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Published ahead of print on April 25, 2007
Clin J Am Soc Nephrol 2: 653-660, 2007
© 2007 American Society of Nephrology
doi: 10.2215/CJN.03160906
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Dialysis

Mortality Predictors after 10 Years of Dialysis: A Prospective Study of Japanese Hemodialysis Patients

Junya Ajiro*, Bassam Alchi*, Ichiei Narita*, Kentaro Omori*, Daisuke Kondo*, Minoru Sakatsume*, Junichiro J. Kazama*, Kohei Akazawa{dagger}, and Fumitake Gejyo*

* Division of Clinical Nephrology and Rheumatology and {dagger} Department of Medical Informatics, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan

Address correspondence to: Dr. Ichiei Narita, Division of Clinical Nephrology and Rheumatology, Niigata University Graduate School of Medical and Dental Sciences, 757, Asahimachi-dori, Niigata, 951-8510, Japan. Phone: +81-25-227-2193; Fax: +81-25-227-0775; E-mail: naritai{at}med.niigata-u.ac.jp


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 Conclusion
 Disclosures
 References
 
Background: This work aimed to examine the predictive value for death of various clinical variables after long-term hemodialysis (HD).

Design, setting, participants, and measurements: A total of 947 patients (597 men and 350 women, aged 21 to 93 yr) who were undergoing maintenance HD in Niigata, Japan, were stratified into two cohorts: Those with >10 yr of prior HD at study enrollment (n = 391) and those with ≤10 yr of previous therapy (n = 556). The survival of patients was examined for up to 40 mo (1999 to 2003) with the Cox proportional hazards model. Baseline clinical and dialysis data and serum biochemistries were used as independent variables. For adjustment for bias in patient selection, patient survival in either cohort was analyzed separately.

Results: In patients with >10 yr of HD, high pulse pressure, cerebrovascular disease, low serum creatinine, and low Kt/V values were the mortality risk predictors, whereas for those with ≤10 yr of HD, age and cerebrovascular disease were independent risk predictors for death. Diabetes, coronary artery disease, serum albumin, and C-reactive protein were NS predictors in those with long-term HD.

Conclusions: Providing adequate dosage of dialysis and achieving a better control of pulse pressure may further improve survival in selected patients who had undergone HD for >10 yr.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 Conclusion
 Disclosures
 References
 
Patients who have ESRD and are on hemodialysis (HD) are characterized by an exceptionally high mortality rate compared with the general population. Several factors for such a high mortality rate have been identified, including advanced age, cardiovascular disease (CVD), and infection. Among them, CVD remains the leading cause of death. The cause of CVD in HD patients is multifactorial. Although many of the traditional risk factors for atherosclerotic heart disease, such as hypertension, diabetes, and disorders of lipids and calcium metabolism, are particularly common among patients who undergo maintenance HD, they cannot adequately account for that excess CVD. Therefore, it has been assumed that other, nontraditional risk factors, such as chronic inflammation and malnutrition, may be more important for the development of atherosclerosis in this patient group. The so-called malnutrition inflammation atherosclerosis syndrome, which commonly exists in patients with ESRD and atherosclerosis, signifies a dire outcome (1–3).

The impact of BP on mortality in patients who have ESRD and undergo HD is surprisingly different from that in the general population. Although hypertension is associated with adverse outcome in the general population, elevated BP is associated with decreased mortality in HD patients (4–6). It has also been reported that the relationship of BP with mortality changes over time among patients who undergo HD (7).

Survival rates among dialysis patients depend partly on the delivered dosage of dialysis (8). The annual survey of the Japanese Society of Dialysis therapy that was published in 1997 suggested that the death risk decreases progressively with increasing dialysis dosage up to a Kt/V of 1.80 (9). However, the predictive value of Kt/V in relation to HD duration has not been well investigated. The primary results of the Hemodialysis (HEMO) Study, which was by far the largest randomized, controlled trial, revealed little evidence to support the relationship between dialysis dosage and mortality (10–12). The lack of benefit of increasing HD dosage appeared not only in the primary outcome of mortality but also in a variety of main secondary composite outcomes relating to various causes of hospitalization combined with mortality.

The annual crude mortality rate in Japanese HD patients has been <10% in the past two decades (13). This combined with the growing numbers of patients who have ESRD are started on an HD program every year have resulted in an exponential increase of the HD population nationwide, with more patients having survived longer terms on maintenance therapy. Many studies have investigated the prognostic significance of biomarkers as mortality predictors among patients who undergo HD (14–20). To our knowledge, no studies of the effects of dialysis duration, especially in patients who are on long-term HD, on clinical outcomes have been performed. Therefore, this study focused at testing the prognostic significance of the multiple risk factors for death in patients with >10 yr of HD therapy.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 Conclusion
 Disclosures
 References
 
In 1999, a total of 3490 adult patients underwent long-term HD treatment at 41 facilities in Niigata Prefecture, Japan. Among them, 947 patients, who consented to participate in the prospective cohort study on a voluntary basis, were recruited in November 1999 and prospectively followed up until death or April 1, 2003. They were 597 men and 350 women, aged 21 to 93 yr (mean 60.1 ± 12.5 yr). Patients who were on dialysis for <1 yr were not eligible for enrollment into the study. The underlying renal diseases were chronic glomerulonephritis (n = 640), diabetic nephropathy (n = 156), nephrosclerosis (n = 43), polycystic kidney disease (n = 46), chronic pyelonephritis (n = 12), postrenal disease (n = 4), other diseases (n = 37), and unknown (n = 9). In all patients, dialysis was conducted three times a week for a minimum of 4 h using high-flux dialysis membranes, such as polymethylmethacrylate, poly-acrylonitrile, polysulfone, and triacetate, with bicarbonate as a dialysis buffer.

Upon enrollment, patients were stratified into two groups according to the duration of HD: Those with ≤10 yr of previous dialysis (n = 556; 58.7%) and those with >10 yr of previous treatment (n = 391; 41.3%). This cut point was arbitrarily chosen, largely for convenience because the figure 10 is often available to be quoted. Patient clinical and laboratory data were collected at the time of study entry. Clinical characteristics included age; gender; predialysis BP and pulse pressure (PP; average of three readings); body mass index (BMI; calculated by the formula of postdialysis weight in kg per height in m2); duration of HD; primary cause of ESRD; and the presence of comorbid conditions, including diabetes, coronary artery disease (CAD), and cerebrovascular disease (CBVD). Baseline blood samples, drawn before the first dialysis session of the week, were obtained from all patients, and the levels of serum creatinine (mg/dl), albumin (g/dl), total cholesterol (mg/dl), serum C-reactive protein (s-CRP; mg/dl), ß-2 microglobulin (mg/dl), phosphate (mg/dl), calcium (mg/dl), and blood hematocrit (%) were measured using routine methods. Normalized protein catabolic rate (nPCR) was calculated from urea generation rate and assumed to reflect daily protein intake. The dosage of delivered HD was quantified by both Kt/Vurea and urea reduction ratio (URR). nPCR, Kt/V, and URR were measured from predialysis and immediately postdialysis blood urea nitrogen levels of the same dialysis treatment by using a formal single-compartment model of HD urea kinetics (21), thereby avoiding errors from access recirculation of urea rebound (22).

For testing the significance of clinical and biochemical variables as predictive risk factors for death, patients were monitored for up to 40 mo, and their survival was examined using the Cox proportional hazards model based on the data recorded on initial enrollment. Survival rates as well as causes of death in the group of patients with HD >10 yr were compared with those of patients with ≤10 yr of dialysis history. No patient was lost to follow-up. Patients who received a renal transplant during the follow-up period were censored at the time of surgery. A change of treatment modality (initiation of peritoneal dialysis) was also a censoring event. During the period of follow-up, all deaths were accurately recorded with the exact cause of death provided by the attending renal physician. Causes of death were classified as cardiovascular, infection, dialysis withdrawal, sudden death, and others. Dialysis withdrawal–associated deaths were noted in patients who were unable to undergo regular dialysis because of severe malnutrition or unstable hemodynamic condition.

Statistical Analyses
Statview 5.0 statistical software (Abacus Concepts, Berkeley, CA) was used for the analyses on a Macintosh G4 computer. Unless otherwise stated, the results are expressed as means ± SD. The {chi}2 analysis was used when comparing categorical variables. Continuous variables were compared using the Mann-Whitney U test or Kruskal-Wallis ANOVA. P < 0.05 was considered significant. All statistical tests were two-sided.

For adjustment for survivor bias in patient selection, the survival of patients with ≤10 yr of previous dialysis at the time of enrollment were analyzed separately from that of patients with >10 yr of previous treatment. A similar statistical approach was adopted in a previous study (14).

The Kaplan-Meier test was used for analysis of the survival, and the difference was assessed by the log-rank test. For continuous variables, which were distributed differently in each patient group, we compared survival of patients who were above and below the median (upper and lower 50th percentile) in each group. An exception was s-CRP, for which the median value could not be defined because CRP values <0.1 mg/dl were not quantified by the laboratory. Therefore, for CRP, we compared survival of patients who were above and below the highest tertile (upper tertile versus sum of middle and lower tertiles).

To control for possible confounding, we performed Cox proportional hazard analyses, including factors (age, diabetes, PP, CAD, CBVD, predialysis serum creatinine, albumin, s-CRP, and Kt/V) that demonstrated significant effects on mortality in analyses of Kaplan-Meier survival curves with the log-rank test.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 Conclusion
 Disclosures
 References
 
Clinical Data
Baseline clinical and dialysis data and serum biochemistries are presented in Table 1. As a reflection of natural selection, patients who received >10 yr of HD treatment at the study entry were younger and had lower BP and BMI levels; lower prevalence of diabetes, CVD, and CBVD; and higher levels of hematocrit and serum creatinine than those with ≤10 yr of maintenance therapy. Serum level of calcium was higher and that of phosphate was lower in patients with >10 yr of HD. The daily protein intake, estimated by nPCR, and the delivered dosage of dialysis, calculated by Kt/Vurea and URR, were higher in the patients with >10 yr of HD.


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  		Table 1. Baseline clinical and laboratory characteristics of studied patients according to previous HD durationa

 
Patient Survival and Causes of Death
After 40 mo, 807 patients were still on HD treatment, 137 (14.5%) patients had died while being treated, and three patients were censored either because of having renal transplants or being switched to peritoneal dialysis. The main causes of death were CVD (30%), followed by CBVD (17%) and infection (16%). There was no association between the cause of death and the duration of HD treatment and no difference between men and women with regard to the cause of death (data not shown).

Comparison between Survivors and Nonsurvivors
Table 2 shows data from the initial cross-sectional study in the survivors and the nonsurvivors in each cohort. The latter had higher mean values for age and PP, a lower mean value for serum creatinine, and a higher prevalence of CBVD than the nonsurvivors irrespective of the duration of HD. In patients with >10 yr of HD, the nonsurvivors had higher prevalence of CVD and a lower level of delivered dialysis dosage evaluated by Kt/V and URR than the survivors. In patients with ≤10 yr of HD, diabetes was more common among the nonsurvivors than among the survivors. The former group also had lower hematocrit and serum albumin levels and a higher s-CRP. Gender, systolic (SBP) and diastolic BP (DBP), BMI, total serum cholesterol, calcium, phosphate, nPCR, and ß-2 microglobulin were not different in the survivors and nonsurvivors.


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  		Table 2. Comparison between initial data in survivors and nonsurvivors in relation to HD duration

 
Kaplan-Meier Analysis of Survival
The cumulative survival was markedly dependent on age in both groups (P < 0.0001 and P = 0.0007, respectively; curve not shown). Gender had no effect on the mortality. Although SBP and DBP were not significantly associated with survival, the PP was a strong predictor of mortality in patients with >10 yr of HD (P = 0.0004) but not in patients with ≤10 yr of HD therapy (P = 0.28; Figure 1A). Variability in PP between patients was driven primarily by variation in SBP, evidenced by a large correlation coefficient for the relationship between SBP and PP (r2 = 0.67, P < 0.0001) compared with the relationship between DP and PP (r2 = –0.02, P < 0.0001). Patients with diabetes had a higher morality rate than patients without diabetes in the group with ≤10 yr of HD (P = 0.0214); however, they were not at a greater risk for death in the group with >10 yr of HD (P = 0.29; curve not shown), probably because only a few patients with diabetes (n = 17) survived >10 yr on HD in our study. CAD and CBVD were associated with higher mortality risk in both groups of patients (P = 0.0406 and P = 0.0019, and P = 0.0088 and P = 0.0002, respectively; curves not shown). Predialysis serum creatinine was a strong predictor of mortality as well (Figure 1B). Serum albumin (P = 0.0105) and s-CRP (Figure 1C) were significant predictors only in patients with ≤10 yr of HD, whereas Kt/V (Figure 1D) and URR (P = 0.013) predicted survival in patients with >10 yr of HD when the upper and lower 50th percentiles were compared. Serum levels of calcium and phosphate were not associated with survival.


Figure 1
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  		Figure 1. Kaplan-Meier survival curves. (A) Patients who were above and below the median of pulse pressure (PP). (B) Patients who were above and below the median of serum creatinine (s-Cre). (C) Patients who were above and below the highest tertile of serum C-reactive protein (CRP). (D) Patients who were above and below the median of Kt/V.

 
Cox Proportional Hazard Analysis of Survival
The results of the Cox proportional hazards analysis, conducted separately in each group, are presented in Figure 2. All-cause mortality rates depended on PP (hazard ratio [HR] 2.34; 95% confidence interval [CI] 1.06 to 5.10), presence of CBVD (HR 3.06; 95% CI 1.32 to 7.09), s-CRP ≥0.23 mg/dl (upper tertile versus sum of middle and lower tertile; HR 2.32; 95% CI 1.03 to 3.94), and Kt/V <1.28 (HR 3.02; 95% CI 1.45 to 6.31) in patients with >10 yr of HD. In contrast, age (HR 3.80; 95% CI 2.11 to 6.85) and CBVD (HR 1.88; 95% CI 1.10 to 3.19) were the independent predictors of mortality in patients with ≤10 yr of HD. s-CRP was a NS predictor in the latter group, and it was strongly correlated with CBVD (Figure 3).


Figure 2
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  		Figure 2. Cox proportional hazards analysis of factors that predicted mortality comparing the relative mortality ratios between patients with >10 yr of hemodialysis (HD) with those with ≤10 yr of HD. For each hazards ratio, the 95% confidence interval (CI) is given in parentheses.

 

Figure 3
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  		Figure 3. Patients with cerebrovascular disease had significantly higher levels of serum CRP than those without in the group with ≤10 yr of HD. The error bars represent 95% CI.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
Conclusion
 Disclosures
 References
 
The main purpose of this study was to examine the prognostic significance of predictive factors on survival after long-term HD therapy. In patients with >10 yr of HD, high PP, CBVD, low serum creatinine, and low Kt/V values were identified as the independent mortality risk predictors. In this study, patients who were on HD therapy were recruited to enter to the prospective cohort study on a voluntary basis. Although we did not intend to make any selection bias, an incomplete recruitment of patients associated with a positive selection of patients with high compliance might be inevitably caused by this entry procedure. Nevertheless, the results of our study did not deny the significance of common risk factors, such as inflammation, diabetes, and preexisting CAD, which are well established in the general HD population. It is thought that the factors that were found in this study became detectable as a consequence of exclusion of patients with these conventional risk factors. Therefore, the findings of our study are applicable to selected HD patients without conventional risk factors. Age was associated with mortality in both groups when analyzed by univariate analysis; however, it did not appear in the Cox model in the group with >10 yr of HD, although the mean age of nonsurvivors was 8 yr older than that of survivors. We assumed that this is because of the higher risk associated with PP that indirectly reflects the influence of age on risk. In fact, the interaction between PP and age was highly significant. With age, increased arterial stiffness results in a selective elevation of PP caused by an increase of SBP and a decrease of DBP. The principal arterial alterations of patients who have ESRD and undergo HD are increased stiffness of large conduit arteries together with increased PP, similar to but largely independent of that of aging (23,24). Several renal factors have been proposed for such a high arterial stiffness in patients with ESRD, such as those related to fluid redistribution, the accumulation of advanced glycosylation end product and/or the accumulation of an endogenous inhibitor of nitric oxide synthesis, and, finally, oxidative stress–related tissue damage (23,25,26). The effect of these factors in patients who undergo maintenance HD is likely to intensify over time. Increased arterial stiffness and elevated PP are strong independent predictors of all-cause mortality and mainly cardiovascular mortality among patients with ESRD (27–30). Taken together, this may explain the correlation between PP and hazard for death in patients with >10 yr of HD. We could not collect precise data about BP control and mineral metabolism, such as 24-h BP monitoring and administration of antihypertensive agents, vitamin D, and phosphate binders. Because this study was not a controlled but an observational cohort study, antihypertensive agents, active vitamin D, and phosphate binders were generally administered according to the guidelines of the Kidney Disease Outcomes Quality Initiative (K/DOQI) or based on the judgments of the physicians in charge. For estimation of the influences of these therapeutic modalities on the outcome, a randomized controlled study with a fixed therapeutic protocol is necessary.

We found that low serum creatinine was associated with high death risk. The negative influence of lower levels of serum creatinine on survival has been demonstrated by others and is thought to indicate poor nutritional status (15,20). Patients with high serum creatinine may be better nourished with greater somatic protein mass. A strong negative correlation between age and serum creatinine was noted in the patients with ≤10 yr of HD and is the reason that serum creatinine was not sufficiently predictive of their outcome.

Serum albumin is a strong predictor of death in long-term dialysis patients (8,20,31,32). In this study, serum albumin was not an independent predictor in the Cox model, because patients with low albumin had higher age, high s-CRP levels, and low serum creatinine, which may have a more direct effect on survival. In addition, the level of serum albumin was relatively higher in our patients than in the previous studies (20,31,32). Lowrie et al. (20) showed that the risk for death increases exponentially as serum albumin concentration falls from 4.0 to 2.5 g/dl. Therefore, the notion that serum albumin is an independent predictor is more likely to be true at lower serum levels.

Patients who survived had significantly lower s-CRP level than those who died, as shown by Kaplan-Meier analysis. This finding is in good agreement with previous studies (10,33–35). However, with the addition of other variables, the predictive value of s-CRP was lost in patients with ≤10 yr of HD, possibly because of the strong correlation between s-CRP and CBVD in this patient group. Inflammation is an important factor in atherosclerosis. Recently, a 12-yr prospective study demonstrated that elevation of s-CRP level is an independent risk factor for future ischemic stroke in Japanese men but not for hemorrhagic stroke in either gender (36). The lack of association between s-CRP and CBVD in long-term HD patients may suggest that other risk factors for atherosclerosis, such as hypertension, may be more crucial than inflammation in this patient group.

The effect of the dosage of dialysis on mortality among patients who undergo maintenance HD is somewhat controversial. The HEMO Study is the largest randomized clinical trial designed to determine whether increasing the dosage of dialysis alters survival among patients who undergo HD (12). It concluded that patients who undergo HD thrice weekly have no major benefit from a higher dialysis dosage than recommended by current US guidelines. Nonetheless, some observational studies (37–40), including the survey conducted by the Japanese Society of Dialysis Therapy (9), have reported continuing improvement in morbidity and mortality at dialysis dosages well above those recommended in the current guidelines. No study, however, has evaluated the effect of dialysis dosage in selected patients with long-term HD. In our study, the prognostic significance of Kt/V in patients with >10 yr of HD became apparent by virtue of excluding patients who had common risk factors, which might interfere with the beneficial effect of increasing dosage of HD.

A strength of this study is that it adjusted for numerous comorbidity and risk factors and evaluated a considerable number of patients who had survived on HD for >10 yr. A limitation that should be acknowledged is that our study lacked information on drug use, because this datum was not collected, especially antihypertensive agents and other medications that may influence patients’ biochemical characteristics.


   Conclusion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Conclusion
Disclosures
 References
 
This report suggests that providing a single-pool Kt/V of at least 1.28 and achieving a better control of PP may further improve survival in patients who had undergone maintenance HD for >10 yr.


   Disclosures
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Conclusion
 Disclosures
References
 
None.


   Acknowledgments
 
This work was supported in part by a Health and Labor Science Research Grants for Research on Specific Diseases from the Ministry of Health, Labor and Welfare to F.G. and by Grants-in-Aid for Scientific Research (15390267 to F.G. and 16390242 and 17659254 to I.N.) from the Ministry of Education, Culture, Sports, Science and Technology of Japan.

We deeply thank all of the staff of associated institutions in cooperation with this investigation.


   Footnotes
 
Published online ahead of print. Publication date available at www.cjasn.org.

Received September 17, 2006. Accepted March 14, 2007.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Conclusion
 Disclosures
 References
 

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