Incidence Of Cardiovascular Events Research Articles

Advancements in diabetic kidney disease management: integrating innovative therapies and targeted drug development.

Diabetic kidney disease (DKD) is a leading cause of chronic kidney disease and affects approximately 40% of individuals with diabetes . Cases of DKD continue to rise globally as the prevalence of diabetes mellitus increases, with an estimated 415 million people living with diabetes in 2015 and a projected 642 million by 2040. DKD is associated with significant morbidity and mortality, representing 34% and 36% of all chronic kidney disease deaths in men and women, respectively. Common comorbidities including hypertension and ageing-related nephron loss further complicate disease diagnosis and progression. The progression of DKD involves several mechanisms including glomerular endothelial cell dysfunction, inflammation, and fibrosis. Targeting these mechanisms has formed the basis of several therapeutic agents. Renin-angiotensin-aldosterone system (RAAS) blockers, specifically angiotensin receptor blockers (ARBs), demonstrate significant reductions in macroalbuminuria. Sodium-glucose transporter type 2 (SGLT-2) inhibitors demonstrate kidney protection independent of diabetes control while also decreasing the incidence of cardiovascular events. Emerging agents including glucagon-like peptide 1 (GLP-1) agonists, anti-inflammatory agents like bardoxolone, and mineralocorticoid receptor antagonists show promise in mitigating DKD progression. Many novel therapies including monoclonal antibodies CSL346, lixudebart, and tozorakimab; mesenchymal stem/stromal cell infusion; and cannabinoid-1 receptor inverse agonism via INV-202 are currently in clinical trials and present opportunities for further drug development.

Exploring mitochondrial DNA copy number in circulating cell-free DNA and extracellular vesicles across cardiovascular health status: A prospective case-control pilot study.

Cardiovascular disease (CVD) is a leading global cause of mortality, difficult to predict in advance. Evidence indicates that the copy number of mitochondrial DNA (mtDNAcn) in blood is altered in individuals with CVD. MtDNA released into circulation may act as a mediator of inflammation, a recognized factor in the development of CVD, in the long distance. This pilot study aims to test if levels of mtDNAcn in buffy coat DNA (BC-mtDNA), in circulating cellfree DNA (cf-mtDNA), or in DNA extracted from plasma extracellular vesicles (EV-mtDNA) are altered in CVD patients and if they can predict heart attack in advance. A group of 144 people with different CVD statuses (50 that had CVD, 94 healthy) was selected from the LifeLines Biobank according to the incidence of new cardiovascular event monitored in 6 years (50 among controls had heart attack after the basal assessment). MtDNAcn was quantified in total cf-DNA and EV-DNA from plasma as well as in buffy coat. EVs have been characterized by their size, polydispersity index, count rate, and zeta potential, by Dynamic Light Scattering. BC-mtDNAcn and cf-mtDNAcn were not different between CVD patients and healthy subjects. EVs carried higher mtDNAcn in subject with a previous history of CVD than controls, also adjusting the analysis for the EVs derived count rate. Despite mtDNAcn was not able to predict CVD in advance, the detection of increased EV-mtDNAcn in CVD patients in this pilot study suggests the need for further investigations to determine its pathophysiological role in inflammation.

Long-term cardiovascular outcomes after mini-crush or T and minimal protrusion techniques in complex bifurcation lesions: the EVOLUTE-CRUSH III study.

Mini-crush (MC) and T-stenting and small protrusion (TAP) techniques are frequently used, but the long-term comparison of both techniques in patients with complex bifurcation lesions (CBLs) is still a debatable issue. This study sought to retrospectively evaluate the long-term outcomes of MC and TAP techniques in patients with CBLs. A total of 271 patients [male: 202 (78.9%), mean age: 58.90 ± 10.11 years] patients in whom complex bifurcation intervention was performed between 2014 and 2023 were involved. The primary endpoint was major cardiovascular events (MACE) as the combination of cardiac death, target vessel myocardial infarction, or clinically driven-target lesion revascularization. The Cox proportional hazard models were adjusted by the inverse probability weighting approach to reduce treatment selection bias. The initial management strategy was MC in 146 patients and TAP in 125 cases. MACE occurred in 52 patients (19.2%) during a mean follow-up period of 32.43 ± 16 months. The incidence of MACE (13 vs. 26.4%, P = 0.005) and major cardiovascular and cerebral events (15.1 vs. 28.8%, P = 0.006) were significantly lower in the MC group than in the TAP group. Additionally, the incidence of definite or probable stent thrombosis was numerically lower in the MC group compared with the TAP group but did not differ significantly (2.7 vs. 8%, P = 0.059). The long-term MACE was notably higher in the TAP group than the MC group [adjusted hazard ratio (inverse probability weighted): 1.936 (95% confidence interval: 1.053-3.561), P = 0.033]. In this study involving patients with CBLs, percutaneous coronary intervention with the MC technique had better long-term outcomes than the TAP technique.

Eosinophilic esophagitis and risk of incident major adverse cardiovascular events: a nationwide matched cohort study.

Inflammatory diseases have been associated with an increased cardiovascular risk. However, data on incident major adverse cardiovascular events (MACE) from large population-based cohorts of patients with eosinophilic esophagitis (EoE) is lacking. This study included all Swedish adults with EoE without a record of previous cardiovascular disease (CVD) (1990-2017, N = 1546) with follow-up until 2019. Individuals with EoE were identified from prospectively recorded histopathology reports from all Swedish pathology departments (n = 28). EoE patients were matched at index date for age, sex, calendar year and county with up to five general population reference individuals (N = 7281) without EoE or CVD. Multivariable-adjusted hazard ratios (aHRs) for MACE (ischemic heart disease, congestive heart failure, stroke and cardiovascular mortality) were calculated using Cox proportional hazards models. Full sibling comparisons and adjustment for cardiovascular medication were performed. During a median follow-up of 6.0years, we observed 65 incident MACE in patients with EoE (6.4/1000 person-years (PY)) and 225 in reference individuals (4.7/1000 PY). EoE was not associated with a higher risk of MACE (aHR = 1.14, 95% CI = 0.86-1.51) or any of its components. No differences between age, sex and follow-up time were observed. The results remained stable in sensitivity analyses, including when adjusting for relevant cardiovascular medications and a full sibling comparison. In this large population-based cohort study, patients with EoE had no increased risk of MACE compared to reference individuals and full siblings. The results are reassuring for patients with EoE.

Correlation of hematocrit and cardiovascular events in peritoneal dialysis patients

Objective: To investigate the correlation between hematocrit (HCT) and cardiovascular events in peritoneal dialysis (PD) patients. Methods: Patients undergoing maintenance PD in the PD center of Guizhou Provincial People's Hospital from March 19, 2012 to July 9, 2020 were included. Demographic, baseline clinical and laboratory data of the patients were collected and patients were followed up until April 8, 2022. The primary endpoint was the first occurrence of a cardiovascular event. According to the tertiles of baseline HCT, the patients were divided into group Q1 (HCT≤26.6%), group Q2 (HCT>26.6%-32.4%), and group Q3 (HCT>32.4%). Laboratory indexes and cardiovascular events were compared among the three groups. Kaplan-Meier survival curve, Cox regression analysis and sensitivity analysis were used to analyze the effect of HCT on cardiovascular outcomes. Receiver operating characteristic (ROC) curve was used to analyze the predictive value of HCT for cardiovascular events in PD patients. Results: A total of 860 PD patients were included, including 494 males (57.4%) and 366 females (42.6%), with a mean age of (41.5±15.0) years. There were 287 cases in group Q1, 289 cases in group Q2, and 284 cases in group Q3, respectively. A total of 265 (30.8%) patients experienced first cardiovascular events during the follow-up period. The incidence of cardiovascular events in groups Q1, Q2 and Q3 was 36.2% (104/287), 34.3% (99/289), and 21.8% (62/284), respectively, with a statistically significant difference (P<0.001). The incidence of cardiovascular events decreased with the increase of HCT. Multivariate Cox proportional hazards regression model analysis showed that decreased HCT was a risk factor for cardiovascular events. Compared with group Q3, the risk of cardiovascular events in group Q1 increased by 50.7% (group Q2: HR=1.444, 95%CI: 1.029-2.028, P=0.034; group Q1: HR=1.570, 95%CI: 1.096-2.250, P=0.014). In the sensitivity analysis, using kidney transplantation as the competition event, the risk of cardiovascular events was lower in group Q3 than that in group Q1 (subdistributional HR=1.413, 95%CI: 1.006-1.990, P=0.046). Kaplan-Meier survival curve showed that compared with the other two groups, the cardiovascular events-free survival rate of patients in group Q1 was significantly lower (log-rank χ2=9.722, P=0.008). ROC analysis showed that the area under the curve (AUC) of HCT for predicting cardiovascular events in PD patients was 0.583 (95%CI: 0.542-0.623, P<0.001), with the sensitivity of 40.6% and the specificity of 75.1%. Conclusion: Low-level HCT is associated with an increased risk of the first cardiovascular event in PD patients.

Identifying Giant Cell Arteritis patients with higher risk of relapse and vascular events: a cluster analysis.

Giant cell arteritis (GCA) is one of the most common large vessel (LVV) vasculitis and is associated with a high risk of relapse and cardiovascular complications. Improving risk stratification remains a significant issue in this patient population. We aimed to perform a cluster analysis among GCA to identify clusters and evaluate their prognostic value. In a multicenter cohort study, we performed hierarchical cluster analysis on the factor analysis of mixed data coordinates results with 283 GCA patients' characteristics to generate clusters and assess incidence of relapse, cardiovascular events and death. Three clusters were identified: "Vascular relapsing profile" (23.0%), "Typical GCA profile" (47.7%), and "Ophthalmologic elderly profile" (29.3%). The "Vascular relapsing profile" cluster included younger patients with more frequent relapses and cardiovascular events, particularly thoracic aortic aneurysms. The "Typical GCA profile" was the largest, with classic cranial manifestations and frequently associated polymyalgia rheumatica. The "Ophthalmologic elderly profile" had the oldest patients with more visual loss and the highest mortality rate. Our findings underline the varied prognostic landscape within GCA, emphasizing the poor cardiovascular prognosis of younger patients with LV involvement and the higher mortality among elderly patients. This reinforces the need for further research regarding the screening of aortic abnormalities and whether those patients might benefit from intensive treatment with biotherapy and cardiovascular risk factors management.

Adverse myocardial and vascular side effects of immune checkpoint inhibitors: a prospective multimodal cardiovascular assessment.

Immune checkpoint inhibitors (ICIs) can induce cardiovascular toxicities. To prospectively assess the incidence of major cardiovascular events (MACE) on ICIs in solid cancer patients: myocarditis, pericarditis, acute coronary syndrome, heart failure, high-degree conduction abnormalities or sustained ventricular arrhythmias, or cardiovascular death at 6weeks (early MACE), including asymptomatic clinical changes by an independent adjudication committee using current recommended diagnostic criteria. The secondary objective was the incidence of the above-mentioned events adding atrial fibrillation (AF) at 6months (late MACE). Participants underwent pre-ICIs and repeated multimodality cardiac imaging (echocardiogram, cardiac magnetic resonance (CMR)), serum biomarkers (ultrasensitive troponin I), and rhythm surveillance (ambulatory ECG monitoring) at 6weeks and 6months. Forty-nine patients (38 (77.6%) male; mean age 64.3 (SD 11.0) years old) were included (June 2020-December 2021). Early MACE were observed in 9 (18.4%) patients at mean 40.1 (SD 5.9) days, with heart failure (HF) in 5 (10.2%), ventricular arrhythmias, or new conduction disorders in 4 (8.2%) patients. History of AF (HR 4.49 (CI 1.11-18.14), P = 0.035) predicted early MACE. At 6months follow-up, 18 MACE were observed in 15/49 (31%) patients, with 6 (12.2%) HF events, 5 (10.2%) significant ventricular arrhythmias, or conduction disorders, and 4 (8.2%) AF. There was a significant decline in LVEF (P < 0.001) in patients with no MACE (P = 0.003) or HF (P = 0.0028). Higher creatinine at inclusion (HR 0.99 [0.98-1.00], P = 0.006) predicted HF on multivariate analysis. There were no significant T1 or T2 mapping changes in our study cohort on repeated CMR. Cardiotoxicity on ICIs is more frequent than previously described when using a thorough detection strategy, consisting mainly in HF and asymptomatic rhythm disorders.

Evaluation of Changes in Social Isolation and Loneliness with Incident Cardiovascular Events and Mortality.

It remains unknown how the patterns of change of social isolation and loneliness are associated with the onset of cardiovascular disease (CVD) and mortality. We aimed to investigate the longitudinal association of changes in social isolation and loneliness with incident CVD, all-cause mortality, CVD mortality and subsequent cardiac function. This prospective cohort study included 18,258 participants aged 38-73 years who participated in visit 0 (2006-2010) and visit 1 (2012-2013) using UK Biobank (mean age 57.1, standard deviation [SD] 7.4; 48.7% males). Social isolation or loneliness was categorized into four patterns: never, transient, incident, and persistent. Incident CVD, all-cause and CVD mortality were ascertained through linkage data. Cardiac function was assessed by cardiovascular magnetic resonance imaging in a subsample (N = 5188; visit 2, since 2014). Over a median follow-up of 8.3 (interquartile range [IQR] 8.1-8.6) years, compared with never social isolation, persistent social isolation was associated with the higher risk of incident CVD (hazard ratio [HR] 1.17, 95% confidence interval [CI] 1.03-1.33), all-cause (1.42, 1.12-1.81) and CVD (1.53, 1.05-2.23) mortality. Likewise, persistent loneliness was strongly associated with the greater risk of incident CVD (1.13, 1.00-1.27), all-cause (1.28, 1.02-1.61) and CVD mortality (1.52, 1.06-2.18). Persistent social isolation and loneliness posed a substantially higher risk for incident CVD, all-cause and CVD mortality, and cardiac dysfunction than other patterns. Persistent social isolation and loneliness, along with an increasing cumulative score, are associated with lower cardiac function.

Renal artery stenosis increases the risk of incident atrial fibrillation and cardiovascular events incorporating death

Abstract Background Renal artery stenosis (RAS) remains an under-recognized clinical risk factor for cardiovascular complications. Its long-term impact on AF arrhythmogenesis is unclear. Objective To investigate the role of RAS on incident AF and related adverse cardiovascular events Methods We performed a retrospective cohort study that comprised 100 patients with ultrasonographically-confirmed atherosclerotic RAS, and 50 age- and sex-matched controls who were healthy renal transplant donors (age 52.6 ±5.6 vs 50.1 ±10.7years, women 59% vs 70%). Incident AF was ascertained from clinical records. Primary endpoint was defined as the composite of incident AF, myocardial infarction, unstable angina, heart failure, ischemic stroke, peripheral arterial disease, end-stage renal failure, and cardiovascular death. Results Over a follow-up duration of 4818 ± 2751 days, RAS was significantly associated with incident AF (9.4% versus 0%, P=0.025). Kaplan-Meier analyses showed that RAS was associated with reduced incident AF event-free survival (Log-rank Mantel-Cox=4.6 P=0.032, Figure). Multivariable logistic regression showed that after adjustment for potential confounders (including age, sex, smoking, alcohol use, history of hypertension, diabetes mellitus, myocardial infarction, heart failure, ischemic stroke, renal function and serum low-density lipoprotein level), RAS was independently associated with substantially increased risk of the primary endpoint (OR=27.8, 95%CI [2.3 – 333.9], P=0.009), Conclusions RAS is an important and under-recognized independent risk factor for AF and cardiovascular events incorporating death. Its pathophysiological implications with a view to potential interventions need to be further explored.

#217 Renin-angiotensin-aldosterone system blockers effect in CKD progression in hypertensive elderly patients without proteinuria: PROERCAN trial

Abstract Background and Aims Evidence about nefroprotective effect with RAAS blockers in elderly patients with chronic kidney disease (CKD) without proteinuria is lacking. The primary outcome of our study is to evaluate the impact of RAAS blockers in CKD progression in elderly patients without proteinuria. Method Multicenter open-label, randomized controlled clinical trial including patients over 65 year-old with hypertension and CKD stages 3-4 without proteinuria. Patients were randomized in a 1:1 ratio to either receive RAAS blockers or other antihypertensive drugs and were followed up for three years (Figure). Primary outcome is estimated glomerular filtration rate (eGFR) decline at 3 years. Secondary outcome measures include BP control, renal and cardiovascular events and mortality. Results 88 patients were included with a mean age of 77.9 ± 6.1 years and a follow up period of 3 years: 40 were randomised to RAAS group and 48 to standard treatment. Etiology of CKD was: 53 vascular, 16 interstitial and 19 of unknown etiology. In the RAAS group eGFR slope during follow up was −4.3 ± 1.1 ml/min, whereas in the standard treatment group an increase on eGFR was observed after 3 years (+4.6 ± 0.4 ml/min), p = 0.024. We found no differences in blood pressure control, number of antihypertensive drugs, albuminuria, potassium serum levels, incidence of cardiovascular events nor mortality during the follow up period. Conclusion In elderly patients without diabetes nor cardiopathy and with non proteinuric CKD the use of RAAS blockers does not show a reduction in CKD progression.

#1146 Role of renal dysfunction in the use of anticoagulants in COPD patients with atrial fibrillation

Abstract Background and Aims The renal dysfunction is known to be the most important predictor of outcome in patients with atrial fibrillation (AF). At the same time, assessment of the functional state of the kidneys is an integral part of the protocol when selecting the dose of oral anticoagulants. The prognostic role of the functional state of the kidneys during treatment with oral anticoagulants on a possible worsening of the cardiac prognosis during the treatment of AF in patients with concomitant comorbid background, in particular with COPD, has not been sufficiently studied. The aim of the study was to evaluate the prognostic role of renal dysfunction in terms of possible cardiovascular events and bleeding in patients with COPD and AF treated with oral anticoagulants. Method 56 COPD patients with CHF and AF who received oral anticoagulants were examined. Renal function (creatinine level and estimated glomerular filtration rate - eGFR) was assessed at baseline and follow-up. The functional state of the kidneys was calculated using the CKD-EPI-2011 formula. At baseline, the risk of bleeding was assessed using the HAS-BLED scale. Worsening of the functional state of the kidneys was detected when the level of creatinine increased or eGFR decreased by at least 20%. Results In addition to standard treatment for COPD in the presence of AF, patients received oral anticoagulants during six months of observation. Worsening of the functional state of the kidneys was observed in 18.3% of patients. In patients with renal dysfunction, the frequency of episodes of CHF decompensation and non-major bleeding (MB) was significantly higher. With a reduced glomerular filtration rate, there was no effect on the incidence of bleeding and stroke. The oral anticoagulants used did not have a significant effect on the observed renal dysfunction and did not affect the occurrence of new cardiovascular events in patients with COPD. It turned out that predictors of renal dysfunction in patients with COPD are age, female gender, and lower hemoglobin levels. In multivariate analysis, renal dysfunction was identified as an independent predictor of non-major bleeding (OR 2.04, 95%, p &amp;lt; 0.05). Conclusion In patients with COPD and atrial fibrillation, the presence of renal dysfunction was an additional exacerbating factor associated with a poor mid-term cardiovascular prognosis and the risk of bleeding. However, oral anticoagulants did not affect the degree of deterioration of renal function or the incidence of cardiovascular events.

#356 Low-dose thiazide/fludrocortisone use in advanced CKD can rapidly improve potassium-elevated metabolic acidosis with renal and cardiovascular safety

Abstract Background and Aims Advanced chronic kidney disease (CKD) is often complicated by metabolic acidosis(MA) with elevated serum potassium(K). MA is a risk factor for CKD progression, and elevated serum K forces dietary K restriction, which is also undesirable in CKD, stalling the use and escalation of renin-angiotensin-aldosterone system inhibitors (RAASi). Sodium bicarbonate(SB) and K binders, which are not well tolerated due to gastrointestinal symptoms, are often used to correct MA and hyperkalemia. On the other hand, the concurrent use of thiazide and fludrocortisone to promote urinary excretion of K and hydrogen ions has been reported in the type IV renal tubular acidosis, but its efficacy and safety in advanced CKD is unclear. Method This single-center, retrospective, observational study included CKDG3b-G5 outpatients with MA([HCO3−]&amp;lt;22 mM) and elevated K (serum [K]≥ 5.0 mEq/L) at our center. A total of 59 patients were selected, excluding those who had already been prepared for renal replacement therapy at the start of treatment. Patients who continued to receive trichlormethiazide (1 mg, at 1-3 day intervals) plus fludrocortisone (0.1 mg, at 1-3 day intervals) (low-T/F group, N = 10) or SB(0.5 g-5 g/day) alone (SB group, N = 49) were followed up until 2 years after the start of treatment and the two groups were compared. Background factors including age, sex, cause of CKD, estimated glomerular filtration rate (eGFR), CKD stage, urinary protein(g/gCr),serum [K]/ [HCO3−]/[Na]/[CL]/albumin/phosphate, hemoglobin levels, and the use of RAASi/K binders/diuretics were investigated. Efficacy and safety comparisons between the two groups were evaluated based on changes in serum [HCO3−]and [K] levels before and after starting of treatment (at 2, 6, 12, 18, and 24 months), percentage of patients achieving [HCO3−] ≥22 mM, change in eGFR, incidence of renal events (&amp;gt;30% reduction in eGFR or renal replacement therapy), the incidence of cardiovascular events, and the incidence of treatment-modified events such as initiation or increase of antihypertensive, K-binding, and uric acid-lowering agents. Results In all 59 subjects, the mean age was 72.0±11.7 years, 81% were male, mean eGFR was 19.6 ± 7.2 mL/min/1.73 m2, CKDG4/5 account for 92% (G4 60%/G5 32%), primary disease was diabetic nephropathy 30%, nephrosclerosis 43%, RAASi use 68%, mean [K] was 5.5 ± 0.4 mEq/L and mean [HCO3−] was 18.1 ± 2.2 mM. The low-T/F group consisted of patients who switched due to prior SB intolerance or in whom SB was ineffective, and included 5 patients who received concomitant SB. Comparison of background factors showed no significant difference between the two groups. The changes in the serum [HCO3−] and [K] levels 2 months after starting the treatment were significantly larger in the low-T/F group compared with the SB group ([K]after - [K]before (mEq/L):median −1.2, IQR-1.6 to −0.48 vs −0.57, −0.80 to −0.10, p = 0.036; {[K]after -[K]before}×100/[K]before(%): median −20.3, IQR −26.4 to −9.2 vs −9.3, −14.8 to −1.85, p = 0.032; [HCO3−]after-[HCO3−]before (mM):median +5.2, IQR +3.75 to +8.23 vs +3.2, +1.7 to +5.1, p = 0.022) . The percentage of patients achieving [HCO3−] ≥22 mM at 2 months after treatment was significantly higher in the low-T/F group at 88.9% (SB group 38.8%, p = 0.007). There were no renal events in the low-T/F group, and cumulative renal survival (no renal events) tended to be higher in the low-T/F group than in the SB group in the all conditions such as unadjusted condition, presence of RAASi, CKDG4/5 and matched for age, sex, primary cause of CKD and eGFR (p = 0.06, p = 0.265, p = 0.16, p = 0.14, respectively) (Figure). In patients with no renal events, the low-T/F group had a significantly better mean eGFR change of +4.2% at 6 months (SB group: −11.0%, p = 0.019). There were also no cardiovascular events in the low-T/F group, and there were no significant differences between the two groups in either cardiovascular events or treatment-modified events (Table). Conclusion Even in advanced CKD, the low-dose combination of thiazide and fludrocortisone can rapidly improve K-elevating MA and continue without adverse renal or cardiovascular outcomes.

#3011 Pathophysiological link between renal and cardiovascular disease in patients with type 2 diabetes mellitus: preliminary results from a proteomic study

Abstract Background and Aims Diabetic kidney disease (DKD) affects nearly 40% of people with diabetes and is the leading cause of chronic kidney disease (CKD). A high prevalence of cardiovascular disease (CVD) is known in this population. Indeed, DKD and CVD are often related and lead to worse outcomes in type 2 diabetes mellitus (T2D), i.e. cardiac fibrosis and CV events are frequently described in patients with DKD. However, specific associations and accurate prediction biomarkers for DKD and CVD progression in T2D are still lacking as various proteins may play a multi-mechanistic role. Lipocalin-2 (LCN2) is involved in several pathophysiological processes (inflammation, renal disease and cardiometabolic complications in CKD). Its leukocyte-chemoattractant effect has shown to reduce CVD in experimental models of cardiomyopathy when suppressed. Excess LCN2 in CKD is a determinant of disease progression, but also a potent mediator of cardiac injury in CKD. Insulin-like growth factor binding proteins (IGFBPs) also play an important role in cell homeostasis by regulating cell transcription, migration, and apoptosis. IGFBP-3 down-regulation has demonstrated to be a predictor of rapid renal progression in T2DM. On the other hand, IGFBP-6 increases when GFR drops, being involved in the pathophysiological process of CKD as an apoptosis-inducing protein In this context, a proteomic-based approach would optimise the clinical utility of multiple plasma biomarkers. The aim was to identify proteins associated with DKD, cardiac fibrosis (estimated by the PICP biomarker) and the presence of a new CV event. Method A prospective cohort of 91 T2D patients, with a minimum follow-up of 3 years (mean: 4 years) was analysed. We evaluated the association between rates of change in GFR and PICP during follow-up (fold-change: end/initial) and their interaction with the development of a composite of cardiovascular (CV) events: CV death, stroke, ischaemic heart disease, atrial fibrillation, valvular heart disease and CV-related hospitalisation. In addition, ninety-two proteins were quantified in serum samples using a multiplex proximity extension assay with high-throughput protein detection technology (Olink proteomics, Cardiometabolic panel). Associations between variations in these proteins and changes in PICP and eGFR (all expressed as fold change from baseline) were assessed using linear regression analyses adjusted for their respective baseline values. All analyses were adjusted by multiple testing (Benjamini-Hochberg, FDR = 0.05%) using R software. Results Sixty-eight (74.7%) men and 23 (25.3%) women were included in the analysis. The mean age at baseline was 65.8 years, and the mean follow-up was 4 years (minimum 3 years). Sixteen cardiovascular events were recorded. An inverse association was observed between GFR and PICP (p = 0.003). Interaction analysis showed that this correlation occurred only in patients with incident CV events (p for interaction &amp;lt;0.001) (Fig. 1). By proteomic analysis (Fig. 2) several proteins were found to be significantly related to one of the three parameters studied (change in GFR, change in PICP and change with cardiovascular event), of which 3 proteins presented an overlap for all the parameters analysed: Lipocalin 2 (LCN2) and Insulin-like growth factor binding proteins 3 and 6 (IGFBP3 and IGFBP6). Interestingly, LCN2 and IGFBP6 were more highly expressed in patients with CV events whereas IGFBP3 was downregulated in these patients. Conclusion In patients with DKD, worsening enal function is associated with elevated circulating levels of the collagen synthesis biomarker PICP, particularly in those who developed at least one CV event. The link shown with LCN2, IGFBP-6 and IGFBP-3 shed light on possible multi-mechanistic pathways involved in DKD and narrow the scope towards a common pathway involving an interaction between pro-apoptotic and local inflammatory factors.

#83 Cardiovascular outcomes in home hemodialysis and peritoneal dialysis patients

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.

#2175 Sodium-glucose cotransporter 2 (SGLT2) inhibitors-induced erythropoiesis and cardiovascular events in chronic kidney patients

Abstract Background and Aims Prior research has established that in chronic kidney disease (CKD), elevating hemoglobin (Hb) levels above 11.5 g/dl correlates with heightened thromboembolic event risks and increased mortality. Similar findings are seen in heart failure patients with Hb levels exceeding 13 g/dl, following treatment with erythropoiesis-stimulating agents. Sodium-glucose cotransporter 2 (SGLT2) inhibitors consistently raise Hb levels in CKD patients, both anemic and non-anemic. This study aims to evaluate the consequences of Hb level elevation due to SGLT2 inhibitors beyond the safe threshold in CKD patients and to investigate its association with cardiovascular (CV) events. Method A retrospective observational study was conducted from January 2016 to December 2021, focusing on CKD patients treated with SGLT2 inhibitors. Patients receiving erythropoiesis-stimulating agents or undergoing renal replacement therapy were excluded. We assessed the impact of Hb level changes on atheroembolic events, blood pressure variations, and mortality, while considering demographic data, red blood cell parameters, and renal function indicators. Patients receiving iron treatment were excluded to ensure accurate ferrokinetic parameter assessment. Results The study included 79 CKD patients, predominantly male (76%) and primarily with type 2 diabetes mellitus (T2DM) as the CKD cause (67%). Average follow-up post-SGLT2 inhibitor initiation was 3.5 years (SD 1.4, 0.7-6.7 years). Hb levels increased mainly in the first six months of treatment, with an average increase of 0.7 g/dl/year from baseline (p &amp;lt; 0.01). Ferritin levels slightly decreased (p 0.002), while the transferrin saturation index remained stable. Baseline estimated glomerular filtration rate (eGFR) did not influence Hb increase. Various responses to SGLT2 inhibitors were noted based on baseline Hb levels. No significant association was found between elevated Hb levels (&amp;gt;16.0 g/dl) and increased atheroembolic events, mortality, or blood pressure changes. However, patients with Hb levels &amp;gt;13.0 g/dl experienced more CV events compared to those maintaining Hb ≤13.0 g/dl, though not statistically significant (0% vs 17.5%: p 0.30). Conclusion SGLT2 inhibitor treatment led to a significant Hb increase unless baseline levels were above 16.0 g/dl. Importantly, elevating Hb levels above 13.0 g/dl appears to be linked with a higher incidence of cardiovascular (CV) events, suggesting a potential risk associated with such an increase in Hb levels in this patient population. This finding underscores the necessity for further research to confirm this correlation and to delineate the safe therapeutic window for Hb levels in CKD patients treated with SGLT2 inhibitors.

#1578 Left ventricular ejection fraction: association with risk of mortality and the incidence of AVF dysfunction

Abstract Background and Aims Ejection fraction (EF) and chronic heart failure (HF) are often considered as criteria for the possibility of arteriovenous fistula (AVF) creation in relation to an increased risk of death, without sufficient evidence for this. There is, however, rare but compelling evidence that low EF increases the risk of AVF dysfunction. Aims: to evaluate the association between EF at the time of AVF creation and the incidence of adverse cardiovascular events, all-cause mortality, as well as AVF dysfunction Method This retrospective cohort study included 962 adult patients who had a first-time created functioning AVF. Only patients with a more than three months period after AVF creation and within a five-year period were included. The mean follow-up period was 34 ± 13 months. Four groups were identified based on EF and the presence of HF at the time of AVF creation (transthoracic echocardiogram): HF with reduced EF (rEF) &amp;lt;40%, with mid-range (mrEF) of 40-49%, or with preserved EF (pEF) ≥50% + HF, and a “no HF” group with EF ≥50% and no HF. Results In the univariate analysis, a reduced EF was associated with an increased risk of mortality, with the hazard ratios (HRs) of 2.706 [95% CI 1.330; 5.507], p = 0.006 for mrEF and 8.250 [95% CI 2.621; 25.97], p &amp;lt; 0.001 for rEF, compared to the “no HF” group (here and thereafter)—Fig. 1. However, after adjusting for age, sex, and Charlson Comorbidity Index (CCI), the EF was not significantly associated with the risk of death. Only the CCI score remained a significant factor (HR = 1.748 [95% CI 1.482; 2.063], p &amp;lt; 0.001). A decreased EF was associated with the incidence of AVF dysfunction both in the univariate analysis and after adjustments. In the univariate analysis, the incidence rate ratios (IRRs) of 6.88 [95% CI 3.88; 12.1], p &amp;lt; 0.001 for mrEF, and 19.9 [95% CI 8. 64; 41.6], p &amp;lt; 0.001 for rEF, were shown. After adjusting for age, sex, and CCI, the IRR for mrEF was 8.96 [95% CI 5.81; 13.7], p &amp;lt; 0.001, and for rEF it was 23.4 [95% CI 13.8; 38.6], p &amp;lt; 0.001. Even in the presence of polycystic kidney disease and diabetes mellitus in the fully adjusted model, the association between EF and the incidence of AVF dysfunction remained statistically significant: the IRR was 8.61 [95% CI 5.61; 13.1], p &amp;lt; 0.001 for mrEF, and 33.4 [95% CI 19.5; 56.2], p &amp;lt; 0.001 for rEF. The findings were confirmed in a sensitivity analysis that included adjustments for unplanned onset of dialysis and competing risks survival analysis (death—outcome of interest, conversion of HD to PD or kidney transplantation and conversion of AVF to CVC—competing events). According to our results patients with EF&amp;lt;40% will inevitably lose AVF function for various reasons within 3.5 years—Fig. 2. Meanwhile, this approach will give the patient additional time of HD via AVF, but not CVC, without increasing the risk of death, subject to Qa monitoring. Conclusion In patients with CKD 5 who are initiating treatment with maintenance hemodialysis, a decreased EF is associated to a greater extent with a higher risk of AVF dysfunction than with an increased risk of mortality. The burden of comorbidities, rather than a standalone assessment of EF, is one of the major risk factors determining patient survival.

#2437 Association between iron deficiency and risk of major events in chronic kidney disease—CKD-REIN Cohort

Abstract Background and Aims Iron deficiency (ID) is common in patients with chronic kidney disease (CKD) but remains under-diagnosed and its prognosis poorly documented in the absence of anemia. Data from CKDopps showed low TSAT levels were associated with increased risk of all-cause mortality and incidence of major cardiovascular events in patients with moderate to advanced CKD, an effect that was not modified by the presence of anemia [1]. Additionally, patients with both low TSAT and high ferritin levels displayed the highest risk of all-cause mortality. The aim of the study was to assess the relationship between ID and the risk of major adverse outcomes in patients with CKD in France. Method Using data from the French CKD-REIN cohort which included and followed over 5 years, 3,033 nephrology outpatients with CKD stage 2 to 5 CKD [2], we estimated the prevalence of ID, defined by a ferritin level &amp;lt; 100 mg/L and/or a transferrin saturation (TSAT) &amp;lt; 20%, and associated hazard ratios (HR) of kidney failure with replacement therapy, kidney failure defined by an eGFR &amp;lt; 15 ml/min per 1.73 m2 or initiation of kidney replacement therapy, all-cause mortality, all-cause hospitalization and death or hospitalization for heart failure. The analysis was conducted using a Cox model in which ID was included as a time-dependent variable and adjusted for identified confounders (socio-demographic characteristics, comorbidities, and biological measures) and hemoglobin level. Results A total of 2 914 patients with at least one ferritin or TSAT measurement at baseline or during follow-up were included in the analysis. The majority were men (66%), with a mean age of 67 ± 13 years; 49.6%, 41.2%, and 9.2%, had CKD stage 2/3, 4, and 5, respectively. Baseline prevalence of ID in the cohort was 50% [48-52]. Mean hemoglobin was 13 ± 1.7 g/dL, and only 31% of patients with ID also had a hemoglobin &amp;lt; 12 g/dL. Of the 2 914 patients included in the analysis, 627 (22%) required dialysis or transplantation, and 382 (13%) died before kidney replacement therapy. The incidence rate of kidney failure with replacement therapy was 6.76 versus 3.53 per 100 person-years in patients with and without ID. ID was associated with significant increased risk of kidney failure with replacement therapy, with adjusted HRs for confounders and hemoglobin level of 1.51 [1.24-1.82] (Fig. 1). A total of 836 patients (29%) progressed to kidney failure during the study period, and 341 (12%) died before this stage. The incidence rate of kidney failure was 8.66 versus 6.43 per 100 person-years in patients with and without ID. ID was associated with significant increased risk of kidney failure, with adjusted HRs for confounders and hemoglobin level of 1.19 [1.02-1.38] (Fig. 1). Adjusted HRs for all-cause mortality, for all-cause hospitalization, and for hospitalization or death for heart failure, were 1.31 [1.04-1.66], 1.04 [0.93-1.15], and 1.38 [1.07-1.80], respectively (Fig. 2). Conclusion This study confirms that ID is common in patients with CKD and shows that ID is significantly associated with the risk for kidney failure, all-cause mortality, and heart failure, independent of the presence of anemia. An intervention trial would be needed to assess whether correction of this ID in CKD patients is associated with a reduction in associated risks.

#1750 Burden and excess risk of adverse outcomes in patients with type 1 diabetes utilizing KDIGO classification: a national cohort study

Abstract Background and Aims Our investigation was motivated by the underutilization of the “Kidney Disease Improving Global Outcomes” (KDIGO) classification in evaluating the burden and impact of renal and cardiovascular (CV) adverse outcomes in individuals with type 1 diabetes mellitus (T1DM). Focusing on T1DM patients from the Swedish National Diabetes Register, our study aimed to clarify three key aspects: 1) the distribution of various KDIGO categories across the cohort, 2) the incidence of adverse renal and cardiovascular events, including mortality, for each KDIGO category, and 3) the association of baseline KDIGO category and future excess risk for five major outcomes described below. Method The estimated glomerular filtration rate (eGFR) was calculated using the CKD-EPI 2009 equation at baseline and during follow-up. In accordance with KDIGO 2012 guidelines, participants were classified based on their baseline albuminuria and creatinine into G1 to G5 eGFR and A1 to A3 albuminuria categories. Renal outcomes of interest for incidence analysis included: acute kidney injury, 40% eGFR decline from baseline, kidney failure, renal death, and a composite outcome named “MAKE” comprising either of the above renal outcomes. The CV outcomes were coronary heart disease (incorporating acute myocardial infarction and unstable angina), stroke and CV death, the composite outcome “MACE” that included either of the above CV outcomes and heart failure. Additionally, incidence of all-cause mortality was analysed. The cumulative incidence of outcomes was assessed using Kaplan-Meier Survival curves, and incidence rate was calculated per 1000 person-years (py). Cox proportional hazards regression models of risk in the KDIGO strata were employed to examine the association between baseline KDIGO category and the risk of the following five major outcomes: 40% decline, KF, MAKE, MACE and all-cause mortality. Hazard ratios (HR) and 95% confidence intervals were determined. Cox-regression analyses were conducted twice: initially using as reference the conventional KDIGO low-risk categories “combined G1A1 + G2A1” and then using “only G1A1” to specifically evaluate if G2A1 is associated with excess risk. Results Among 39 067 included patients, mean follow-up was 9.1 years (350 000 person-years). The prevalence of chronic kidney disease, defined as eGFR &amp;lt;60 ml/min/1.73 m2 and/or albuminuria, was 18.5% of whom 8.1% were normoalbuminuric. As seen in the figure below, a progressive increase in incidence and adjusted HR for all outcomes was found with advancing eGFR and albuminuria categories, even in individuals with eGFR ≥60 ml/min/1.73 m2. Interestingly, repeat analysis using G1A1 alone as reference revealed significantly elevated risk for all major outcomes even in G2A1 (10% of the entire cohort), conventionally perceived as low risk. Conclusion A progressively increasing burden of adverse cardiorenal outcomes including mortality was observed with advancing KDIGO categories in T1DM population. Even in subjects with preserved eGFR and normoalbuminuria, we identified an elevated risk for all major outcomes, indicating that early screening and implementation of preventive strategies may be beneficial in improving prognosis of this population.

#1853 Comparative analysis of atherosclerotic risk factors in dialysis patients

Abstract Background and Aims Prevailing studies indicate a correlation between elevated serum phosphate levels and an augmented incidence of cardiovascular events. In patients undergoing dialysis, hyperphosphatemia contributes to vascular and valvular calcifications. This study analyzes the interrelation of phosphate levels, inflammatory markers, and additional risk determinants in the development of carotid artery atherosclerosis in individuals receiving peritoneal dialysis (PD) versus hemodialysis (HD). Method A cohort of 39 PD and 53 HD patients were recruited, all undergoing stable renal replacement therapy (RRT) for three to thirty-six months. B-mode ultrasonography assessed the carotid artery intima-media thickness (CIMT) and detected plaque and calcification occurrences. Patients were specified as having atherosclerosis when CIMT was greater than 1 cm, and the presence of plaque was identified. Logistic regression analysis was employed to discern the connection between potential risk factors and the incidence of atherosclerosis. Results The study encompassed 92 participants, 61% undergoing HD and an average age of 53.4 years (standard deviation ± 14.5 years). The tubulo-interstitial disease was the predominant initial pathology, followed by chronic glomerulonephritis and nephroangiosclerosis. Diabetic nephropathy was identified as the etiology of end-stage renal disease (ESRD) in 23.1% of PD and 11.4% of HD subjects (p = 0.047). Notably, PD patients showed better residual renal function (RRF) (p &amp;lt; 0.001), urine volume over 24 hours (p &amp;lt; 0.001), and C-reactive protein (CRP) (p = 0.047), alongside diminished phosphate (p = 0.01), parathyroid hormone (PTH) (p &amp;lt; 0.05), alkaline phosphatase (p &amp;lt; 0.05), and albumin levels (p &amp;lt; 0.001) relative to their HD counterparts. Atherosclerosis prevalence was 66.3%, inclusive of the entire diabetic cohort. The incidence of atherosclerosis did not significantly diverge between PD and HD groups [56.4% vs 73.6% in HD, respectively]. Atherosclerotic patients were older (p &amp;lt; 0.001) and exhibited heightened phosphate levels (p = 0.012), pulse pressure (p = 0.01), and calcium index (Ci) (p = 0.034). Multiple regression analysis elucidated age, phosphate, RRF, PTH, pulse pressure, diabetes, and HD modality as autonomous factors linked to atherosclerosis. Conclusion Beyond conventional risk factors like age and diabetes, metabolic disorders arising from renal insufficiency were identified as contributing to atherosclerotic development. Multivariate analysis identified phosphate, RRF, and pulse pressure (PP) as independent atherosclerotic risk factors. The HD modality carried an elevated atherosclerotic risk compared to PD. It was thought that preserving RRF in PD patients would improve phosphate regulation and maybe even improve endothelial function, explaining the differences found.

#723 The impact of kidney function on arterial stiffness in COVID-19 survivors: an analysis from CARTESIAN Study

Abstract Background and Aims SARS-CoV-2 pandemic has been linked to an increased incidence of cardiovascular events, potentially due to accelerated vascular aging [1]. Conversely, impaired kidney function is known to contribute to the pathogenesis of heightened arterial stiffness, independent of traditional cardiovascular risk factors [2]. This study aimed to assess the impact of COVID-19 on arterial stiffness among a cohort of survivors of the first pandemic wave, with varying degrees of infection severity. The assessment was conducted at 6 ± 3 (T1) and 12 ± 3 months (T2) post-infection, with the population stratified based on kidney function. Method the CARTESIAN study, a large international multicenter cohort study, was designed to assess the long-term effects of COVID-19 on vascular aging. A total of 938 subjects were stratified into three groups based on their estimated glomerular filtration rate (eGFR) percentiles using the CKD-EPI_2021 equation: 1) &amp;gt;75th percentile, 2) 75th-25th percentile, and 3) &amp;lt;25th percentile, respectively. The same population was further categorized based on the severity of COVID-19 into three groups: 1) patients who were not hospitalized (No-Hosp), 2) subjects requiring hospitalization in a medical unit (Hosp), or 3) those in an intensive care unit (ICU). Arterial stiffness was evaluated using carotid-femoral pulse wave velocity (cf-PWV). A hierarchical repeated measures mixed model analysis was conducted to compare cf-PWV across these groups (&amp;gt;75th, 75th-25th, and &amp;lt;25th groups, respectively). Results in the cross-section analysis (T1) &amp;lt;25th group exhibited higher age, increased cardiovascular risk factors, and higher prevalence of severe COVID-19 compared to the &amp;gt;75th group. Using hierarchical linear modeling, the &amp;lt;25th exhibited higher cf-PWV than the &amp;gt;75th group, even after adjusting for both all the random and fixed variables, included the three COVID-19 group (+0.51 m/s, p = 0.013). In longitudinal analysis, globally, no substantial changes were found in the cf-PWV between T1 and T2, remained significantly higher in the &amp;lt;25th group compared to the &amp;gt;75th group (p = 0.003), in a linear mixed model adjusted for all the random and fixed variables. Interestingly, a significant interaction between eGFR groups* COVID-19 groups was found in repeated measures analysis (p = 0.039). In particular, within ICU group, we found a significant increase of cf-PWV between 6- and 12-months in &amp;lt;25th group, from 8.64 [7.59-9.31] to 9.41 [8.89-10.41] m/s, p = 0.021) (Fig. 1). Conclusion the findings suggest that individuals with both lower eGFR and a history of severe COVID-19 may be at a heightened risk of accelerated arterial aging. Understanding these dynamics is crucial for targeted interventions to mitigate long-term cardiovascular consequences in COVID-19 survivors with kidney disease.