Increased Mortality Associated with Higher Pre-Dialysis Serum Sodium Variability: Results of the International MONitoring Dialysis Outcome Initiative.

BACKGROUND: Low serum sodium (SNa) is associated with an increased mortality in chronic hemodialysis (HD) patients. Dialysis patients are thought to have an individual pre-dialysis SNa set-point, yet there is evidence for variability of pre-dialysis SNa in individual patient. In this study, we explored the association of several SNa variability metrics with all-cause mortality in a large patient population from the international MONitoring Dialysis Outcomes (MONDO) Initiative. METHODS: All adult incident patients from the MONDO database with more than 5 SNa measurements during the first year on HD were included. All patients were required to survive the first year on HD (defined as the baseline). During the subsequent 2 years of follow-up, all-cause mortality was recorded. The following variability indicators were calculated during baseline: mean SNa and its SD; average real variability (ARV, average the absolute distance of the 2 consecutive SNa measurements), and average directional range (DR, the difference between minimum and maximum values). We used Cox Proportional hazard model with bivariate spline terms to analyze the joint association of SNa and SD, ARV and DR, respectively, with all-cause mortality. While conducting the multivariate Cox regression analyses, patients were stratified into 3 groups of DR (Negative DR: -20≤ DR ≤ -6, Null DR: -6< DR < 6 and Positive DR: 6≤ DR ≤20) with the Null DR as the reference group. RESULTS: We included 20,216 patients in the study. A SNa ≤135 mEq/L was observed to be the strongest predictor of evaluated mortality risk. Higher SNa variability (quantified as SD, ARV, and DR) was also associated with an increased mortality irrespective of SNa levels. When compared with higher SD or ARV, greater DR showed a stronger association with an elevated risk of death. Controlling the Cox Proportional hazard models for additional parameters showed consistent results. CONCLUSION: Higher SNa variability associated with increased all-cause mortality at all levels of SNa. DR of SNa showed the strongest association with mortality and may constitute a Simple and novel prognostic indicator, easily applicable at the bedside.

A Cross-Sectional Study of Growth and Metabolic Bone Disease in a Pediatric Global Cohort Undergoing Chronic Hemodialysis.

OBJECTIVE: We sought to assess worldwide differences among pediatric patients undergoing hemodialysis. Because practices differ widely regarding nutritional resources, treatment practice, and access to renal replacement therapy, investigators from the Pediatric Investigation and Close Collaboration to examine Ongoing Life Outcomes, the pediatric subset of the MONitoring Dialysis Outcomes Cohort (PICCOLO MONDO) performed this cross-sectional study. We hypothesized that growth would be better in developed countries, possibly at the expense of bone mineral disease. STUDY DESIGN: In this cross-sectional study, we analyzed growth by height z score and recommended age-specific bone mineral metabolism markers from 225 patients <18 years of age maintained on hemodialysis, between the years of 2000 to 2012 from 21 countries in different regions. RESULTS: The patients' median age was 16 (IQR 14-17) years, and 45% were females. A height z score less than the third percentile was noted in 34% of the cohort, whereas >66% of patients reported normal heights, with patients from North America having the greatest proportion (>80%). More than 70% of the entire cohort had greater than the age-recommended levels of phosphorus, particularly in the Asia-Pacific and North America, where we also observed the greatest body mass index z score (0.99 ± 1.6) and parathyroid hormone levels (557.1 [268.4-740.5]). Below-recommended parathyroid hormone levels were noted in 26% and elevated levels in 61% of the entire sample, particularly in the Asia Pacific region. Lower-than-recommended calcium levels were noted in 36% of the entire cohort, particularly in Latin America. CONCLUSIONS: We found regional differences in growth- and age-adjusted bone mineral metabolism markers. Children from North America had the best growth, received the most dialysis, but also had the worst phosphate control and body mass index z scores.

Dialysis Access as an Area of Improvement in Elderly Incident Hemodialysis Patients: Results from a Cohort Study from the International Monitoring Dialysis Outcomes Initiative.

BACKGROUND: Commencing hemodialysis (HD) using a catheter is associated with a higher risk of adverse outcomes, and early conversion from central-venous catheter (CVC) to arteriovenous fistula/graft (non-CVC) improves outcomes. We investigated CVC prevalence and conversion, and their effects on outcomes during the first year of HD in a multinational cohort of elderly patients. METHODS: Patients ≥70 years from the MONDO Initiative who commenced HD between 2000 and 2010 in Asia-Pacific, Europe, North-, and South-America and survived at least 6 months were included in this investigation. We stratified by age (70-79 years [younger] vs. ≥80 years [older]) and compared access types (at first and last available date) and their changes. We studied the association between access at initiation and conversion, respectively, and all-cause mortality using Kaplan-Meier curve and Cox regression, and predicted the absence of conversion from catheter to non-CVC using adjusted logistic regression. RESULTS: In 14,966 elderly, incident HD patients, survival was significantly worse when using a CVC at all times. In Europe, the conversion frequency from CVC to non-CVC was higher in the younger fraction. Conversion from non-CVC to CVC was associated with worsened outcomes only in the older fraction. CONCLUSION: These results corroborate the need for early HD preparation in the elderly HD population. Treatment of elderly patients who commence HD with a CVC should be planned considering aspects of individual clinical risk assessment. Differences in treatment practices in predialysis care specific to the elderly as a population may influence access care and conversion rate.

Associations between global population health indicators and dialysis variables in the Monitoring Dialysis Outcomes (MONDO) consortium.

BACKGROUND: The number of patients receiving renal replacement therapy (RRT) increases annually and worldwide. Differences in the RRT incidence, prevalence, and modality vary between regions and countries for reasons yet to be clarified. AIMS: Gain a better understanding of the association between hemodialysis (HD)-related variables and general population global health indicators. METHODS: The present study included prevalent HD patients from 27 countries/regions from the monitoring dialysis outcomes (MONDO) database from 2006-2011. Global population health indicators were obtained from the 2014 World Health Organization report and the Human Development Index from the Human Development Report Office 2014. The Spearman rank test was used to assess the correlations between population social economic indicators and HD variables. RESULTS: A total of 84,796 prevalent HD patients were included. Their mean age was 63 (country mean 52-71), and 60% were males (country mean 52-85%). Significant correlations were found between HD demographic clusters and population education, wealth, mortality, and health indicators. The cluster of nutrition and inflammation variables were also highly correlated with population mortality, wealth, and health indicators. Finally, cardiovascular, fluid management, and dialysis adequacy clusters were associated with education, wealth, and health care resource indicators. CONCLUSION: We identified socioeconomic indicators that were correlated with dialysis variables. This hypothesis-generating study may be helpful in the analysis of how global health indicators may interfere with access to HD, treatment provision, dialytic treatment characteristics, and outcomes.

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.

Interdialytic weight gain, systolic blood pressure, serum albumin, and C-reactive protein levels change in chronic dialysis patients prior to death.

Reports from a United States cohort of chronic hemodialysis patients suggested that weight loss, a decline in pre-dialysis systolic blood pressure, and decreased serum albumin may precede death. However, no comparative studies have been reported in such patients from other countries. Here we analyzed dynamic changes in these parameters in hemodialysis patients and included 3593 individuals from 5 Asian countries; 35,146 from 18 European countries; 8649 from Argentina; and 4742 from the United States. In surviving prevalent patients, these variables appeared to have notably different dynamics than in patients who died. While in all populations the interdialytic weight gain, systolic blood pressure, and serum albumin levels were stable in surviving patients, these indicators declined starting more than a year ahead in those who died with the dynamics similar irrespective of gender and geographic region. In European patients, C-reactive protein levels were available on a routine basis and indicated that levels of this acute-phase protein were low and stable in surviving patients but rose sharply before death. Thus, relevant fundamental biological processes start many months before death in the majority of chronic hemodialysis patients. Longitudinal monitoring of these dynamics may help to identify patients at risk and aid the development of an alert system to initiate timely interventions to improve outcomes.

The MONitoring Dialysis Outcomes (MONDO) initiative.

BACKGROUND: Systematic collection and analysis of global hemodialysis patient data may help to improve patient outcomes. METHODS: The MONitoring Dialysis Outcomes (MONDO) initiative comprises data from eight dialysis providers worldwide. Data are combined into one repository. Extensive procedures are employed to merge data across countries and providers. RESULTS: The MONDO database comprises longitudinal data of currently 128,000 hemodialysis patients from 26 countries on five continents. Here we report data from 62,345 incident hemodialysis patients. We found lower catheter rates in South-East Asia and Australia, lower hemoglobin levels in South-East Asia, and a higher prevalence of diabetes in North America. Longitudinal analyses suggest that there is a decline in interdialytic weight gain and serum phosphorus and an increasing neutrophil-to-lymphocyte ratio before death in all regions studied. CONCLUSIONS: While organizationally lean and low-cost, MONDO is the largest global dialysis database initiative to date, with a particular focus on high longitudinal data density and geographical diversity.

Monitoring dialysis outcomes across the world--the MONDO Global Database Consortium.

BACKGROUND/AIMS: Dialysis providers frequently collect detailed longitudinal and standardized patient data, providing valuable registries of routine care. However, even large organizations are restricted to certain regions, limiting their ability to separate effects of local practice from the pathophysiology shared by most dialysis patients. To overcome this limitation, the MONDO (MONitoring Dialysis Outcomes) research consortium has created a platform for the joint analysis of data from almost 200,000 dialysis patients worldwide. METHODS: We examined design and operation of MONDO as well as its methodology with respect to patient inclusion, descriptive data and other study parameters. RESULTS: MONDO partners contribute primary databases of anonymized patient data and collaboratively analyze populations across national and regional boundaries. To that end, datasets from different electronic health record systems are converted into a uniform structure. Patients are enrolled without systematic exclusions into open cohorts representing the diversity of patients. A large number of patient level treatment and outcome data is recorded frequently and can be analyzed with little delay. Detailed variable definitions are used to determine if a parameter can be studied in a subset or all databases. CONCLUSION: MONDO has created a large repository of validated dialysis data, expanding the opportunities for outcome studies in dialysis patients. The density of longitudinal information facilitates in particular trend analysis. Limitations include the paucity of uniform definitions and standards regarding descriptive information (e.g. comorbidities), which limits the identification of patient subsets. Through its global outreach, depth, breadth and size, MONDO advances the observational study of dialysis patients and care.

Multitargeted interventions to reduce dialysis-induced systemic stress.

Hemodialysis (HD) is a life-sustaining therapy as well as an intermittent and repetitive stress condition for the patient. In ridding the blood of unwanted substances and excess fluid from the blood, the extracorporeal procedure simultaneously induces persistent physiological changes that adversely affect several organs. Dialysis patients experience this systemic stress condition usually thrice weekly and sometimes more frequently depending on the treatment schedule. Dialysis-induced systemic stress results from multifactorial components that include treatment schedule (i.e. modality, treatment time), hemodynamic management (i.e. ultrafiltration, weight loss), intensity of solute fluxes, osmotic and electrolytic shifts and interaction of blood with components of the extracorporeal circuit. Intradialytic morbidity (i.e. hypovolemia, intradialytic hypotension, hypoxia) is the clinical expression of this systemic stress that may act as a disease modifier, resulting in multiorgan injury and long-term morbidity. Thus, while lifesaving, HD exposes the patient to several systemic stressors, both hemodynamic and non-hemodynamic in origin. In addition, a combination of cardiocirculatory stress, greatly conditioned by the switch from hypervolemia to hypovolemia, hypoxemia and electrolyte changes may create pro-arrhythmogenic conditions. Moreover, contact of blood with components of the extracorporeal circuit directly activate circulating cells (i.e. macrophages-monocytes or platelets) and protein systems (i.e. coagulation, complement, contact phase kallikrein-kinin system), leading to induction of pro-inflammatory cytokines and resulting in chronic low-grade inflammation, further contributing to poor outcomes. The multifactorial, repetitive HD-induced stress that globally reduces tissue perfusion and oxygenation could have deleterious long-term consequences on the functionality of vital organs such as heart, brain, liver and kidney. In this article, we summarize the multisystemic pathophysiological consequences of the main circulatory stress factors. Strategies to mitigate their effects to provide more cardioprotective and personalized dialytic therapies are proposed to reduce the systemic burden of HD.

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.

Body composition and survival in dialysis patients: results from an international cohort study.

BACKGROUND AND OBJECTIVES: High body mass index appears protective in hemodialysis patients, but uncertainty prevails regarding which components of body composition, fat or lean body mass, are primarily associated with survival. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Data between April 2006 and December 2012 were extracted from the Fresenius Medical Care Europe subset of the international MONitoring Dialysis Outcomes initiative. Fresenius Medical Care Europe archives a unique repository of predialysis body composition measurements determined by multifrequency bioimpedance (BCM Body Composition Monitor). The BCM Body Composition Monitor reports lean tissue indices (LTIs) and fat tissue indices (FTIs), which are the respective tissue masses normalized to height squared, relative to an age- and sex-matched healthy population. The relationship between LTI and FTI and all-cause mortality was studied by Kaplan-Meier analysis, multivariate Cox regression, and smoothing spline ANOVA logistic regression. RESULTS: In 37,345 hemodialysis patients, median (25th-75th percentile) LTI and FTI were 12.2 (10.3-14.5) and 9.8 (6.6-12.4) kg/m(2), respectively. Median (25th-75th percentile) follow-up time was 266 (132-379) days; 3458 (9.2%) patients died during follow-up. Mortality was lowest with both LTI and FTI in the 10th-90th percentile (reference group) and significantly higher at the lower LTI and FTI extreme (hazard ratio [HR], 3.37; 95% confidence interval [95% CI], 2.94 to 3.87; P<0.001). Survival was best with LTI between 15 and 20 kg/m(2) and FTI between 4 and 15 kg/m(2) (probability of death during follow-up: <5%). When taking the relation between both compartments into account, the interaction was significant (P=0.01). Higher FTI appeared protective in patients with low LTI (HR, 3.37; 95% CI, 2.94 to 3.87; P<0.001 at low LTI-low FTI, decreasing to HR, 1.79; 95% CI, 1.47 to 2.17; P<0.001 at low LTI-high FTI). CONCLUSIONS: This large international study indicates best survival in patients with both LTI and FTI in the 10th-90th percentiles of a healthy population. In analyses of body composition, both lean tissue and fat tissue compartments and also their relationship should be considered.

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.