Cause-specific Hazards Model Research Articles

Radiofrequency ablation via catheter and transpapillary access in patients with cholangiocarcinoma (ACTICCA-2 trial) – a multicenter, randomized, controlled, open-label investigator-initiated trial

BackgroundDespite the recent advances in cancer treatment, the therapeutic options for patients with biliary tract cancer are still very limited and the prognosis very poor. More than 50% of newly diagnosed patients with biliary tract cancer are not amenable to curative surgical treatment and thus treated with palliative systemic treatment. Malignant bile duct obstructions in patients with perihilar and/or ductal cholangiocarcinoma (CCA) represents one of the most important challenges in the management of these patients, owning to the risk represented by developing life-threatening cholangitis which, in turn, limits the use of systemic treatment. For this reason, endoscopic stenting and/or bile duct decompression is the mainstay of treatment of these patients. Data on efficacy and safety of adding radiofrequency ablation (RFA) to biliary stenting is not conclusive. The aim of this multicenter, randomized trial is to evaluate the effect of intraductal RFA prior to bile duct stenting in patients with unresectable perihilar or ductal CCA undergoing palliative systemic therapy.Methods/DesignACTICCA-2 is a multicenter, randomized, controlled, open-label, investigator-initiated trial. 120 patients with perihilar or ductal CCA with indication for biliary stenting and systemic therapy will be randomized 1:1 to receive either RFA plus bile duct stenting (interventional arm) or bile duct stenting alone (control arm). Patients will be stratified by trial site and tumor location (perihilar vs. ductal). Both arms receive palliative systemic treatment according to the local standard of care determined by a multidisciplinary tumorboard. The primary endpoint is time to first biliary event, which is determined by an increase of bilirubin to > 5 mg/dl and/or the occurrence of cholangitis leading to premature stent replacement and/or disruption of chemotherapy. Secondary endpoints include overall survival, safety according to NCI CTCAE v5, quality of life assessed by questionnaires (EORTC QLQ-C30 and QLQ-BIL21), clinical event rate at 6 months after RFA and total days of over-night stays in hospital. Follow-up for the primary endpoint will be 6 months, while survival assessment will be continued until end of study (maximum follow-up 30 month). All patients who are randomized and who underwent endoscopic stenting will be used for the primary endpoint analysis which will be conducted using a cause-specific Cox proportional hazards model with a frailty for trial site and fixed effects for the treatment group, tumor location, and stent material.DiscussionACTICCA-2 is a multicenter, randomized, controlled trial to assess efficacy and safety of adding biliary RFA to bile duct stenting in patients with CCA receiving palliative systemic treatment.Trial registrationThe study is registered with ClinicalTrials.gov (NCT06175845) and approved by the local ethics committee in Hamburg, Germany (2024-101232-BO-ff). This manuscript reflects protocol version 1 as of January 9th, 2024.Graphical

A competing risks model to estimate the risk of graft failure and patient death after kidney transplantation using continuous donor-recipient age combinations

Graft failure and recipient death with functioning graft are important competing outcomes after kidney transplantation. Risk prediction models typically censor for the competing outcome thereby overestimating the cumulative incidence. The magnitude of this overestimation is not well described in real-world transplant data. This retrospective cohort study analyzed data from the European Collaborative Transplant Study (n = 125 250) and from the American Scientific Registry of Transplant Recipients (n = 190 258). Separate cause-specific hazard models using donor and recipient age as continuous predictors were developed for graft failure and recipient death. The hazard of graft failure increased quadratically with increasing donor age and decreased decaying with increasing recipient age. The hazard of recipient death increased linearly with increasing donor and recipient age. The cumulative incidence overestimation due to competing risk-censoring was largest in high-risk populations for both outcomes (old donors/recipients), sometimes amounting to 8.4 and 18.8 percentage points for graft failure and recipient death, respectively. In our illustrative model for posttransplant risk prediction, the absolute risk of graft failure and death is overestimated when censoring for the competing event, mainly in older donors and recipients. Prediction models for absolute risks should treat graft failure and death as competing events.

Multiple air pollutant exposure is associated with higher risk of all-cause mortality in dialysis patients: a French registry-based nationwide study.

Little is known about the effect of combined exposure to different air pollutants on mortality in dialysis patients. This study aimed to investigate the association of multiple exposures to air pollutants with all-cause and cause-specific death in dialysis patients. This registry-based nationwide cohort study included 90,373 adult kidney failure patients initiating maintenance dialysis between 2012 and 2020 identified from the French REIN registry. Estimated mean annual municipality levels of PM2.5, PM10, and NO2 between 2009 and 2020 were combined in different composite air pollution scores to estimate each participant's exposure at the residential place one to 3 years before dialysis initiation. Adjusted cause-specific Cox proportional hazard models were used to estimate hazard ratios (HRs) per interquartile range (IQR) greater air pollution score. Effect measure modification was assessed for age, sex, dialysis care model, and baseline comorbidities. Higher levels of the main air pollution score were associated with a greater rate of all-cause deaths (HR, 1.082 [95% confidence interval (CI), 1.057-1.104] per IQR increase), regardless of the exposure lag. This association was also confirmed in cause-specific analyses, most markedly for infectious mortality (HR, 1.686 [95% CI, 1.470-1.933]). Sensitivity analyses with alternative composite air pollution scores showed consistent findings. Subgroup analyses revealed a significantly stronger association among women and fewer comorbid patients. Long-term multiple air pollutant exposure is associated with all-cause and cause-specific mortality among patients receiving maintenance dialysis, suggesting that air pollution may be a significant contributor to the increasing trend of CKD-attributable mortality worldwide.

The Association Between Angiotensin-Converting Enzyme Inhibitor or Angiotensin Receptor Blocker Exposure and Key Cirrhosis-Related Outcomes.

Angiotensin-converting enzyme inhibitors (ACE-I) and angiotensin receptor blockers (ARB) may have hepatic benefits in patients with primarily chronic liver disease. ACE-I/ARB have not been evaluated in broad cohorts inclusive of those with decompensated cirrhosis. We analyzed the real-world association between ACE-I/ARB exposure and cirrhosis-related outcomes in a national cohort. We performed a retrospective, active comparator new user study of patients with cirrhosis in the Veterans Health Administration. We identified new initiators of ACE-I/ARB or calcium channel blockers (comparator). Inverse probability treatment weighting balanced key confounders and Cox regression evaluated the association between ACE-I/ARB and outcomes of mortality, cirrhosis decompensation, and hepatocellular carcinoma (HCC). In exploratory analysis, cause-specific competing risk models evaluated liver-related vs cardiovascular (CV)-related vs nonliver/non-CV-related mortality. There were 904 ACE-I/ARB and 352 calcium channel blocker new initiators. In inverse probability treatment weighting Cox regression, ACE-I/ARB exposure was associated with reduced mortality (hazard ratio [HR] 0.70, 95% confidence interval [CI] 0.61-0.81, P < 0.001). In patients with compensated cirrhosis, ACE-I/ARB were not associated with hepatic decompensation or HCC. Cause-specific hazard models showed ACE-I/ARB exposure was associated with reduction in nonliver/non-CV-related mortality (cause-specific HR 0.49, 95% CI 0.38-0.62, P < 0.001) but not liver-related or CV-related mortality. In Child-Turcotte-Pugh A patients, ACE-I/ARB were associated with decreased CV-related mortality (cause-specific HR 0.41, 95% CI 0.26-0.65, P < 0.001). ACE-I/ARB exposure was associated with reduced mortality, potentially through CV and other (renal, malignancy-related) mechanisms. In patients with compensated disease, ACE-I/ARB were not associated with hepatic decompensation or HCC. Future research should identify subsets of patients who benefit from ACE-I/ARB exposure.

Absolute risk from double nested case-control designs: cause-specific proportional hazards models with and without augmented estimating equations.

We estimate relative hazards and absolute risks (or cumulative incidence or crude risk) under cause-specific proportional hazards models for competing risks from double nested case-control (DNCC) data. In the DNCC design, controls are time-matched not only to cases from the cause of primary interest, but also to cases from competing risks (the phase-two sample). Complete covariate data are available in the phase-two sample, but other cohort members only have information on survival outcomes and some covariates. Design-weighted estimators use inverse sampling probabilities computed from Samuelsen-type calculations for DNCC. To take advantage of additional information available on all cohort members, we augment the estimating equationswith a term that is unbiased for zero but improves the efficiency of estimates from the cause-specific proportional hazards model. We establish the asymptotic properties of the proposed estimators, including the estimator of absolute risk, and derive consistent variance estimators. We show that augmented design-weighted estimators are more efficient than design-weighted estimators. Through simulations, we show that the proposed asymptotic methods yield nominal operating characteristics in practical sample sizes. We illustrate the methods using prostate cancer mortality data from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial Study of the National Cancer Institute.

Burden of CKD-Associated Pruritus and Adverse Clinical Outcomes in Patients Receiving Dialysis: The Stockholm Creatinine Measurements (SCREAM) Project

Pruritus is a common but not well-characterized complaint of patients receiving maintenance dialysis. This study sought to quantify the burden of pruritus and its associated adverse health outcomes in this population. Observational study. All patients receiving maintenance dialysis in Stockholm, Sweden, during 2005-2021. Clinically recognized pruritus defined using International Classification of Diseases, Tenth Revision codes or a prescription for antipruritus treatments (including UV therapy). All-cause mortality, severe infection-related hospitalizations (composite of endocarditis, peritoneal dialysis-related peritonitis, hemodialysis/peritoneal dialysis-related catheter infection, sepsis due to Staphylococcus spp., or skin infection) and incident diagnoses of anxiety/depression and sleep disorders. Multivariable logistic regression and cause-specific hazards models to analyze factors associated with prevalent and new-onset pruritus, respectively. Multivariable cause-specific hazards models with time-varying exposure were used to explore the association of prevalent and new-onset pruritus with adverse health outcomes. Among 3,281 dialysis recipients (median age, 64 years; 66% men; 69% receiving hemodialysis, 77% with incident dialysis), 456 (14%) had pruritus at enrollment. During a median follow-up of 3.3 (IQR, 1.3-9.2) years, 539 (19%) additional patients experienced pruritus. Older age, female sex, a lower serum albumin level, and higher C-reactive protein, serum calcium, and phosphorus levels were independently associated with pruritus. Compared with patients without pruritus, patients with pruritus were at a higher risk of sleep disorders (adjusted HR, 1.96; 95% CI, 1.60-2.39), developing anxiety/depression (adjusted HR, 1.56; 95% CI, 1.23-1.98), and being hospitalized for severe infections (adjusted HR, 1.36; 95% CI, 1.18-1.57), the latter attributed to higher risk of sepsis and peritoneal dialysis-related peritonitis. There was no detectable association between the development of pruritus and all-cause mortality. Potential misclassification bias if pruritus is not clinically recognized, lack of information on pruritus intensity/severity, use of diagnostic codes for exposure and outcome diagnoses. At least one third of patients experience pruritus during their first years undergoing dialysis, and pruritus was consistently associated with adverse health outcomes. Pruritus is a common but not well-characterized symptom of patients receiving dialysis. We analyzed data from 3,281 patients receiving maintenance hemodialysis or peritoneal dialysis in the region of Stockholm, Sweden. At baseline, 14% of patients had pruritus, and pruritus developed in an additional 19% of patients during their time receiving dialysis. We identified conditions associated with the development of pruritus (eg, older age, female sex, lower serum albumin level, and higher C-reactive protein, serum calcium, and phosphorus levels) and observed that the presence of pruritus was associated with higher risks of sleep disorders, developing anxiety and depression, and being hospitalized for severe infections. No association between pruritus and all-cause mortality was identified.

Components of Residential Neighborhood Deprivation and Their Impact on the Likelihood of Live-Donor and Preemptive Kidney Transplantation.

Adults residing in deprived neighborhoods face various socioeconomic stressors, hindering their likelihood of receiving live-donor kidney transplantation (LDKT) and preemptive kidney transplantation (KT). We quantified the association between residential neighborhood deprivation index (NDI) and the likelihood of LDKT/preemptive KT, testing for a differential impact by race and ethnicity. We studied 403937 adults (age ≥ 18) KT candidates (national transplant registry; 2006-2021). NDI and its 10 components were averaged at the ZIP-code level. Cause-specific hazards models were used to quantify the adjusted hazard ratio (aHR) of LDKT and preemptive KT across tertiles of NDI and its 10 components. Candidates residing in high-deprivation neighborhoods were more likely to be female (40.1%vs. 36.2%) and Black (41.9%vs. 17.7%), and were less likely to receive both LDKT (aHR=0.66, 95% confidence interval [CI]: 0.64-0.67) and preemptive KT (aHR=0.60, 95% CI: 0.59-0.62) than those in low-deprivation neighborhoods. These associations differedby race and ethnicity (Black: aHRLDKT=0.58, 95% CI: 0.55-0.62; aHRpreemptive KT=0.68, 95% CI: 0.63-0.73; Pinteractions: LDKT<0.001; Preemptive KT=0.002). All deprivation components were associated with the likelihood of both LDKT and preemptive KT (except median home value): for example, higher median household income (LDKT: aHR=1.08, 95% CI: 1.07-1.09; Preemptive KT: aHR=1.10, 95% CI: 1.08-1.11) and educational attainments (≥high school [LDKT: aHR=1.17, 95% CI: 1.15-1.18; Preemptive KT: aHR=1.23, 95% CI: 1.21-1.25]). Residence in socioeconomically deprived neighborhoods is associated with a lower likelihood of LDKT and preemptive KT, differentially impacting minority candidates. Identifying and understanding which neighborhood-level socioeconomic status contributes to these racial disparities can be instrumental in tailoring interventions to achieve health equity in LDKT and preemptive KT.

Severity of Inhalation Injury and Risk of Nosocomial Pneumonia: A Retrospective Cohort Study

BackgroundThe impact of inhalation injury on risk of nosocomial pneumonia, an important complication in burn patients, is not well established. Research QuestionIs more severe inhalation injury associated with increased risk of nosocomial pneumonia? Study Design and MethodsWe performed a retrospective cohort study of patients with suspected inhalation injury admitted to a regional burn center from 2011 to 2022 who underwent diagnostic bronchoscopy within 48 hours of admission. We estimated the association of high-grade inhalation injury (abbreviated injury score [AIS] 3-4) versus low-grade inhalation injury (AIS 1-2) with nosocomial pneumonia (NP) adjusted for age, burn size, and comorbid obstructive lung disease. Death and hospital discharge were considered competing risks. ResultsOf the 245 patients analyzed, 51 (21%) had high-grade injury, 180 (73%) had low-grade injury, and 14 (6%) had no inhalation injury. Among the 236 patients hospitalized for >48 hours, NP occurred in 24/50 (48%) patients in the high-grade group, 54/172 (31%) in the low-grade group, and 2/14 (14%) in the no inhalation injury group. High-grade (vs low-grade) inhalation injury was associated with higher hazard of NP in both the proportional cause-specific hazard model (CSHR 2.04; 95% CI, 1.26-3.30; p=0.004) and Fine-Gray subdistribution hazards model (SHR for NP, 2.24; 95% CI, 1.38-3.64; p=0.001). InterpretationAmong patients with inhalation injury, more severe injury was associated with higher hazard of NP in competing risk analysis. Additional research is needed to investigate mechanisms that may explain the relationship between inhalation injury and NP and to identify more effective prevention strategies.

Why you should avoid using multiple Fine–Gray models: insights from (attempts at) simulating proportional subdistribution hazards data

Abstract Studies considering competing risks will often aim to estimate the cumulative incidence functions conditional on an individual’s baseline characteristics. While the Fine–Gray subdistribution hazard model is tailor-made for analysing only one of the competing events, it may still be used in settings where multiple competing events are of scientific interest, where it is specified for each cause in turn. In this work, we provide an overview of data-generating mechanisms where proportional subdistribution hazards hold for at least one cause. We use these to motivate why the use of multiple Fine–Gray models should be avoided in favour of better alternatives such as cause-specific hazard models.

Sex and the Risk of Atheromatous and Nonatheromatous Cardiovascular Disease in CKD: Findings From the CKD-REIN Cohort Study

Sex differences in cardiovascular disease (CVD) are well-established, but whether chronic kidney disease (CKD) modifies these risk differences, and whether they differ between atheromatous (ACVD) and non-atheromatous (N-ACVD) CVD is unknown. Assessing this interaction was the principal goal of this study. Prospective cohort study. Adults enrolled in the CKD-Renal Epidemiology and Information Network (CKD-REIN) cohort from from 2013 to 2020, a nationally representative sample of 40 nephrology clinics in France. Sex. Fatal and non-fatal composite ACVD events (ischaemic coronary, cerebral, and peripheral artery disease) and composite N-ACVD events (heart failure, haemorrhagic stroke, and arrhythmias). Multivariable cause-specific Cox proportional hazards models. 1,044 women and 1,976 men with moderate to severe CKD (median age, 67 vs. 69; mean estimated glomerular filtration rate [eGFR], 32±12 vs. 33±12 mL/min/1.73m2) were studied. Over a median follow-up of 5.0 (interquartile range, 4.8;5.2) years, the ACVD rate (per 100 patient-years) was significantly lower in women than men: 2.1 (95% confidence interval: 1.6-2.5) vs 3.6 (3.2-4.0) (P<0.01), while the N-ACVD rate was not: 5.7 (5.0-6.5) vs 6.4 (5.8-7.0) (P=0.55). N-ACVD had a steeper relationship with eGFR than did ACVD. There was an interaction (P<0.01) between sex and baseline eGFR and the ACVD hazard: the adjusted hazard ratio for women compared to men was 0.42 (0.25;0.71) at 45 mL/min/1.73m2 and gradually attenuated at lower levels of eGFR, reaching 1.00 (0.62;1.63) at 16 mL/min/1.73m2. In contrast, the N-ACVD hazard did not differ between the sexes across the eGFR range studied. Cardiovascular biomarkers and sex hormones were not assessed. This study shows how the lower risk of ACVD among women compared to men attenuates fully with kidney disease progression. The equal risk of N-ACVD between sexes across CKD stages and its steeper association with eGFR suggest an important contribution of CKD to the development of this CVD type.

Survival and its relationship with the type of peritoneal solute transfer rate, in patients with chronic kidney disease incident on peritoneal dialysis therapy in RTS Colombia between the years 2007–2017

IntroductionIn some studies, the peritoneal solute transfer rate (PSTR) through the peritoneal membrane has been related to an increased risk of mortality. It has been observed in the literature that those patients with rapid diffusion of solutes through the peritoneal membrane (high/fast transfer) and probably those with high average transfer characterized by the Peritoneal Equilibrium Test (PET) are associated with higher mortality compared to those patients who have a slow transfer rate. However, some authors have not documented this fact. In the present study, we want to evaluate the (etiological) relationship between the characteristics of peritoneal membrane transfer and mortality and survival of the technique in an incident population on peritoneal dialysis in RTS Colombia during the years 2007–2017 using a competing risk model. Materials and methodsA retrospective cohort study was carried out at RTS Colombia in the period between 2007 and 2017. In total, there were 8170 incident patients older than 18 years, who had a Peritoneal Equilibration Test (PET) between 28 and 180 days from the start of therapy. Demographic, clinical, and laboratory variables were evaluated. The (etiological) relationship between the type of peritoneal solute transfer rate at the start of therapy and overall mortality and technique survival were analyzed using a competing risk model (cause-specific proportional hazard model described by Royston-Lambert). ResultsPatients were classified into four categories based on the PET result: Slow/Low transfer (16.0%), low average (35.4%), high average (32.9%), and High/Fast transfer (15.7%). During follow-up, with a median of 730 days, 3025 (37.02%) patients died, 1079 (13.2%) were transferred to hemodialysis and 661 (8.1%) were transplanted. In the analysis of competing risks, adjusted for age, sex, presence of DM, HTA, body mass index, residual function, albumin, hemoglobin, phosphorus, and modality of PD at the start of therapy, we found cause-specific HR (HRce) for high/fast transfer was 1.13 (95% CI 0.98–1.30) p = 0.078, high average 1.08 (95% CI 0.96–1.22) p = 0.195, low average 1.09 (95% CI 0.96–1.22) p = 0.156 compared to the low/slow transfer rate. For technique survival, cause-specific HR for high/rapid transfer of 1.22 (95% CI 0.98–1.52) p = 0.66, high average HR was 1.10 (95% CI 0.91–1.33) p = 0.296, low average HR of 1.03 (95% CI 0.85–1.24) p = 0.733 compared with the low/slow transfer rate, adjusted for age, sex, DM, HTA, BMI, residual renal function, albumin, phosphorus, hemoglobin, and PD modality at start of therapy. Non-significant differences. ConclusionsWhen evaluating the etiological relationship between the type of peritoneal solute transfer rate and overall mortality and survival of the technique using a competing risk model, we found no etiological relationship between the characteristics of peritoneal membrane transfer according to the classification given by Twardowski assessed at the start of peritoneal dialysis therapy and overall mortality or technique survival in adjusted models. The analysis will then be made from the prognostic model with the purpose of predicting the risk of mortality and survival of the technique using the risk subdistribution model (Fine & Gray).

Impact of Neighborhood Social Deprivation on Delays to Access for Transcatheter Aortic Valve Replacement: Wait-Times and Clinical Consequences.

Transcatheter aortic valve replacement (TAVR) has become the standard of care for severe aortic stenosis treatment. Exponential growth in demand has led to prolonged wait times and adverse patient outcomes. Social marginalization may contribute to adverse outcomes. Our objective was to examine the association between different measures of neighborhood-level marginalization and patient outcomes while on the TAVR waiting list. A secondary objective was to understand if sex modifies this relationship. We conducted a population-based retrospective cohort study of 11 077 patients in Ontario, Canada, referred to TAVR from April 1, 2018, to March 31, 2022. Primary outcomes were death or hospitalization while on the TAVR wait-list. Using cause-specific Cox proportional hazards models, we evaluated the relationship between neighborhood-level measures of dependency, residential instability, material deprivation, and ethnic and racial concentration with primary outcomes as well as the interaction with sex. After multivariable adjustment, we found a significant relationship between individuals living in the most ethnically and racially concentrated areas (quintile 4 and 5) and mortality (hazard ratio [HR], 0.64 [95% CI, 0.47-0.88] and HR, 0.73 [95% CI, 0.53-1.00], respectively). There was no significant association between material deprivation, dependency, or residential instability with mortality. Women in the highest ethnic or racial concentration quintiles (4 and 5) had significantly lower risks for mortality (HR values of 0.52 and 0.56, respectively) compared with quintile 1. Higher neighborhood ethnic or racial concentration was associated with decreased risk for mortality, particular for women on the TAVR waiting list. Further research is needed to understand the drivers of this relationship.

Conditional score approaches to errors-in-variables competing risks data in discrete time.

Analysis of competing risks data has been an important topic in survival analysis due to the need to account for the dependence among the competing events. Also, event times are often recorded on discrete time scales, rendering the models tailored for discrete-time nature useful in the practice of survival analysis. In this work, we focus on regression analysis with discrete-time competing risks data, and consider the errors-in-variables issue where the covariates are prone to measurement errors. Viewing the true covariate value as a parameter, we develop the conditional score methods for various discrete-time competing risks models, including the cause-specific and subdistribution hazards models that have been popular in competing risks data analysis. The proposed estimators can be implemented by efficient computation algorithms, and the associated large sample theories can be simply obtained. Simulation results show satisfactory finite sample performances, and the application with the competing risks data from the scleroderma lung study reveals the utility of the proposed methods.

The Association between Bone Mineral Density and Risk of Mortality: A Prospective Cohort Study of 233,397 Taiwanese

PurposeOsteoporosis is an important public health challenge given its high prevalence in western populations and the prevalence has shown an upward trend in recent decades in Asia. However, epidemiological evidence on the association between bone mineral density (BMD) and mortality risk in the Asian population is sparse. MethodsThe Cox proportional hazards model and cause-specific hazard models were used to investigate the association of BMD with the risk of all-cause mortality and cause-specific mortality. ResultsThe present study comprised of 3,332,207 person-years with a median follow-up of 14.6 years. 27,508 participants (15,967 men and 11,541 women) died among 233,397 participants (112,348 men and 121,049 women) during the follow-up period. Compared to those with normal BMD level, both men and women with low BMD had a significantly higher risk of all-cause, cardiovascular disease (CVD), and cancer mortality after adjusting for the covariates. [For men with osteoporosis: all-cause: 1.37 (1.27–1.49); CVD: 1.28 (1.08–1.52); cancer: 1.29 (1.12–1.49); For women with osteoporosis: all-cause: 1.72 (1.63–1.82); CVD: 1.85 (1.64–2.08); cancer: 1.47 (1.35–1.61)]. The P for interactions for BMD with sex were significant for all-cause and CVD mortality. The adverse effects of BMD on the risk of all-cause and CVD were higher in women than in men [men vs. women: all-cause: 1.37 (1.27–1.49) vs. 1.72 (1.63–1.82); CVD: 1.28 (1.08–1.52) vs. 1.85 (1.64–2.08)]. In the nonlinear dose-response analyses, the association between BMD increments and all-cause mortality risk shows an L-shaped pattern in men and a similar U-shaped trend in women (P for non-linear association: <0.001). Likewise, a similar L-shaped association was observed between BMD levels and cancer mortality risk in men. ConclusionsLow BMD had an increased risk of all-cause, CVD, and cancer mortality in both men and women. Women had a stronger positive association between low BMD and an increased risk of all-cause and CVD mortality compared to men.

The association of diet quality and physical activity with cardiovascular disease and mortality in 85,545 older Australians: A longitudinal study

BackgroundA quality diet and an active lifestyle are both important cornerstones of cardiovascular disease (CVD) prevention. However, despite their interlinked effects on metabolic health, the 2 behaviors are rarely considered jointly, particularly within the context of CVD prevention. We examined the independent, interactive, and joint associations of diet and physical activity with CVD hospitalization, CVD mortality, and all-cause mortality. MethodsCVD-free Australian participants aged 45–74 years (n = 85,545) reported physical activity, diet, sociodemographic, and lifestyle characteristics at baseline (2006–2009) and follow-up (2012–2015), and data were linked to hospitalization and death registries (03/31/2019 for CVD hospitalization and all-cause mortality and 12/08/2017 for CVD mortality). Diet quality was categorized as low, medium, and high based on meeting dietary recommendations. Physical activity was operationalized as (a) total moderate-to-vigorous physical activity (MVPA) as per guidelines, and (b) the composition of MVPA as the ratio of vigorous-intensity physical activity (VPA) to total MVPA. We used a left-truncated cause-specific Cox proportional hazards model using time-varying covariates. ResultsDuring a median of 10.7 years of follow-up, 6576 participants were admitted to the hospital for CVD and 6581 died from all causes (876 from CVD during 9.3 years). A high-quality diet was associated with a 17% lower risk of all-cause mortality than a low-quality diet, and the highest MVPA category (compared with the lowest) was associated with a 44% and 48% lower risk of CVD and all-cause mortality, respectively. Multiplicative interactions between diet and physical activity were non-significant. For all outcomes, the lowest risk combinations involved a high-quality diet and the highest MVPA categories. Accounting for total MVPA, some VPA was associated with further risk reduction of CVD hospitalization and all-cause mortality. ConclusionFor CVD prevention and longevity, one should adhere to both a healthy diet and an active lifestyle and incorporate some VPA when possible.

#1798 Infection-related outcomes in CKD patients with lupus nephritis: a nationwide cohort study

Abstract Background and Aims Although absolute risks of infection in patients with lupus nephritis (LN) are believed high, it is not known whether they differ from those of patients with other etiologies of moderate and advanced chronic kidney disease (CKD). The aim of this study was to compare infection outcomes between patients with LN-CKD and other forms of CKD. Method Using data from the Swedish Renal Registry (2006-2021), we compared infection-related outcomes between LN-patients with moderate and advanced, non-dialysis, CKD and patients with 1) diabetic kidney disease (DKD), 2) primary glomerular diseases (PGD, i.e. IgA nephropathy, focal segmental glomerulosclerosis, membranous nephropathy), and 3) autosomal dominant polycystic kidney disease (ADPKD). Cause-specific Cox proportional hazard models were used to estimate the adjusted hazard ratios of death due to infection, first all-cause infection-related hospitalization and first cause-specific infection-related hospitalization (sepsis, pulmonary, gastrointestinal, genitourinary, and other infections). Results We identified 317 patients with LN (61 years, 76% women, median eGFR 30 mL/min per 1.73 m²), 8877 patients with DKD (71 years, 33% women, eGFR 24 mL/min per 1.73 m²), 2296 patients with PGD (57 years, 30% women, eGFR 29 mL/min per 1.73 m²) and 1855 patients with ADPKD (59 years, 45% women, eGFR 26 mL/min per 1.73 m²). Over a median follow-up of 2.8 [1.2; 5.0] years, 667 (5%) deaths due to infection and 4034 (30%), infection-related (first-time) hospitalizations occurred, including 2127 (16%) pulmonary, 1507 (11%) genitourinary, 1130 (8%) gastrointestinal, 615 (5%) other infections, and 450 (3%) sepsis. In multivariable analyses, and when compared to DKD, patients with LN had a similar risk of death due to infection (adjusted HR 1.15 [95% CI: 0.62-2.11]) and sepsis (HR 1.24 [0.64-2.4]), but a higher risk of all infection-related hospitalization (HR 1.31 [1.04-1.65]), the latter being mainly driven by pulmonary, gastrointestinal, and other infections (Figure panel A). The risks of death due to infection (HR LN vs PGD 2.78 [1.62-4.77], HR LN vs ADPKD 2.34 [1.31-4.19]), of infection-related hospitalization (HR 1.87 [1.52-2.31], HR 1.43 [1.16-1.77]), and of cause-specific infection-related hospitalization were higher in LN than in PGD and ADKPD, respectively, except for the risk of sepsis which was similar between LN and ADPKD. The risk of genitourinary infection tended to be lower in LN than in ADPKD, although the 95% CI slightly overlapped (Figure panels B-C). Conclusion LN patients had higher risk of infection-related hospitalization than all other investigated CKD etiologies, and a higher risk of death due to infections than patients with PGD and ADPKD. Our findings highlight the need for improvements in infection prevention in patients with LN. Whether a more tailored immunosuppressive treatment approach could further improve outcomes in this high-risk population remains to be investigated.

#1956 Effect of hemodialysis modalities on infection-related mortality

Abstract Background and Aims A growing body of evidence have suggested hemodiafiltration (HDF) provide survival benefit for dialysis patients. HDF may improve immune modulation with enhanced clearance of azotemic toxins, compared to high-flux hemodialysis (HD). We therefore assess the effect of dialysis modalities on infection-related mortality in patients treated in real-world settings. Method We conducted a retrospective cohort-study based on 85,117 adult haemodialysis (HD) patients who were treated in EMEA NephroCare Clinics between January 1, 2019 and December 31, 2022. All patients’ data were extracted from the European Clinical Database (EuCliD®), including mortality from any infection, viral infection, and COVID-19 infection. The definition of mortality cause is based on ICD-10 codes. Any infection related mortality includes a broad range of infection disease types, such as viral, bacterial, parasitic, and fungal infections. The associations between dialysis modality and infection-related mortality were analyzed by multivariable Cox regression models, with both dialysis modality and COVID-19 infection as time-dependent covariates. To account for potential impact of difference in patients’ characteristics, we adjusted for multiple confounding factors. Competing risk analyses with death from non-infection as the competing event were performed by cause-specific and Fine-Gray subdistribution hazard models. Results At baseline 45.0% patients were treated with HDF, which changed to 52.6% by the end of follow-up. Of all HDF treatments in post-dilution mode (account for 98.4% HDF treatments) during follow-up, the average convection volume was 25.7 liters (median [interquartile range], 25.8 [23.9–28.0]). Patients treated with HDF at baseline were younger, with less comorbidities and longer dialysis vintage, compared to patients with HD (Table 1). During a median follow-up of 22.6 months, death from any infection occurred among 6.9% patients, of which 40.1% died from COVID-19 infection. Compared to HD, HDF was associated with a reduced risk of dying from any infection (hazard ratio [HR], 0.89 [95% CI, 0.82–0.97]), which however disappeared if excluding death from COVID-19 infection (Table 2). Similar pattern was also observed for death from viral infection. Association of HDF with death from COVID-19 infection persisted after controlling for multiple confounders (HR, 0.81 [95% CI, 0.71–0.93]). Similar results yielded from competing risk analyses. Conclusion In this large, unselected patient population, the beneficial effect of HDF for infection-related mortality was confined to mortality from COVID-19 infection. Further studies are needed to unravel the relation between dialysis modalities and death from different types of infection.

#1091 Quantifying the potential contribution of drugs to the occurrence of acute kidney injury in patients with chronic kidney disease

Abstract Background and Aims Patients with CKD have high risk of AKI. Quantifying the contribution of drugs to the occurrence of AKI in this population and assessing its risk factors is important to design preventive interventions. We sought to comprehensively describe drug-related components associated with AKI in patients with CKD. We documented the incidence of drug-related AKI, the proportion of preventable AKI, identified the various drugs potentially associated with it, explored the risk factors, and assessed the one-year incidences of the recurrence of drug-related AKI, kidney failure, and death. Method The CKD-REIN study is a national prospective cohort of 3,033 nephrology outpatients with a confirmed diagnosis of CKD (eGFR &amp;lt;60 mL/min/1.73 m²) in France. AKIs and adverse drug reactions (ADRs) were prospectively identified from hospital charts, medical records, and patient interviews. Nephrologists used the Kidney Disease: Improving Global Outcomes criteria to adjudicate all stages of AKI, and expert pharmacologists used validated tools to adjudicate ADRs (including drug-related AKIs). A drug-related AKI was considered serious when the outcome is death, a life-threatening situation, hospital admission, disability, permanent damage, or another important medical event. We used cause-specific Cox proportional hazard models to investigate the patients’ baseline clinical characteristics associated with the risk of drug-related AKI. Results Over a median [interquartile range] period of 4.9 [3.4-5.1] years, 832 cases of AKI were reported in 639 (21%) of the 3,033 study participants. Over a quarter of the AKI events were drug-related (n = 236, 28%); from those, 47% were hospital- and 53% community-acquired AKI. From the 168 serious drug-related AKI events, 28% were considered preventable or potentially preventable. The three most frequently implicated drug classes were diuretics, renin-angiotensin system inhibitors, and contrast agents. At least two concomitant medications were implicated in more than half of the AKIs with a drug-related component, RASis and diuretics, two diuretics, and diuretics and antibiotics were the 3 most frequent associations (Figure). A history of cardiovascular events, and the presence of diabetes, lower levels of hemoglobin and eGFR, poor medication adherence, and ≥5 drugs being taken daily were associated with a greater risk of drug-related AKI. The one-year cumulative incidences of recurrent drug-related AKI, kidney replacement therapy, and death were 7%, 15%, and 11%, respectively, after the first drug-related AKI. Conclusion Drug-related AKI is prevalent among patients with CKD. Further training in drug management for both CKD patients and healthcare professionals involved in their care might mitigate the incidence of drug-related AKI.

#431 Ionized and total magnesium levels in patients with chronic kidney disease: associated factors and outcomes

Abstract Background and Aims Association between hypo- and/or hypermagnesaemia and cardiovascular (CV) outcomes or mortality showed conflicting results in chronic kidney disease (CKD) and was mostly conducted on total magnesium (tMg) levels and not ionized magnesium (iMg). Thus, the objectives of the present study were to (i) describe the serum iMg concentration in patients at various CKD stages, (ii) measure the correlation between iMg and tMg concentrations, (iii) identify their associated factors and (iv) determine whether serum tMg and/or iMg concentrations are associated with adverse outcomes, such as major adverse cardiovascular events (MACE) and death before kidney replacement therapy (KRT, defined as the initiation of chronic dialysis or kidney transplantation) in CKD patients, after adjustment for confounding factors. Method CKD-REIN is a French prospective cohort of patients with stage 3 to 5 CKD (estimated glomerular filtration rate (eGFR) &amp;lt;60 mL/min/1.73 m²) recruited from 40 nephrology facilities, neither on maintenance dialysis nor transplanted, and followed up for 5 years. Baseline iMg and tMg serum concentrations were centrally measured. Patients were compared by subgroups according to serum tMg tertiles (Tertile 1 (T1): ≤0.73 mmol/L, T2: 0.74-0.81 mmol/L, T3: &amp;gt;0.81 mmol/L). Multivariate linear regressions were used to identify factors associated with iMg and tMg serum concentrations. Adjusted cause-specific Cox proportional hazard models were used to test the association between the risk of first MACE, all-cause mortality, and CV mortality with serum iMg and tMg concentrations at baseline. Results Of the 2, 419 included patients, 66% were men, median age was 68, and the mean eGFR was 34.8 mL/min/1.73 m². Mean serum iMg and tMg concentrations were respectively 0.48 mmol/L and 0.77 mmol/L. They were strongly correlated (r = 0.89, P &amp;lt; .001) and were independently associated with eGFR. Overall, iMg and tMg concentrations were associated with the same factors. The adjusted HR [95% CI] for MACE associated with the baseline serum tMg level was 1.27 [0.95; 1.69] for patients in T1, and 1.56 [1.18; 2.06] for patients in T3, relative to patients in T2. The adjusted HR [95% CI] for MACE associated with baseline serum iMg was 0.93 [0.71; 1.23] for patients in T1, and 1.14 [0.88; 1.48] for patients in T3, relative to patients in T2. The risks of all-cause death (HR [95% CI] = 1.48 [1.11; 1.97]) and CV mortality (HR [95% CI] = 1.98 [1.27; 3.10]) were also increased in T3 of tMg compared with T2. The adjusted risks for mortality (all-cause or CV) associated with the baseline serum iMg level were not significantly different from one tertile to another. Conclusion Our analysis of a large cohort of patients with moderate-to-advanced CKD demonstrated that individuals with higher serum tMg concentrations, although still within the normal range, had a greater likelihood of MACE and mortality. Total magnesium is routinely assayed in hospital laboratories and might be a useful variable to monitor in CKD patients. We failed to demonstrate the added value of iMg when studying its association with CV outcomes and mortality.

#1657 Impact of cumulative fluid and sodium imbalance exposure on cause-specific mortality in hemodialysis

Abstract Background and Aims Even mild fluid overload and prolonged exposure to salt excess showed to be associated with all-cause mortality in hemodialysis patients. This analysis aims to estimate the effect of fluid and sodium imbalance on cause-specific mortality. Method The study followed 68,196 incident hemodialysis patients from 875 clinics in 25 countries for a decade (2010-2020) using the European Clinical Database 5. Fatal events (21,644) were classified through ICD10- codes and free text descriptions into different endpoints: cardiac death (7,926 events)—with subcomponents sudden cardiac death (2,815 events), coronary death (1,705 events) and heart failure death (3,248 events); cerebrovascular death (1,516 events), non-cardiovascular death (10,898 events)—with subcomponents death by sepsis (2,054) or other infection (1,217 events), cancer death (2,095), other non-cardiovascular death (5,532 events) and death of unknown origin (1,304 events). Time-varying cumulative exposure times (in months) of relative fluid overload/-depletion, hypo-/hypernatremia and low dialysate sodium (≤ 138) were assessed and hazard ratios (HR) were calculated using a multivariate Cox model. Results Fluid overload showed the most consistent exposure risk associations for cardiovascular endpoints with strongest associations in cardiac causes (arrythmia death: HR peak at 7.5 (95% CI: 4.2-3.6), heart failure death: HR peak at 4.2 (95% CI: 3.3-5.4) and sudden cardiac death: HR peak at 3.8 (95% CI: 2.6-4.5)). Fluid depletion was less important but consistently associated with all causes of death. By contrast, Hyponatremia showed heterogeneity of cause specific effects. We found slightly stronger associations for non- cardiovascular causes: Death by sepsis (HR peak at 2.3 (95% CI: 1.8-2.8)) or death by other infections (HR peak at 2.1 (95% CI: 1.6-2.7)) showed the strongest cumulative exposure risk association pattern. Hypernatremia was less important with substantially smaller effects and slightly higher associations for non-cardiovascular endpoints. For low dialysate sodium, we observed evidence of heterogeneity in cause specific effects. The risk of death due to heart failure was notably pronounced with low dialysate sodium (HR peak at 5.8 (95% CI: 1.9-17.9)), while other endpoints did not show this effect. Sensitivity analysis in patients with 48 or more months of follow-up indicated that HR in higher exposure categories might be biased downwards due to non-survival of high-risk individuals. Conclusion Cause-specific hazard models confirm the role of fluid and sodium imbalance as independently acting risk factors for mortality. Fluid overload has the most pronounced effect on cardiac death, especially death by heart failure, arrhythmia, or sudden death. In contrast, hyponatremia is a more critical risk factor for non-cardiovascular death, particularly death caused by sepsis or other infections. The significantly increased risk in patients on low dialysate sodium prescriptions is primarily driven by a dramatic increase in risk of death by heart failure.