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. 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. Clinical experience shows that chronic hemodialysis (HD) patients expected to die within weeks share certain characteristics, such as poor nutrition and weight loss, increased inflammation, and worsening of cardiovascular status. However, more subtle changes in other clinical and laboratory parameters might occur before significant clinical deterioration becomes apparent. Various risk factors have emerged that have significant value in predicting the greatly increased mortality of dialysis patients. However, most of the studies have focused on single point in time measurements, whereas the longitudinal trend of surrogate outcome parameters and the dynamic evolution before death have not been widely studied.1.Himmelfarb J. Kliger A.S. End-stage renal disease measures of quality.Annu Rev Med. 2007; 58: 387-399Crossref PubMed Scopus (12) Google Scholar Insight into temporal trends of surrogate outcome indicators are relevant both from a pathophysiological point of view and for the future development of predictive models, which might aid the clinician in timely identifying patients at risk for adverse outcomes. Recent reports from Renal Research Institute (RRI) suggested that in chronic HD patients from the United States, a decline in systolic blood pressure (SBP),2.Raimann J.G. Usvyat L.A. Thijssen S. et al.Blood pressure stability in hemodialysis patients confers a survival advantage: results from a large retrospective cohort study.Kidney Int. 2011; 81: 548-558Abstract Full Text Full Text PDF Scopus (19) Google Scholar,3.Li Z. Lacson E. Lowrie E.G. et al.The epidemiology of systolic blood pressure and death risk in hemodialysis patients.Am J Kidney Dis. 2006; 48: 606-615Abstract Full Text Full Text PDF PubMed Scopus (160) Google Scholar body weight, and serum albumin levels4.Kotanko P. Thijssen S. Usvyat L. et al.Temporal evolution of clinical parameters before death in dialysis patients: a new concept.Blood Purif. 2009; 27: 38-47Crossref PubMed Scopus (24) Google Scholar were associated with an increased mortality risk. It is noteworthy that these dynamic changes were already apparent months before death and qualitatively independent of age, gender, and race. These observations led to the hypothesis that fundamental biological processes may be operative in the majority of chronic HD patients weeks and even months before death, notwithstanding race and gender. However, the observed patterns of clinical and laboratory parameters before death may be associated with specific dialysis practices or environmental factors. As RRI clinics follow similar dialysis procedures, the relatively homogeneous dialysis practice pattern renders the testing of this hypothesis difficult. Therefore, MONDO (MONitoring Dialysis Outcomes), a multinational consortium of HD databases encompassing patient-level data, was founded to further study this aspect. MONDO allows us to combine HD dialysis databases containing patient-level data from Asia, North and South America, and Europe. Because of its outreach, MONDO encompasses patients of different national, racial, and ethnic backgrounds. Currently, the MONDO database contains longitudinal patient-level measurements of key variables from >145,000 patients in 25 countries over a time period of up to 11 years. The MONDO database allowed us to test the hypothesis that the temporal evolution of certain clinical and laboratory indicators over several months before death is comparable among the majority of chronic HD patients, independent of gender and region of the world. We chose to study the temporal evolution of indicators of the nutritional, cardiovascular, and inflammatory domains, namely interdialytic weight gain (IDWG), SBP, serum albumin, and C-reactive protein (CRP). A total of 145,317 HD patients from 25 countries received at least one in-center HD treatment between January 2000 and December 2010. Of this number, 41,903 patients died (Europe: 30,539 deaths (18 countries); Asia: 1809 deaths (5 countries); South America: 6298 deaths; North America: 3257 deaths). In all, 10,277 incident patients survived ≥4 years on HD (Europe: 4607; Asia: 1784; South America: 2351; North America: 1485). Figure 1 presents the flowchart of the study design. Baseline characteristics of patients who died and incident patients who survived for ≥4 years are presented in Table 1.Table 1Characteristics of the study populationsContinentNumber of patientsAge (years)Male %Diabetic %With CVD (other than hypertension) %With hypertension %With hepatitis %With residual renal function at dialysis initiation %With catheters at dialysis initiation %Postdialysis weight (kg)Equilibrated Kt/VTreatment time (min)Predialysis SBP (mmHg)Interdialytic weight gain (as % of postweight)Albumin (g/dl)Patients who died (N=41,903) North America325769.9 (69.4–70.4)55.656.843.049.02.022.070.069.8 (69.1–70.5)1.34 (1.33–1.36)202 (200–203)134.6 (133.4–135.7)3.35 (3.26–3.44)3.31 (3.29–3.33) South America629868 (67.7–68.3)58.234.3NANANANANA65.9 (65.5–66.4)NANA124.5 (123.9–125)3.16 (3.07–3.24)3.51 (3.5–3.53) Europe30,53972.0 (71.3–72.6)58.834.850.034.05.0NA39.664.2 (62.1–67.0)1.34 (1.32–1.37)223 (209–240)122.1 (121.6–123)2.74 (2.69–2.88)3.50 (3.46–3.56) Asia180967.9 (67.2–68.5)53.447.0NANA5.0NA13.053.4 (52.9–54)1.42 (1.39–1.44)236 (235–237)135.8 (134.2–137.4)4.22 (4.06–4.38)3.44 (3.41–3.47)Incident patients who survived >4 years (N=10,227) North America148556 (55.3–56.8)56.852.948.072.05.034.062.077.9 (76.8–79.1)1.43 (1.42–1.45)208 (206–210)147.6 (146.1–149)3.36 (3.26–3.45)3.9 (3.87–3.92) South America235152 (51.3–52.7)57.431.8NANANANANA69.6 (68.9–70.2)NANA128 (127.2–128.8)3.03 (2.95–3.12)3.92 (3.91–3.94) Europe460761.4 (60.9–61.8)62.148.442.043.06.0NA36.869.5 (67–71)1.46 (1.40–1.52)236 (230–239)133.4 (132.4–134.3)2.71 (2.67–2.87)3.76 (3.70–3.88) Asia178454 (53.3–54.6)52.936.1NANA1.0NA3.057 (56.5–57.5)1.48 (1.47–1.5)242 (241–242)138.4 (137.3–139.5)4.11 (4.01–4.2)3.91 (3.89–3.93)Abbreviations: CVD, cardiovascular disease; NA, not reliably available; SBP, systolic blood pressure.All continuous variables are presented as mean (95% confidence interval (CI)).Countries in the Fresenius Medical Care (FMC) Asia-Pacific region include Taiwan, Hong Kong, South Korea, Singapore, and Australia. Countries in the FMC Europe network include Bosnia, Czech Republic, France, Hungary, Ireland, Italy, Poland, Portugal, Romania, Russia, Sweden, Slovakia, Slovenia, Spain, Serbia, Turkey, and the United Kingdom.Incident and prevalent patients are represented disproportionately in the different databases, owing largely to the way they developed during the period of 2000–2010. This significantly affects the number of patients a database could contribute to the ‘incident survivors’ and ‘patients who died’ cohorts. Therefore, patient counts above cannot be used to calculate mortality rates. Open table in a new tab Abbreviations: CVD, cardiovascular disease; NA, not reliably available; SBP, systolic blood pressure. All continuous variables are presented as mean (95% confidence interval (CI)). Countries in the Fresenius Medical Care (FMC) Asia-Pacific region include Taiwan, Hong Kong, South Korea, Singapore, and Australia. Countries in the FMC Europe network include Bosnia, Czech Republic, France, Hungary, Ireland, Italy, Poland, Portugal, Romania, Russia, Sweden, Slovakia, Slovenia, Spain, Serbia, Turkey, and the United Kingdom. Incident and prevalent patients are represented disproportionately in the different databases, owing largely to the way they developed during the period of 2000–2010. This significantly affects the number of patients a database could contribute to the ‘incident survivors’ and ‘patients who died’ cohorts. Therefore, patient counts above cannot be used to calculate mortality rates. Nearly all patients from Europe and South and North America were prescribed to dialyze thrice weekly. More than 85% of patients were dialyzed three times weekly in Singapore and Taiwan, whereas >70% were dialyzed twice weekly in Hong Kong. Dialyzer reuse is a standard practice in South America, and in most clinics in Singapore and Hong Kong. All other countries use single-use dialyzers on >90% of the treatments. In all regions studied, serum albumin levels dropped between 0.33 (Asia) and 0.52 (North America) g/dl in the 2 years preceding death in female patients (Figure 2a, left). The rate of serum albumin decline accelerated before death and was comparable in Europe and South and North America, and less pronounced in Asia (Figure 2a, right). The results were materially identical in male patients (Figure 2b) and comparable irrespective of diabetes status (data not shown). In Europe and North and South America, IDWG declined significantly before death, whereas the IDWG changes in Asia were either flat or nonsignificant with wide confidence intervals (Figures 3a and b). In female patients from Europe and North and South America, SBP levels dropped between 7.8 (South America) and 12.4 (North America) mmHg in the 2 years preceding death (Figure 4a, left); SBP decline was less pronounced in patients from The rate of SBP decline accelerated before death and was similar in patients from Europe and North and South America, but less pronounced in Asia (Figure 4a, right). The results were materially identical in male patients, the decline in Asian patients was not significant (Figure levels increased in the 2 years before death (Figure left). The rate of accelerated before death and was similar in both (Figure right). of the of deaths and indicated that the majority of patients in region died of cardiovascular with the in North America in Asia the of deaths in region. of the of death, the dynamics of albumin, SBP, and were qualitatively comparable before death to In a of patients who died of death, we an in and a decline in albumin before death in those patients (data not shown). with Because processes before and processes in surviving patients cannot be we to dynamics in and In the we incident patients who not die during the study period and who survived ≥4 years on We albumin, SBP, and in the 2 years on dialysis in those patients to changes in (Figure Figure Figure Figure In the surviving patients, albumin, SBP, and not to in the 2 years on In other than the in albumin, SBP, and IDWG stable the period (Figures left). The of the indicated no (Figures right). In the we patients who survived with patients with the who died. and incident patients who survived the 2 years on dialysis patients who survived the but died between and of 2 years on dialysis Figure in and in the and patients who survived the years on dialysis patients who survived the 2 years on dialysis but died between year 2 and years Figure in both and These results in the patterns in the patients who died during the time with surviving patients no whereas a In patients who the confidence intervals as the number of weeks from start on dialysis patients are as time interdialytic weight gain as of and confidence interdialytic weight gain as of and confidence interval in the weeks from the start of dialysis in female patients who survived >4 years. The of the and the of rate of with confidence IDWG and confidence interval in the weeks from start of dialysis in male patients who survived >4 Figure systolic blood pressure and confidence systolic blood pressure and confidence interval in the weeks from the start of dialysis in female patients who survived >4 years. The of the and the of rate of SBP and confidence interval in the weeks from the start of dialysis in male patients who survived >4 Figure C-reactive protein and confidence interval in the weeks from the start of dialysis in patients who years. The shows of the and the shows of rate of Figure study chronic HD patients from 25 countries and patients who and who survived >4 years of The is of comparable temporal of key clinical and laboratory parameters before death. of SBP, and serum albumin to decline more than a year before death, with the decline in IDWG and SBP less apparent in In the Fresenius Medical Care (FMC) Europe routine measurements were which a before death. the of this is the study the dynamic changes of key clinical and laboratory parameters before death in of chronic HD patients. In a study in HD patients from Renal Research Institute comparable trends for weight and serum albumin were P. Thijssen S. Usvyat L. et al.Temporal evolution of clinical parameters before death in dialysis patients: a new concept.Blood Purif. 2009; 27: 38-47Crossref PubMed Scopus (24) Google Scholar However, the large of mortality and treatment patterns the P. et in dialysis mortality cardiovascular 2006; PubMed Scopus Google from the Dialysis and PubMed Scopus Google et risk in hemodialysis patients and changes in Int. 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