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Nihms 271845
Author Manuscript
Am J Kidney Dis. Author manuscript; available in PMC 2012 June 1.
Published in final edited form as:
NIH-PA Author Manuscript
5Design and Data Resource Center, Institute for Clinical Research and Health Policy Studies,
Tufts Medical Center, Boston, MA, USA
6Divisionof Nephrology, Sunnybrook Health Sciences Center and the Departments of Medicine
and of Health Policy Management and Evaluation, University of Toronto, Toronto, ON, Canada
Abstract
Background—The risk of death in dialysis patients remains high, but varies significantly among
patients. No prediction tool is widely used in current clinical practice. We aimed to predict long-
term mortality in incident dialysis patients with easily obtainable variables.
Study Design—Prospective nationwide multicenter cohort study in the United Kingdom (UK
Renal Registry); Models were developed using Cox proportional hazards.
Setting and Participants—Patients initiating hemodialysis or peritoneal dialysis between 2002
and 2004, who survived at least three months on dialysis treatment, were followed for three years.
Analyses were restricted to subjects in whom information on comorbid conditions and laboratory
measurements were available (n=5447). The dataset was divided into datasets for model
development (n=3631, training) and validation (n=1816) by random selection.
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© 2011 The National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.
Corresponding author: Martin Wagner, MD MS, Department of Medicine I, Division of Nephrology, Zentrum Innere Medizin,
Oberdürrbacher Strasse 6, 97080 Würzburg, Germany, Phone: +49 (931) 201-1, Fax: +49 (931) 201-639300, [email protected]
wuerzburg.de.
Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our
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Financial Disclosure: The authors declare that they have no relevant financial interests.
Wagner et al. Page 2
(6%), intermediate (19%), high (33%) and very high (59%) mortality risk. The model was further
applied to the validation dataset and achieved a C-statistic of 0.73 (95% CI, 0.71–0.76).
Limitations—Number of missing comorbidity data and lack of an external validation dataset.
Conclusions—Basic patient characteristics, comorbidity and laboratory variables can predict
three-year mortality in incident dialysis patients with sufficient accuracy. Identification of
subgroups of patients according to mortality risk can guide future research and subsequently target
treatment decisions in individual patients.
Index Words
End stage renal disease; predictive model; mortality; hemodialysis; peritoneal dialysis
The risk of death in patients with end stage renal disease (ESRD) remains high 1, despite
advances in dialysis care 2. The primary cause of death is typically cardiovascular disease
(CVD), but infections and non-vascular sudden cardiac death also contribute significantly
3;4. Mortality risk varies considerably among ESRD patients, and it is dependent on
preexisting conditions and comorbidities such as diabetes, CVD, anemia, impairment of
bone mineral metabolism and chronic inflammation 5–7.
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Several instruments have been developed to assess the burden of comorbid conditions and to
predict outcome in ESRD patients 8–15, reflecting the elevated risk when compared to the
general population 16. However, these approaches frequently ignore patient characteristics,
such as gender, race, primary kidney disease, treatment modality or important comorbidities
and none of these models is commonly used in clinical practice. Clinical experience may be
sufficient to classify the patients according to their mortality risk 17, but to make risk
assessment comparable and widely applicable, a more generalizable approach is needed. A
predictive model that can accurately stratify patients according to their risk for mortality
would be useful to assess the “case-mix” of renal centers and adjust for baseline risk in
comparative studies 2;18. Such a tool could further be employed to focus future research to
those patients likely to benefit from more or less intense treatment, thus providing the
evidence for clinical decision making.
The purpose of the current study was to develop a model predicting all cause mortality
within the first three years after starting dialysis in an unselected cohort of incident dialysis
patients in the United Kingdom who were still on dialysis treatment after three months since
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inception. We aimed to include only readily available and easily obtainable patient
characteristics, comorbidities and basic laboratory variables.
Methods
Study Participants of the United Kingdom Renal Registry
The detailed organization of the United Kingdom Renal Registry (UKRR) has been
described previously 19. In brief, the UKRR is operated under the auspices of the UK Renal
Association and provides independent audit and analysis of renal care in the UK. Although
the UKRR now receives patient level data from all UK renal units, during the period of this
study, information was prospectively collected electronically from 60 renal units in England
and Wales at quarterly intervals for all patients receiving renal replacement therapy. Data
arriving at the UKRR are subjected to algorithms which identify suspicious values, which
are further verified and corrected if necessary by contacting the renal center.
The present analysis included all adult (≥18 yrs) incident dialysis patients who started
dialysis in 2002, 2003 and 2004 and who still received dialysis treatment three months after
inception. Thus, we excluded patients (n=1310) who died, underwent transplant or who
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recovered kidney function within 90 days after initiation of dialysis (Figure 1). This reflects
the standard approach to investigate “true” ESRD patients amongst all those receiving
dialysis because the diagnosis of ESRD is commonly made after three months. Thus most of
the patients with dialysis-dependent acute kidney injury are excluded, but unfortunately,
ESRD patients who are at extremely high risk for death and die within the first three months
are not considered as well. Data on study subjects were available until December 31st 2007.
Patients were followed for at least three years.
graft or aneurysm, amputation for peripheral vascular disease) 19. Socio-economic status
was assed by Townsend scores, which are based on postal codes, and range from least
deprived to most deprived (score 1 to 5) 20. In addition, hemoglobin, serum albumin,
calcium, phosphate, creatinine (predialysis) and ferritin were considered for the analyses.
We did not include body mass index (BMI), blood pressure, cholesterol and iPTH due to
missing data >20%. Anemia was defined as hemoglobin <12 g/dl in women and <13.5 g/dl
in men 21.
Since we considered comorbidities and laboratory variables as being essential for the
development of the prediction model, we excluded patients in whom none of the
comorbidity information was available (n=4859) or in whom laboratory data of the first six
months was missing (n=596) (Figure 1). Some renal centers reported comorbidity data more
frequently to the UKRR than other centers 22; therefore we investigated potential
differences in mortality risk between these renal units, but did not detect strong evidence for
center effects (data not shown).
The purpose of our prediction model was to assess the patient’s three-year mortality risk
after three months of dialysis treatment. Thus we used laboratory data that was obtained in
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the second quarter of dialysis treatment. If this information was missing in patients who died
in the second quarter, we used laboratory measurements of the first quarter. At the start of
dialysis therapy, several impairments such as anemia, metabolic acidosis, hypervolemia and
hyperparathyreoidism may not be treated adequately. After three months of dialysis
treatment, these variables might be better controlled; however, with the variables available
in this dataset, specific impairments such as resistance to erythropoietin stimulating agents
cannot be identified. The final dataset was randomly split in a training dataset (2/3 of the
original cohort, n=3631) and a validation dataset (1/3 of the original cohort, n=1816) (Figure
1).
Statistical Methods
Cox proportional hazards models were used to model all cause mortality, censored for
transplant, recovery of kidney function (after 90 days) and loss to follow up. Age, gender
and treatment modality three months after dialysis initiation were forced in all analyses. We
included the continuous outcomes ferritin, albumin and calcium in their logarithmic forms.
The proportional hazards assumption was met by all variables as investigated with
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Schoenfeld residuals. Outliers and influence points were identified by checking deviance
residuals and difference in betas (dfbetas). The performance of the models was assessed
with the time-dependent C-statistic 23. Similar to the area under the receiver operator curve,
it describes the probability that the model will assign the higher mortality risk to the patient
who actually died as compared to the patient who remained alive or was censored. Models
resulting from the training dataset were applied to the validation dataset with fixed Hazard
Ratios, i.e., the variables and their exact beta-coefficients were kept as developed for the
prediction model in the training dataset. To calibrate the model, mortality risk was split into
quartiles and observed versus predicted risk was investigated across risk strata 24. We chose
quartiles to reflect clinically useful categories of patients with low, intermediate, high and
very high risk, although a sufficient number of patients and outcomes were available to
investigate mortality risk across deciles, which is also commonly presented in the literature.
The analyses were performed on a complete case basis. We tested the robustness of our
model by (1) excluding patients who died in the second quarter and in whom laboratory
variables from the first quarter were used; (2) using laboratory data from quarter one rather
than from quarter two in all subjects; (3) imputing missing values by employing the Markov
Chain Monte Carlo method (SAS procedure proc mi) 25. We further investigated in
univariate and multivariate logistic regression models how patients with missing
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comorbidity and laboratory information differed from those patients in whom this
information was available. All analyses were performed in SAS 9.1 (www.sas.com). The
analysis of this preexisting dataset was approved by the institutional review board at Tufts
Medical Center, Boston.
Results
Study population
Patient characteristics, comorbidities and laboratory data of study subjects in the training
and the validation dataset are displayed in table 1. Patients were predominantly male, the
median age was 64 yrs, and more than two third of the patients received hemodialysis three
months after dialysis inception. A third of the patients were diabetic or reported a history of
CVD. Approximately three quarters of the patients were classified as being anemic (79% in
training dataset and 73% in validation dataset).
Outcomes
In the training dataset, a total of 1078 patients (29.7%) died within the observation period
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from day 90 until three years (Table 2), while 563 patients (15.5%) underwent transplant.
Half of the patients were alive and still on dialysis after three years. Only a few patients
were either lost to follow-up or recovered kidney function (approximately 1.5% each).
Similar results were observed in the validation dataset.
Predictors of Mortality
When only patient characteristics were included in the multivariate model (Table 3, model
1), older age, white race, diabetes as cause of ESRD and HD treatment (versus PD) were
independently associated with an increased risk for all cause mortality. In this analysis, a
change from HD to PD within the first three months of renal replacement therapy was
associated with a lower mortality risk as compared to a change from PD to HD. However,
this association did not achieve formal significance level (p=0.07) and was further diluted in
subsequent modeling. In a second step (model 2), the comorbidities diabetes, history of
CVD and smoking status were added and also independently associated with worse
outcome. The interaction term built by diabetes and CVD emerged as significant, indicating
a different effect of diabetes on mortality depending on whether or not the patient had a
history of CVD. Finally (model 3), the laboratory measures of hemoglobin, serum albumin,
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creatinine and calcium appeared as predictors of mortality, after accounting for phosphate
and ferritin.
The accuracy of the Cox proportional hazards models was assessed by the C-statistic (Table
3). The model with basic patient characteristics already achieved considerable accuracy as
indicated by a C-statistic of 0.69 (95% confidence interval [CI], 0.67–0.71; model 1), which
further increased by adding comorbidity data and laboratory measurements (C-statistic,
0.75; 95% CI, 0.73–0.77]), mainly due to the latter.
To check the robustness of the model, we performed a number of sensitivity analyses. First,
we excluded patients who died in their second quarter of dialysis treatment and in whom
laboratory measurements from the first quarter were used rather than from quarter two. The
variables of the final model remained unchanged, and the hazard ratios were similar, as was
the C-statistic (0.74; 95% CI, 0.72–0.77). Second, when we used laboratory measurements
from quarter one in all patients of the training dataset, the model achieved a C-statistic of
0.72 (95% CI, 0.69–0.75) with all variables of the final model except race and hemoglobin.
Finally, since the described analyses were performed on the basis of complete cases, we
imputed all missing data. The hazard ratios of the complete case model were within the 95%
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significant difference between observed and predicted mortality risk was found (p=0.9).
Discussion
In the UK Renal Registry database we developed a model that predicted three-year mortality
in patients who survived up to three months after dialysis inception and were still on dialysis
treatment. The model included exclusively easily obtainable and routinely collected patient
characteristics and laboratory variables. It achieved sufficient accuracy and was able to
discriminate accurately across risk strata.
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It is a particular strength of this model that the underlying data were prospectively collected
on an incident cohort without any exclusion criteria. Data in the UKRR are considered of
good quality 26 and are representative for the UK and likely even for larger parts of
Europe19. We also included only variables which are routinely captured in the UK and
worldwide, making the model widely applicable to a variety of settings. Furthermore, we
judged the outcome three year all cause mortality – a very heterogeneous outcome with a
variety of underlying causes – as more important than short term mortality 9;12;15 or events
with less heterogeneity (e.g., CVD events 8), although these are frequently easier to predict.
There are only a few reports predicting long-term mortality in dialysis patients that
employed Cox models and provided data on model performance. Their results are in line
with our findings that patient characteristics, comorbidity data and basic laboratory variables
are important to predict mortality in long-term dialysis patients. Geddes et al. retrospectively
collected data about dialysis patients who died in 1997 from voluntarily participating renal
centers throughout Europe 10. Their analyses were thus based on patients who differed in
their time to death. Hence, patients who survived on dialysis or underwent transplant in the
same observation period were not included. Their model was further validated prospectively
in patients starting dialysis in the same renal centers and who were followed up to five years.
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Unfortunately, the measures of accuracy provided, negative and positive predictive values,
ignore information on time to the event. The recently published index developed by Liu et
al. 11 used data from the United States Renal Data System (USRDS) to primarily assess the
prognostic value of comorbidities on mortality in incident dialysis patients who survived the
first 9 months on treatment. Patients undergoing transplant were excluded and laboratory
variables were not considered. Miskulin et al. described how a variety of comorbid
conditions impact on three-year mortality in prevalent dialysis patients of the US population
in the Dialysis Outcome and Practice Patterns Study (DOPPS) 14. Their final model reached
a C-statistic of 0.73 (95% CI, 0.72–0.74) and included patient characteristics, basic
laboratory variables, comorbidities (17 variables) and physical impairments (3 variables).
However, this model lacked routinely collected variables and could not be electronically
implemented into practice.
Although our model – as well as those from other groups – achieved considerable accuracy
and discrimination to classify patients according to their mortality risk, we suggest that the
results of this risk assessment should not (yet) be applied to individual patients in current
clinical practice. Therefore we refrained from transforming the model into an easy-to-use
score at this stage. While it seems intuitive that the model may provide clinically useful
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In our model we show that basic patient characteristics and laboratory markers are sufficient
to classify patients according to their mortality risk. These variables are not novel or
surprising, and in the last decade a variety of more specific factors, for example cardiac
function or biomarkers, such as CRP, adiponectin or NT-proBNP (N-terminal pro-brain
natriuretic peptide) 27–31, have been found to be associated with mortality in ESRD
patients. The challenge would be to test the markers regarding their incremental value on the
performance of our model, since the model already achieved good accuracy and
discrimination. In particular, it may be relevant to examine how many patients get correctly
(re-)classified by including versus ignoring the additional variables 32.
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Furthermore, the model can form the basis for risk-stratified analyses of randomized
controlled trials (RCTs). Summary results of RCTs may reflect the treatment effect of a
relatively small subgroup of influential patients, and do not accurately describe the treatment
effect of the typical patient enrolled in the trial. While conventional subgroup analyses have
important limitations, risk-stratified analyses can frequently identify patients who
particularly benefit from a given treatment if there is considerable variation of baseline
risk33. Since the latter is certainly the case in the setting of dialysis, it is conceivable that an
analysis according to the patient’s mortality risk would provide clinical useful information.
Finally, the prediction model can be useful to evaluate the composition of patients treated in
a given center. Demographic and comorbidity features vary between facilities within certain
areas, which impact on mortality; this scenario is best described as variability in “case-mix”
2. Financial incentives to improve quality of care are increasingly considered in many health
care systems throughout the world 34. In the US, dialysis centers are evaluated by
performance and reimbursement is dependent on the “success” of the treatment of each
center (“pay for performance”) 35. A similar scenario is in discussion in the UK between the
NHS Information Centre, the NHS Healthcare Quality Improvement Programme (HQIP)
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and the renal community. We hypothesize that our prognostic model could potentially be
used to create a “standardized mortality ratio” for UK renal units, making data between
centers more comparable to patients, health care providers, insurance companies and
researchers.
We are aware of several limitations of the current study. First, a priori to the modeling
process, we excluded a large number of patients in whom comorbidity and laboratory data
were not available. Although some of these variables were not missing completely at
random, we could not find center effects for missingness. Our basic model also validated
well in patients in whom these important data were missing. This finding suggests that the
differences in mortality rate may in fact be explained by the covariates in the model. We
therefore argue that the final model could be generalizable to the cohort with missing
comorbidity and laboratory data. As the amount of missing data decreases prospectively in
the UK, it is possible that the performance of our model may be further improved with the
addition of these variables. Second, certain parameters that may have improved the
performance of our model were not available, such as CRP-level, information on dialysis
access, dialysis dose or residual renal function; or due to a large number of missing data
(BMI, blood pressure, iPTH, cholesterol). Third, although we tested the robustness of our
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Our model suggests that a limited number of basic patient characteristics and easily
obtainable and commonly measured variables are sufficient to predict with good accuracy
three-year mortality in patients who survived the first three months of dialysis treatment. We
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would propose that novel biomarkers or other associations predicting mortality in long-term
dialysis patients should be added to and tested against our model to determine their
incremental value. Identification of subgroups of patients according to mortality risk can
guide future research that may be able to target treatment decisions in individual patients.
Acknowledgments
We thank the patients and the clinicians in the renal units who contributed data to the UK Renal Registry as well as
we thank Julie Gilg at the UK Renal Registry for administrative support. We thank Hocine Tighiouart for providing
the SAS macros for calculation of the C-statistic and model calibration in Cox proportional hazards models. We
also thank Andrew S. Levey and Bertram L. Kasiske for helpful discussions and critical revision of the manuscript.
Support: Dr Wagner receives funding from the fellowship training program of the National Kidney Foundation
Center for Clinical Practice Guideline Development and Implementation at Tufts Medical Center. Dr Kent is
supported by a grant of the National Institute of Health (NIH/NCRR 1UL1 RR025752). Dr Tangri is supported by
the KRESCENT postdoctoral fellowship award, a joint initiative of the Kidney Foundation of Canada, the Canadian
Institute of Health Research and the Canadian Society of Nephrology. The UK Renal Registry is funded by an
annual capitation charge to UK renal units and is independent of industry and government.
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Figure 2. Three year mortality according to risk strata, calibration of the model
Observed (grey columns) and predicted (white columns) mortality risk within 3 years after
starting dialysis treatment in patients in the UK Renal Registry according to risk strata
derived from the final prediction model; panel A: training dataset, panel B: validation
dataset; * p-value between observed and predicted mortality risk.
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Table 1
Characteristics of study subjects
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treatment modality2
HD 70.1 72.3
PD 29.9 27.7
Townsend score4
1 16.7 16.3
2 18.3 18.4
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3 18.8 18.7
4 22.9 23.4
5 23.3 23.3
race category5
cause of ESRD
comorbidity
laboratory measurements
Categorical data are given as percentage; continuous Data are means ± standard deviation or medians (25th; 75th percentile)
abbreviations: BMI, body mass index; PD, peritoneal dialysis; HD, hemodialysis; ESRD, end stage renal disease; CVD, cardiovascular disease;
iPTH, intact parathyroid hormone; BP, blood pressure; SCr, serum creatinine
conversion factors for units: serum creatinine in mg/dL to mol/L, ×88.4; cholesterol in mg/dL to mmol/L ×0.02586, albumin in g/dL to g/L ×10;
calcium in mg/dL to mmol/L ×0.2495; phosphorus in mg/dL to mmol/L ×0.3229; no conversion necessary for ferritin in ng/mL and ug/L, and
iPTH in pg/mL and ng/L
1
>20% missing data
2
Treatment modality after 3 months of dialysis treatment
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3
Predialysis measurements
4
Socioeconomic status; least deprived (score 1), most deprived (score 5)
5
Self reported, patients of South Asian origin (i.e. excludes Chinese patients) are classified as “Asian”
6
Including diabetes as non primary cause of ESRD
7
Cardiovascular disease assessed according to a questionnaire about ischemic heart disease, cerebrovascular disease and peripheral vascular
disease
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Table 2
Outcomes within 3 years of dialysis initiation
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death
transplant
loss to follow-up
Table 3
Mortality within 3 years of dialysis initiation, training dataset
Predictors of Mortality
age 1.04 (1.03–1.05) 177.6 1.04 (1.03–1.05) 152.5 1.04 (1.03–1.04) 99.3
gender, male 1.03 (0.89–1.18) 0.1 0.93 (0.80–1.08) 0.9 0.95 (0.80–1.12) 0.4
treatment modality3 1.25 (1.05–1.47) 6.5 1.19 (1.00–1.43) 3.1 1.32 (1.09–1.60) 8.3
Model Performance
Wagner et al.
Variables age, gender and treatment modality forced in all multivariate Cox proportional hazards models;
abbreviations: HR, hazard ratio; CI, confidence interval; ESRD, end stage renal disease; GN, glomerulonephritis; PKD, polycystic kidney disease; RVD, renovascular disease; CVD, cardiovascular disease;
DM, diabetes mellitus; SCr, serum creatinine
1
Adjusted for start-year of dialysis, Townsend score, change in treatment modality within the first 3 months of dialysis treatment
2
Adjusted for start-year of dialysis, Townsend score, change in treatment modality within the first 3 months of dialysis treatment, phosphate, ferritin (log)
3
Treatment modality (hemodialysis vs. peritoneal dialysis) after 3 months of dialysis treatment
4
Including DM as non primary cause of ESRD
5
Cardiovascular disease assessed according to a questionnaire about ischemic heart disease, cerebrovascular disease and peripheral vascular disease
6
Interaction term of diabetes and CVD
a
“Asian” defined as patients of South Asian origin (i.e. excludes Chinese patients)