion of the first patient is expected in January 2024, the final inclusion is expected to take place in November 2024.

#614 Identifying distinct patient phenotypes in patients with chronic kidney disease

Abstract Background and Aims Patients with chronic kidney disease (CKD) are heterogeneous in terms of age, causes of CKD, and comorbidities. Although individual risk factors greatly influence patients’ risk of clinical outcomes, this heterogeneity is rarely used to guide clinical decision-making. In this study we aimed to derive phenotypes in patients with CKD based on characteristics commonly available in routine clinical practice and evaluated whether these phenotypes were associated with clinical outcomes. Method Patients from the Utrecht Patient Oriented Database (UPOD) who were 18 years or older with CKD (defined as an eGFR <60 ml/min/1.73 m2 or an UACR > 3 mg/mmol present for >3 months) and visited one of the cardiovascular outpatient clinics of the University Medical Center Utrecht between 2012 and 2019 were included. Patient phenotypes were derived with latent class analyses based on age, sex, CKD stage, cause of kidney disease, and (cardiovascular) comorbidities. The incidence rate/100 person years (IR/100PY) for all-cause mortality and kidney failure (defined as initiation of kidney replacement therapy or a sustained eGFR <15) and 95% confidence interval (95% CI) was calculated for each phenotype. Results Overall 9005 patients were included (mean age 65 ± 14 years, 42% women, mean estimated glomerular filtration rate (eGFR) 49 ± 17 ml/min/1.73 m2). The median follow-up was 3.8 years [interquartile range 1.8–6.4]. Latent class analysis identified 7 phenotypes with the following characteristics: phenotype 1 were young patients with primary kidney disease (10%); phenotype 2 were patients with diabetes and a preserved eGFR (9%); phenotype 3 were patients with low comorbidity and inflammation (28%); phenotype 4 were older patients with a history of cardiovascular disease (27%); phenotype 5 were older patients with a history of cardiovascular disease and severe CKD (16%); phenotype 6 were younger patients with a kidney transplant and low comorbidity (6%); and phenotype 7 were older patients with a kidney transplant and cardiovascular disease (6%). The risk of all-cause mortality and kidney failure differed significantly between the identified phenotypes. The phenotypes of younger kidney transplant recipients, younger patients with primary kidney disease, and diabetes with preserved eGFR had the lowest risk for all-cause mortality (for all, IR/100 PY <5) (Fig. 1). The phenotypes with an intermediate incidence rate for all-cause mortality were the low comorbidity and inflammation phenotype (IR/100PY 7.4, 95% CI 6.9–8.0), the phenotype of older patients with cardiovascular disease (IR/100PY 7.2, 95% CI 6.7–7.8), and the phenotype of older patients with a kidney transplant and cardiovascular disease (IR/100PY 6.5, 95% CI 5.5–7.6). The phenotypes with highest incidence rate for all-cause mortality was the phenotype of older patients with cardiovascular disease and severe CKD (IR/100PY 12.5, 95% CI11.5–13.4). The phenotypes with the lowest risk for kidney failure were the diabetes phenotype, the low comorbidity and inflammation phenotype, and the phenotype of older patients with cardiovascular disease (all IR/100 PY <1). The phenotype of older patients with cardiovascular disease and severe CKD also had the highest risk to develop kidney failure (IR/100PY 5.8, 95% CI 5.1–6.6), followed by the phenotype of patients with primary kidney disease (IR/100PY 4.4, 95% CI 3.7 −5.5). Conclusion We identified 7 different phenotypes of patients with CKD including 2 phenotypes of patients with a kidney transplant with different clinical characteristics and prognosis. The differences in risk of all-cause mortality and kidney failure warrants a different monitoring and follow-up across the different phenotypes within the setting of CKD. Future studies should invest In evaluating the implementation of our identified phenotypes in routine clinical practice or clinical trial design with respect to differences in treatments.

#615 Generalisability of cardiovascular RCTs to patients with chronic kidney disease in clinical practice: a comparison between RCTs and real-world data

Abstract Background and Aims Randomised controlled trials (RCTs) often apply stringent eligibility criteria, which could limit the external applicability of RCTs to patients in routine clinical practice. This is specifically troublesome in the setting of chronic kidney disease (CKD) given that kidney disease is commonly used as an ineligibility criterion in RCTs. In this pilot study we estimated the eligibility of patients with CKD in routine clinical practice in five major cardiovascular outcome trials - CREDENCE, DAPA-CKD, CIBIS II, CIBIS III, and AUGUSTUS - and described reasons for ineligibility. Method We included patients with CKD (defined as an estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m2 or an urinary albumin creatinine ratio (UACR) >3 mg/mmol present for >3 months) from the Utrecht Patient Oriented Database (UPOD) who visited a cardiovascular outpatient clinic in the University Medical Centre Utrecht between 2012 and 2019. The eligibility criteria were extracted from the selected RCTs and consequently modelled on the patients from UPOD. The percentage of eligible patients and reasons for ineligibility were described descriptively. The percentage of eligible patients for CIBIS II and CIBIS III were only calculated for patients with heart failure, and for the AUGUSTUS trial for patients with coronary artery disease as patients with these conditions were targeted. Patients could not fulfil multiple inclusion criteria and or meet multiple exclusion criteria or both. Results In total, 9005 UPOD patients with CKD were included. Patients had a mean age of 65 ± 14 years, 42% was female, mean eGFR was 49 ± 17, 1741 (19%) had a history of atherosclerotic cardiovascular disease, and 765 (8%) of heart failure. Overall, 0.05% of patients would be eligible for the DAPA-CKD trial and 0% for the CREDENCE trial. Of included patients with heart failure, 2% would have been eligible for CIBIS II and 3% for CIBIS III. Of included patients with coronary artery disease, 2% would have been eligible for the AUGUSTUS trial. Main reasons for ineligibility for DAPA-CKD were not fulfilling the inclusion criteria for UACR (52%), eGFR (20%), or the prescription of RAAS-inhibitors (arb) (49%) or meeting the exclusion criteria for primary kidney disease (PRD, 6%), or a kidney transplant (15%), or other comorbidities. Similarly, patients were often ineligible for the CREDENCE trial because they did not fulfill the inclusion criteria for UACR (48%), eGFR (18%), HbA1c (35%), or prescription of a RAAS-inhibitor (43%) or met one of the exclusion criteria for PRD (29%), cardiovascular disease (23%), or prescription of a mineralocorticoid receptor antagonist (10%). For CIBIS II, main reasons for ineligibility were not fulfilling the inclusion criteria for left-ventricular ejection fraction (LVEF, 50%) or prescription of an ace-inhibitor (42%) or diuretic (33%) or meeting the exclusion criteria of coronary artery disease (17%) or prescription of a calcium-channel blocker (16%). For CIBIS III, patients were also ineligible because they were not fulfilling the inclusion criteria for age (46%), LVEF (46%), or prescription of diuretics (31%) or met the exclusion criteria for serum creatinine (9%) or prescription of an angiotension receptor blocker (14%). Lastly, for the AUGUSTUS trial, patients were mainly ineligible due to not fulfilling the inclusion criteria of atrial fibrillation (79%) or percutaneous coronary interventions (PCI, 91%) or meeting the eGFR exclusion criteria (14%). Conclusion Based on this pilot study, less than 3% of patients with CKD in routine clinical practice would be eligible to participate in cardiovascular RCTs. Patients were often ineligible because they did not fulfil the inclusion criteria and a substantial number of patients was ineligible due to kidney disease. The low eligibility rate of patients with CKD in cardiovascular trials could limit the generalisability of results to patients with CKD treated in practice. To improve generalisability, RCTs in patients with CKD should aim to include more patients who reflect the patients with CKD treated in practice.

#1436 Donor plasma cystatin C, but not creatinine, is associated with measured GFR at one year after kidney transplantation

Abstract Background and Aims Although widely used during deceased kidney donor selection, donor plasma creatinine has limited capacity to predict future recipient kidney graft function. Cystatin C is a muscle-mass independent kidney function marker that could serve as alternative for this purpose. However, the association between donor cystatin C and subsequent recipient graft function remains unclear. We aim to assess the association of pre-donation cystatin C concentrations with recipient iothalamate-measured GFR (mGFR) one year after kidney transplantation and compare it to the association of donor creatinine concentrations. Method All deceased kidney donors, within the affiliated donation region of the University Medical Center Groningen (UMCG), who donated at least one kidney to a kidney transplant recipient (KTR) affiliated to the same hospital during a period of 15 years (2004-2019) were included. We excluded all subjects with missing data on donor plasma cystatin C or recipient mGFR at 1 year. Donor plasma creatinine concentrations were measured using an enzymatic assay, while donor cystatin C concentrations were measured using a validated particle-enhanced turbidimetric immunoassay (Roche). Associations of donor plasma creatinine and cystatin C concentrations with recipients’ mGFR one year after transplant were assessed using linear regression. Results A total of 53 deceased kidney donors (55% male, age 47 ± 18 years, 47% donation after circulatory death) donated a kidney to 53 kidney transplant recipients (55% male, age 57 ± 12 years). Median pre-donation plasma creatinine and cystatin C concentrations were 64 [55 to 82] μmol/L and 0.64 [0.51 to 0.82] mg/L respectively. Mean recipient mGFR one year after transplantation was 52.7 ± 17.1 ml/min. In univariable linear regression, higher donor cystatin C was significantly associated with lower mGFR (β −0.42, 95% CI: −0.67 to −0.16, p = 0.002), while donor creatinine was not associated (β −0.03 95% CI: −0.32 to 0.25, p = 0.81). The association between donor cystatin C and recipients’ mGFR remained independent of adjustment for potential confounders, including donor sex and age, t (p = 0.008). Conclusion Higher donor cystatin C, but not creatinine, is associated with lower measured GFR one year after kidney transplant. Consequently, donor cystatin C could be valuable for inclusion in the pre-transplant evaluation of deceased kidney donors.

#234 Clinical spectrum and genetic variants of Alport syndrome and thin basement membrane nephropathy—single center experience

Abstract Background and aims Alport syndrome (AS) and thin basement membrane nephropathy (TBMN) are genetically heterogeneous kidney diseases that manifest with kidney involvement, AS also with hearing and visual impairment. Electron microscopic examination shows characteristic ultrastructural changes in the glomerular basement membrane (GBM) in AS and TBMN, but cannot reliably distinguish between the two entities. Therefore, molecular genetic studies and the identification of individual pathogenic variants in the target genes are crucial to confirm the diagnosis. The aim of our study is to determine the significance of the genetic variants associated with the ultrastructural changes of GBM found in the renal biopsy. Method We retrospectively analyzed records of patients from the University Medical Centre Ljubljana in which ultrastructural GBM changes characteristic for AS and TBMN were found in the renal biopsy, including their clinical, laboratory and histological features. Molecular genetic investigations were made using the new generation sequencing method (NGS) to determine germline pathogenic variants in genes directly related to AS and TBMN (COL4A3, COL4A4 and COL4A5) and in genes that are important in syndromes with a related clinical picture (COL4A6, CD151, LMX1B, MYH9, FN1 and MYO1E). The pathogenicity of variants was determined according to the Clinical Molecular Genetic Society best practice guidelines. Results The study included 73 patients with ultrastructurally confirmed thin GBM. Indications for kidney biopsy were chronic nephritis syndrome in 33 patients (45%), acute worsening of renal function in 16 (22%), nephrotic syndrome in 9 (12%), nephrotic proteinuria and chronic kidney disease in 6 (8%), isolated proteinuria in 5 (7%) and suspected vasculitis in 4 patients (6%). At the time of kidney biopsy average age was 50 ± 16 years, average creatinine 112 ± 70 µmol/L and average estimated glomerular filtration rate (eGFR) 65 ± 24 ml/min/1.73 m2, 7 patients had eGFR below 30 ml/min/1.73 m2. Average daily proteinuria was 2.4 ± 3.3 gr and 88% of patients had hematuria. 38% of them have hearing impairment and 43% had positive familiar history of kidney disease. We recorded 33 patients (45%) with genetic variants associated with AS or TBMN: 22 patients (67%) with pathogenic variants, 2 patients (6%) with likely pathogenic and 9 patients (27%) with variants of uncertain significance. The presence of a positive genetic analysis was associated with a higher level of hematuria (p = 0.003), a lower level of proteinuria (p = 0.004) and a positive family history of kidney disease (p < 0.001). It was also associated with hearing loss, but the association was not statistically significant (p = 0.099). Patients with genetic variants had similar eGFR to those with negative genetics (63.9 ml/min/1.73 m2 (58.3-69.4) vs 66.2 ml/min/1.73 m2 (60.0-72.3)), p = 0.698. We also found no differences in GBM thickness in patients without compared to those with identified gene variants (213 nm (160-315) vs. 209 nm (140-410)), p = 0.761. 32 patients (44%) had only focal chronic changes and ultrastructural changes of thin GBM present on kidney biopsy and 41 patients (56%) had also been diagnosed with other renal pathology. When comparing these two groups, patients without associated pathology had lower daily proteinuria (p = 0.048), higher level of hematuria (p = 0.021), frequent hearing impairment (p = 0.008) and also positive genetics analysis (p = 0.016). Conclusion We have shown that in patients with proven ultrastructural alterations in GBM, the presence of so far recognized genetic variants associated with AS and TBMN is 45%, and corresponds to the frequency of other phenotypic characteristics of AS, including hearing impairment and positive family history. In the future, additional clinical tools will be required to accurately determine the role of coexistent thin GBM on the prognosis of patients with other relevant kidney pathology and other genetic tools beyond NGS should be employed to explore other pathologic genetic variants associated with the AS spectrum.

#2388 Relevance of anti-PLA2R levels in therapy decision and prediction of therapy outcome in patients with membranous nephropathy

Abstract Background and Aims Detection of anti-phospholipase A2 receptor (PLA2R) antibodies in patients with primary membranous nephropathy (MN) supports diagnosis as well as disease monitoring. An individualised therapy approach was introduced for anti-PLA2R positive MN patients at the Radboud University Medical Center. Immunosuppressive treatment (cyclophosphamide combined with steroids) was stopped when anti-PLA2R results by indirect immunofluorescence testing (IIFT) became negative. Here, we evaluated the relevance of anti-PLA2R levels for therapeutic decisions and the outcome of MN, comparing qualitative and quantitative detection methods. Method Stored serum samples were retrieved for beginning of treatment (baseline), decision point, and follow-up. Anti-PLA2R levels were determined qualitatively by IIFT as well as quantitatively by enzyme-linked immunosorbent assay (ELISA) and chemiluminescence immunoassay (ChLIA) at baseline as well as after treatment and correlated to immunological remission and persistence. Results For an evaluation of the relevance of anti-PLA2R levels at the start of therapy, serum samples of 60 patients were available. Patients sampled at the beginning of the therapy were grouped according to tertiles of anti-PLA2R levels determined by ChLIA (n[lowest tertile] = 20, n[middle tertile] = 20, n[highest tertile] = 20). Lower anti-PLA2R levels were seen in patients with relapsing disease. Higher anti-PLA2R levels were associated with more severe proteinuria. Patients in the lowest tertile of anti-PLA2R were more likely to develop immunological remission after 8 weeks of therapy. In total, 90% vs 75% vs 45% of patients in the tertiles turned anti-PLA2R negative after being treated for 8 weeks. Moreover, in this subgroup of patients who showed immunological remission after 8 weeks of therapy, only 11% of the patients in the lowest tertile needed renewed immunosuppressive therapy, while this percentage increased in the middle and highest tertiles (11% vs 53% vs 33%, p=0.033). For the assessment of anti-PLA2R levels before and after therapy, samples at baseline and week 8 of treatment were examined. At baseline, 50/50 (100%) tested positive in IIFT and ChLIA as well as 48/50 (94%) in ELISA. After 8 weeks on treatment, immunological remission based on IIFT was found in 37/51 (73%) patients. At this point, the overall agreement compared to IIFT was 92% for ChLIA and 82% for ELISA. Yet the availability of quantitative levels provided further insight into this group of patients in whom treatment was discontinued. With ChLIA, anti-PLA2R titers >5 RU/mL after 8 weeks of therapy were found in 4% of IIFT negative patients with persistent remission, vs 55% of IIFT negative patients with early relapse (p=0.006). Conclusion Individualised treatment of MN patients with cyclophosphamide and steroids has been recently introduced. In this respect, the quantitative determination of anti-PLA2R levels adds further value. Of the examined quantitative methods, ChLIA demonstrated the highest agreement with IIFT. Additional studies are needed to evaluate the impact on clinical decision making and outcome.

Complications Rate and Related Factors After Laparoscopic Sphincter-Preserving Total Mesorectal Excision for Low Rectal Cancer: A Single-Center Study in Vietnam.

Colorectal cancer is a significant health concern. Surgery remains a critical component of the multimodal treatment strategy. The laparoscopic sphincter-preserving total mesorectal excision (TME) is increasingly utilized and effective, offering enhanced quality of life for patients compared to previous traditional methods. This study aims to determine the rate of complications and the related factors associated with complications following laparoscopic sphincter-preserving total mesorectal excision for low rectal cancer. This retrospective study was conducted at the University Medical Center of Ho Chi Minh City from March 2022 to March 2023. It included patients aged 18 years and older diagnosed with low rectal cancer who underwent laparoscopic sphincter-preserving total mesorectal excision. Data on patient demographics, surgical details, and postoperative complications were retrospectively collected and analyzed. Follow-ups were conducted up to six months after surgery. Of the 83 patients included, the postoperative complications rate was 14.5%. The complications observed included surgical wound infections (five cases), anastomotic leaks (five cases, including three recto-vaginal fistulas and two pelvic abscesses), urinary retention (one case), and pneumonia (one case). A significant finding was the higher rate of distant metastases in patients with complications compared to those without (p=0.033). Laparoscopic sphincter-preserving total mesorectal excision for low rectal cancer is safe and effective, with a high success rate and low complication rate during or after surgery. Anastomotic leakage remains the most significant complication. Despite advancements in surgery, modern suturing tools, and preoperative patient optimization, complications are avoidable. Therefore, understanding the related factors and implementing preventive interventions is crucial.

Enhancing Surgical Safety: Microbiological Air Control in Operating Theatres at University Medical Centre Maribor.

the aim of the study was to assess microbiological air quality in operating theatres by determining the level of microbiological contamination of the air and critical surfaces using the passive air sampling method and compliance of the operating theatre staff with infection control measures. The prospective study was conducted in the surgical block of the University Medical Centre Maribor. For two months continuously, ten operating theatres were assessed for microbial contamination of air and surfaces during quiet and active times of the day. A passive air sampling method with Petri dishes on an agar specially adapted for this purpose (plate count agar) was used. In addition, ten surgical procedures were observed to assess staff compliance with recommended practises. Air samples met microbiological standards in all operating theatres. In both sampling sessions of the day (quiet and active periods), microbial contamination of the air was always within the limit of 10 CFU/m3. The average number of bacterial colonies was zero to two during quiet phases and one to four during active phases. Approximately 60% of the isolates from the operating theatres belonged mainly to the genus Staphylococcus: S. epidermidis (36% of the isolates), S. hominis (17.5%) and S. haemolyticus (5.5%). The rest were identified as Streptococcus anginosus (23%) and Bacillus sp. (18%). Pathogenic bacteria and moulds were not present. In regard to staff compliance with good surgical practise, the former varied by behaviour and function, with non-compliance in pre-operative skin preparation and operating theatre congestion being notable. The cleanliness of the environment was satisfactory. Microbiological air control is extremely important for the safety and success of both surgical and postoperative practises. In spite of good results obtained in the study, further improvements in surgical staff compliance with good surgical practise are essential to reduce surgical site infections.

An innovative method to strengthen evidence for potential drug safety signals using Electronic Health Records

Reports from spontaneous reporting systems (SRS) are hypothesis generating. Additional evidence such as more reports is required to determine whether the generated drug-event associations are in fact safety signals. However, underreporting of adverse drug reactions (ADRs) delays signal detection. Through the use of natural language processing, different sources of real-world data can be used to proactively collect additional evidence for potential safety signals. This study aims to explore the feasibility of using Electronic Health Records (EHRs) to identify additional cases based on initial indications from spontaneous ADR reports, with the goal of strengthening the evidence base for potential safety signals. For two confirmed and two potential signals generated by the SRS of the Netherlands Pharmacovigilance Centre Lareb, targeted searches in the EHR of the Leiden University Medical Centre were performed using a text-mining based tool, CTcue. The search for additional cases was done by constructing and running queries in the structured and free-text fields of the EHRs. We identified at least five additional cases for the confirmed signals and one additional case for each potential safety signal. The majority of the identified cases for the confirmed signals were documented in the EHRs before signal detection by the Dutch Medicines Evaluation Board. The identified cases for the potential signals were reported to Lareb as further evidence for signal detection. Our findings highlight the feasibility of performing targeted searches in the EHR based on an underlying hypothesis to provide further evidence for signal generation.