Modifiable Risk Factors Are Important Predictors of COVID-19-Related Mortality in Patients on Hemodialysis.

Introduction: Patients with end-stage kidney disease face a higher risk of severe outcomes from SARS-CoV-2 infection. Moreover, it is not well known to what extent potentially modifiable risk factors contribute to mortality risk. In this historical cohort study, we investigated the incidence and risk factors for 30-day mortality among hemodialysis patients with SARS-CoV-2 infection treated in the European Fresenius Medical Care NephroCare network using conventional and machine learning techniques. Methods: We included adult hemodialysis patients with the first documented SARS-CoV-2 infection between February 1, 2020, and March 31, 2021, registered in the clinical database. The index date for the analysis was the first SARS-CoV-2 suspicion date. Patients were followed for up to 30 days until April 30, 2021. Demographics, comorbidities, and various modifiable risk factors, expressed as continuous parameters and as key performance indicators (KPIs), were considered to tap multiple dimensions including hemodynamic control, nutritional state, and mineral metabolism in the 6 months before the index date. We used logistic regression (LR) and XGBoost models to assess risk factors for 30-day mortality. Results: We included 9,211 patients (age 65.4 ± 13.7 years, dialysis vintage 4.2 ± 3.7 years) eligible for the study. The 30-day mortality rate was 20.8%. In LR models, several potentially modifiable factors were associated with higher mortality: body mass index (BMI) 30-40 kg/m2 (OR: 1.28, CI: 1.10-1.50), single-pool Kt/V (OR off-target vs on-target: 1.19, CI: 1.02-1.38), overhydration (OR: 1.15, CI: 1.01-1.32), and both low (<2.5 mg/dl) and high (≥5.5 mg/dl) serum phosphate levels (OR: 1.52, CI: 1.07-2.16 and OR: 1.17, CI: 1.01-1.35). On-line hemodiafiltration was protective in the model using KPIs (OR: 0.86, CI: 0.76-0.97). SHapley Additive exPlanations analysis in XGBoost models shows a high influence on prediction for several modifiable factors as well, including inflammatory parameters, high BMI, and fluid overload. In both LR and XGBoost models, age, gender, and comorbidities were strongly associated with mortality. Conclusion: Both conventional and machine learning techniques showed that KPIs and modifiable risk factors in different dimensions ascertained 6 months before the COVID-19 suspicion date were associated with 30-day COVID-19-related mortality. Our results suggest that adequate dialysis and achieving KPI targets remain of major importance during the COVID-19 pandemic as well.

Effectiveness of COVID-19 vaccines in a large European hemodialysis cohort.

Background: Hemodialysis patients have high-risk of severe SARS-CoV-2 infection but were unrepresented in randomized controlled trials evaluating the safety and efficacy of COVID-19 vaccines. We estimated the real-world effectiveness of COVID-19 vaccines in a large international cohort of hemodialysis patients. Methods: In this historical, 1:1 matched cohort study, we included adult hemodialysis patients receiving treatment from December 1, 2020, to May 31, 2021. For each vaccinated patient, an unvaccinated control was selected among patients registered in the same country and attending a dialysis session around the first vaccination date. Matching was based on demographics, clinical characteristics, past COVID-19 infections and a risk score representing the local background risk of infection at vaccination dates. We estimated the effectiveness of mRNA and viral-carrier COVID-19 vaccines in preventing infection and mortality rates from a time-dependent Cox regression stratified by country. Results: In the effectiveness analysis concerning mRNA vaccines, we observed 850 SARS-CoV-2 infections and 201 COVID-19 related deaths among the 28110 patients during a mean follow up of 44 ± 40 days. In the effectiveness analysis concerning viral-carrier vaccines, we observed 297 SARS-CoV-2 infections and 64 COVID-19 related deaths among 12888 patients during a mean follow up of 48 ± 32 days. We observed 18.5/100-patient-year and 8.5/100-patient-year fewer infections and 5.4/100-patient-year and 5.2/100-patient-year fewer COVID-19 related deaths among patients vaccinated with mRNA and viral-carrier vaccines respectively, compared to matched unvaccinated controls. Estimated vaccine effectiveness at days 15, 30, 60 and 90 after the first dose of a mRNA vaccine was: for infection, 41.3%, 54.5%, 72.6% and 83.5% and, for death, 33.1%, 55.4%, 80.1% and 91.2%. Estimated vaccine effectiveness after the first dose of a viral-carrier vaccine was: for infection, 38.3% without increasing over time and, for death, 56.6%, 75.3%, 92.0% and 97.4%. Conclusion: In this large, real-world cohort of hemodialyzed patients, mRNA and viral-carrier COVID-19 vaccines were associated with reduced COVID-19 related mortality. Additionally, we observed a strong reduction of SARS-CoV-2 infection in hemodialysis patients receiving mRNA vaccines.

Enhanced Sentinel Surveillance System for COVID-19 Outbreak Prediction in a Large European Dialysis Clinics Network.

Accurate predictions of COVID-19 epidemic dynamics may enable timely organizational interventions in high-risk regions. We exploited the interconnection of the Fresenius Medical Care (FMC) European dialysis clinic network to develop a sentinel surveillance system for outbreak prediction. We developed an artificial intelligence-based model considering the information related to all clinics belonging to the European Nephrocare Network. The prediction tool provides risk scores of the occurrence of a COVID-19 outbreak in each dialysis center within a 2-week forecasting horizon. The model input variables include information related to the epidemic status and trends in clinical practice patterns of the target clinic, regional epidemic metrics, and the distance-weighted risk estimates of adjacent dialysis units. On the validation dates, there were 30 (5.09%), 39 (6.52%), and 218 (36.03%) clinics with two or more patients with COVID-19 infection during the 2-week prediction window. The performance of the model was suitable in all testing windows: AUC = 0.77, 0.80, and 0.81, respectively. The occurrence of new cases in a clinic propagates distance-weighted risk estimates to proximal dialysis units. Our machine learning sentinel surveillance system may allow for a prompt risk assessment and timely response to COVID-19 surges throughout networked European clinics.

Changes in pre-dialysis blood pressure variability in the first year of dialysis associate with mortality in European hemodialysis patients: a retrospective cohort study on behalf of the MONDO Initiative.

Pre-hemodialysis systolic blood pressure variability (pre-HD SBPV) has been associated with outcomes. The association of a change in pre-HD SBPV over time with outcomes, and predictors of this change, has not yet been studied. Therefore, we studied this in a cohort of 8825 incident hemodialysis (HD) patients from the European Monitoring Dialysis Outcomes Initiative database. Patient level pre-HD SBPV was calculated as the standard deviation of the residuals of a linear regression model of systolic blood pressure (SBP) over time divided by individual mean SBP in the respective time periods. The pre-HD SBPV difference between months 1-6 and 7-12 was used as an indicator of pre-HD SBPV change. The association between pre-HD SBPV change and all-cause mortality in year 2 was analyzed by multivariate Cox models. Predictors of pre-HD SBPV change was determined by logistic regression models. We found the highest pre-HD SBPV tertile, in the first 6 months after initiation of HD, had the highest mortality rates (adjusted HR 1.44 (95% confidence intervals (95% CI): 1.15-1.79)). An increase in pre-HD SBPV between months 1-6 and 7-12 was associated with an increased risk of mortality in year 2 (adjusted HR 1.29 (95% CI: 1.05-1.58)) compared with stable pre-HD SPBV. A pre-HD SBPV increase was associated with female gender, higher mean pre-HD SBP and pulse pressure, and lower HD frequency.

Pre-dialysis fluid status, pre-dialysis systolic blood pressure and outcome in prevalent haemodialysis patients: results of an international cohort study on behalf of the MONDO initiative.

Background: Pre-dialysis fluid overload (FO) associates with mortality and causes elevated pre-dialysis systolic blood pressure (pre-SBP). However, low pre-SBP is associated with increased mortality in haemodialysis patients. The objective of this study was to investigate the interaction between pre-dialysis fluid status (FS) and pre-SBP in association with mortality. Methods: We included all patients from the international Monitoring Dialysis Outcome Initiative (MONDO) database with a pre-dialysis multifrequency bioimpedance spectroscopy measurement in the year 2011. We used all parameters available during a 90-day baseline period. All-cause mortality was recorded during 1-year follow-up. Associations with outcome were assessed with Cox models and a smoothing spline Cox analysis. Results: We included 8883 patients. In patients with pre-dialysis FO (>+1.1 to +2.5 L), pre-SBP <110 mmHg was associated with an increased risk of death {hazard ratio (HR) 1.52 [95% confidence interval (CI) 1.06-2.17]}. An increased risk of death was also associated with pre-dialysis fluid depletion (FD; <-1.1 L) combined with a pre-SBP <140 mmHg. In normovolemic (NV) patients, low pre-SBP <110 mmHg was associated with better survival [HR 0.46 (95% CI 0.23-0.91)]. Also, post-dialysis FD associated with a survival benefit. Results were similar when inflammation was present. Only high ultrafiltration rate could not explain the higher mortality rates observed. Conclusion: The relation between pre-SBP and outcome is dependent on pre-dialysis FS. Low pre-SBP appears to be disadvantageous in patients with FO or FD, but not in NV patients. Post-dialysis FD was found to associate with improved survival. Therefore, we suggest interpreting pre-SBP levels in the context of FS and not as an isolated marker.

Association between Heights of Dialysis Patients and Outcomes: Results from a Retrospective Cohort Study of the International MONitoring Dialysis Outcomes (MONDO) Database Initiative.

BACKGROUND: Tall people have improved metabolic profiles and better cardiovascular outcomes, a relationship inverted in dialysis patients. We investigated the relationship between height and outcomes in incident hemodialysis (HD) patients commencing treatment in an analysis of the international Monitoring Dialysis Outcomes (MONDO) database. METHODS: In this retrospective cohort study, we included incident HD patients commencing treatment between -January 1, 2006 and December 31, 2010 and investigated the association between height and mortality using the MONDO database. A 6-months baseline period preceded 2.5 years of follow-up, during which we recorded patient mortality. Patients were stratified in region-specific deciles of the respective database's population (Asia Pacific, North and South America, and Europe) and we developed Cox-proportional hazard models (additionally adjusted for age, gender, post-dialysis weight, eKt/V, albumin, interdialytic weight gain, phosphorus, and predialysis systolic blood pressure) for each database. RESULTS: We studied 23,353 patients (62 ± 15 years old, 42% female, body mass index 26 ± 6 kg/m2, height 165 ± 10 cm). We found a trend of increasing hazard ratio of death (HR) with increasing height for Asia Pacific, Europe, and South America. In the fully adjusted models, for South America, we found a trend of increasing HR without significance among deciles >5. In Europe, deciles 8-10 had significantly increased HR. No clear trend was found in North America. CONCLUSION: We found an increasing risk of death with increasing height in all regions, except North America. While the reasons remain unclear, further research may be warranted.

A comparative study of the risk profile of hemodialysis patients in a for profit network and in two regional registries of the Italian Society of Nephrology.

In 2013, the Italian Society of Nephrology joined forces with Nephrocare-Italy to create a clinical research cohort of patients on file in the data-rich clinical management system (EUCLID) of this organization for the performance of observational studies in the hemodialysis (HD) population. To see whether patients in EUCLID are representative of the HD population in Italy, we set out to compare the whole EUCLID population with patients included in the regional HD registries in Emilia-Romagna (Northern Italy) and in Calabria (Southern Italy), the sole regions in Italy which have systematically collected an enlarged clinical data set allowing comparison with the data-rich EUCLID system. An analysis of prevalent and incident patients in 2010 and 2011 showed that EUCLID patients had a lower prevalence of coronary heart disease, peripheral vascular disease, heart failure, valvular heart disease, liver disease, peptic ulcer and other comorbidities and risk factors and a higher fractional urea clearance (Kt/V) than those in the Emilia Romagna and Calabria registries. Accordingly, survival analysis showed a lower mortality risk in the EUCLID 2010 and 2011 cohorts than in the combined two regional registries in the corresponding years: for 2010, hazard ratio (HR) EUCLID vs. Regional registries: 0.80 [95% confidence interval: 0.71-0.90]; for 2011, HR: 0.76 [0.65-0.90]. However, this difference was nullified by statistical adjustment for the difference in comorbidities and risk factors, indicating that the longer survival in the EUCLID database was attributable to the lower risk profile of patients included in that database. This preliminary analysis sets the stage for future observational studies and indicates that appropriate adjustment for difference in comorbidities and risk factors is needed to generalize to the Italian HD population analyses based on the data-rich EUCLID database.

Impact of fluid status and inflammation and their interaction on survival: a study in an international hemodialysis patient cohort.

In hemodialysis patients extracellular fluid overload is a predictor of all-cause and cardiovascular mortality, and a relation with inflammation has been reported in previous studies. The magnitude and nature of this interaction and the effects of moderate fluid overload and extracellular fluid depletion on survival are still unclear. We present the results of an international cohort study in 8883 hemodialysis patients from the European MONDO initiative database where, during a three-month baseline period, fluid status was assessed using bioimpedance and inflammation by C-reactive protein. All-cause mortality was recorded during 12 months of follow up. In a second analysis a three-month baseline period was added to the first baseline period, and changes in fluid and inflammation status were related to all-cause mortality during six-month follow up. Both pre-dialysis estimated fluid overload and fluid depletion were associated with an increased mortality, already apparent at moderate levels of estimated pre-dialysis fluid overload (1.1-2.5L); hazard ratio 1.64 (95% confidence interval 1.35-1.98). In contrast, post-dialysis estimated fluid depletion was associated with a survival benefit (0.74 [0.62-0.90]). The concurrent presence of fluid overload and inflammation was associated with the highest risk of death. Thus, while pre-dialysis fluid overload was associated with inflammation, even in the absence of inflammation, fluid overload remained a significant risk factor for short-term mortality, even following improvement of fluid status.

Hemodialysis outcomes in a global sample of children and young adult hemodialysis patients: the PICCOLO MONDO cohort.

BACKGROUND: The aim of this study was to describe the experience of pediatric and young adult hemodialysis (HD) patients from a global cohort. METHODS: The Pediatric Investigation and Close Collaborative Consortium for Ongoing Life Outcomes for MONitoring Dialysis Outcomes (PICCOLO MONDO) study provided de-identified electronic information of 3244 patients, ages 0-30 years from 2000 to 2012 in four regions: Asia, Europe, North America and South America. The study sample was categorized into pediatric (≤18 years old) and young adult (19-30 years old) groups based on the age at dialysis initiation. RESULTS: For those with known end-stage renal disease etiology, glomerular disease was the most common diagnosis in children and young adults. Using Europe as a reference group, North America [odds ratio (OR) 2.69; CI 1.29, 5.63] and South America (OR 4.21; CI 2.32, 7.63) had the greatest mortality among young adults. North America also had higher rates of overweight, obesity, hypertension, cardiovascular disease, hospitalizations and secondary diabetes compared with all other regions. Initial catheter use was greater for North American (86.4% in pediatric patients and 75.2% in young adults) and South America (80.6% in pediatric patients and 75.9% in young adults). Catheter use at 1-year follow-up was most common in North American children (77.3%) and young adults (62.9%). Asia had the lowest rate of catheter use. For both age groups, dialysis adequacy (equilibrated Kt/V) ranged between 1.4 and 1.5. In Asia, patients in both age groups had significantly longer treatment times than in any other region. CONCLUSIONS: The PICCOLO MONDO study has provided unique baseline and 1-year follow-up information on children and young adults receiving HD around the globe. This cohort has brought to light aspects of care in these age groups that warrant further investigation.

Seasonal variations in mortality and clinical indicators in international hemodialysis populations from the MONDO registry.

BACKGROUND: Seasonal mortality differences have been reported in US hemodialysis (HD) patients. Here we examine the effect of seasons on mortality, clinical and laboratory parameters on a global scale. METHODS: Databases from the international Monitoring Dialysis Outcomes (MONDO) consortium were queried to identify patients who received in-center HD for at least 1 year. Clinics were stratified by hemisphere and climate zone (tropical or temperate). We recorded mortality and computed averages of pre-dialysis systolic blood pressure (pre-SBP), interdialytic weight gain (IDWG), serum albumin, and log C-reactive protein (CRP). We explored seasonal effects using cosinor analysis and adjusted linear mixed models globally, and after stratification. RESULTS: Data from 87,399 patients were included (northern temperate: 63,671; northern tropical: 7,159; southern temperate: 13,917; southern tropical: 2,652 patients). Globally, mortality was highest in winter. Following stratification, mortality was significantly lower in spring and summer compared to winter in temperate, but not in tropical zones. Globally, pre-SBP and IDWG were lower in summer and spring as compared to winter, although less pronounced in tropical zones. Except for southern temperate zone, serum albumin levels were higher in winter. CRP levels were highest in winter. CONCLUSION: Significant global seasonal variations in mortality, pre-SBP, IDWG, albumin and CRP were observed. Seasonal variations in mortality were most pronounced in temperate climate zones.

Relationship of Neutrophil-to-Lymphocyte Ratio and Serum Albumin Levels with C-Reactive Protein in Hemodialysis Patients: Results from 2 International Cohort Studies.

BACKGROUND/AIM: The neutrophil-to-lymphocyte ratio (NLR), defined as the neutrophil count divided by lymphocyte count, is an inexpensive and readily available parameter, which may serve as a surrogate for inflammation markers, such as C-reactive protein (CRP). The aim of this study was to determine the utility of NLR in the prediction of elevated CRP levels in hemodialysis (HD) patients. METHODS: We analyzed 43,272 HD patients from 2 distinct cohorts within the Monitoring Dialysis Outcomes research collaboration in whom contemporaneous measurements of neutrophil and lymphocyte counts, serum albumin and CRP levels were available. Logistic regression was used to determine the relationship of trichotomized NLR (<2.5, 2.5-5 and >5.0) and albumin levels (<3.1, 3.1-4.0 and >4.0 g/dl) with elevated CRP levels (>10.0, >20.0 and >30.0 mg/l). Congruence of the prediction models was examined by comparing the regression parameters and by cross-validating each regression equation within the other cohort. RESULTS: We found that NLR >5.0 vs. <2.5 (cohort 1: OR 2.3; p < 0.0001 and cohort 2: OR 2.0; p < 0.0001) was associated with CRP levels >10.0 mg/l. Stepwise increase in odds ratio for CRP >10.0 mg/l was observed with the combination of high NLR and low albumin levels (NLR >5.0 and albumin <3.1) (cohort 1: OR 7.6; p < 0.0001 and cohort 2: OR 11.9; p < 0.0001). Cross-validation of the 2 regression models revealed a predictive accuracy of 0.68 and 0.69 in the respective cohorts. CONCLUSION: This study suggests that NLR could serve as a potential surrogate marker for CRP. Our results may add to diagnostic abilities in settings where CRP is not measured routinely in HD patients. NLR is easy to integrate into daily practice and may be used as a marker of systemic inflammation.