Nephrol Dial Transplant (2012) 27 (Supple 3): iii27–iii31
doi: 10.1093/ndt/gfs277
Advance Access publication 4 July 2012
Editorial Review
The EQUAL study: a European study in chronic kidney
disease stage 4 patients
K.J. Jager1, G. Ocak2, C. Drechsler3, F.J. Caskey4,5, M. Evans6, M. Postorino7,
F.W. Dekker2 and C. Wanner3
1
ERA–EDTA Registry, Department of Medical Informatics, Academic Medical Center, University of Amsterdam, Amsterdam,
The Netherlands, 2Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands,
3
Department of Medicine I, Division of Nephrology, University of Würzburg, Würzburg, Germany, 4Richard Bright Renal Unit,
Bristol, UK, 5The School of Clinical Sciences, University of Bristol, Bristol, UK, 6Department Clinical Sciences, Intervention and
Technology, Karolinska Institutet, Stockholm, Sweden and 7CNR-IBIM, Clinical Epidemiology and Physiopathology of Renal
Diseases, Reggio Calabria, Italy
Correspondence and offprint requests to: Kitty J. Jager; E-mail: [email protected]
Dialysis therapy aims to prolong life and improve the
quality of life for patients with ESRD, but mortality rates
remain high, especially in elderly patients––58% of
elderly nursing home residents die in their first year of
treatment [1]. This means that nowadays, at least in
specific groups of patients on dialysis, mortality is importantly higher than in patients suffering from common malignancies. These developments, together with the
tendency of nephrologists in recent years to start dialysis
earlier in the course of disease [2, 3] to try and improve
survival on dialysis, have led to an increasing debate on
when to start dialysis in terms of renal function and in
terms of signs and symptoms. Furthermore, there is substantial discussion concerning the process of decision
making by nephrologists and patients, especially if these
decisions are regarding elderly patients. The international
EQUAL study intends to address these issues. This
review provides details on the study’s background and
gives a short summary of its design.
Abstract
The timing of the start of dialysis in elderly patients is
driven by the desire to optimize the quantity and quality
of life. Limited data exist on how the level of renal function, and uraemic signs and symptoms can be used to determine when dialysis should be initiated in elderly
patients. EQUAL, an international prospective cohort
study, aims to address these issues. To this end, it will
enrol 3500 patients >65 years of age with CKD of various
aetiologies under the care of nephrologists. These patients
will be followed until death, discharge from the nephrology clinic to primary care or until the end of the observation period after 4 years of follow-up. At the time of
enrolment, patients must have an estimated glomerular filtration rate (eGFR) of 20 mL/min/1.73 m2 or lower, but
should not yet be on dialysis. Standardized data collection
will include demographics, lifestyle, comorbidities,
uraemic signs and symptoms, nutritional status, medication and routine blood and urine biochemistry. It will
also comprise quality of life data, information on decision
making including patients preferences and patients
satisfaction.
The timing of the start of dialysis
Introduction
Estimated glomerular filtration rate
Since the 1960s when the first patients began chronic
dialysis, the average end-stage renal disease (ESRD)
patient has changed from a relatively young patient with
glomerulonephritis or polycystic kidney disease into an
elderly person with diabetes mellitus or hypertension as
cause of renal failure and multiple comorbidities. The increased availability of dialysis as well as the ageing of the
general population has contributed to the huge increase in
the number of dialysis patients over this period. This
growth has had a substantial economic impact given the
high costs of dialysis.
Usually, dialysis is started at an estimated glomerular filtration rate (eGFR) of 5 to 15 mL/min/1.73 m2 [3–7]. As
a consequence, the variation in the start of dialysis in
terms of eGFR is substantial. Over the past decades, there
has been a trend to start dialysis at higher levels of
residual renal function [2, 3, 5, 8, 9], also in patients who
have relatively few symptoms and signs, to make a socalled ‘healthy start’ on dialysis with positive effects on
renal function and nutritional parameters. For example,
using the United States Renal Data System (USRDS)
data, Rosansky et al. showed that from 1996 to 2005 the
percentage of US patients starting dialysis with an eGFR
© The Author 2012. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.
For Permissions, please e-mail: [email protected]
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K.J. Jager et al.
2
of >10 mL/min/1.73 m has more than doubled from 19
to 45% [3]. Furthermore, O’Hare et al. recently showed
that, after accounting for changes in the characteristics of
new US dialysis patients, from 1997 to 2007 chronic
dialysis was initiated on average 147 days earlier. In
patients >75 years of age the initiation of dialysis was
even 233 days earlier [2].
Several studies have investigated whether there were
differences in mortality risk between the start of dialysis
at higher levels of eGFR versus the start of dialysis at
lower levels of eGFR. Although not anticipated, most observational studies have shown a decreased survival of
patients who started dialysis at higher levels of eGFR
[4, 6, 9–15] instead of improved survival in these ‘early
starters’. The association between the start of dialysis at
higher eGFR levels and lower patient survival has been
found in both haemodialysis and peritoneal dialysis. Confounding factors may play an important role, as the data
of Lassalle et al. suggest that after adjustment for prognostic factors an effect of starting at higher levels of
eGFR is absent in patients in whom the start of peritoneal
dialysis was ‘planned’ [6]. In addition, many of these
studies suffered from methodological shortcomings including lead-time bias and selection bias [16].
A recent randomized controlled trial, the IDEAL study,
failed to show a benefit in survival between strategies of
starting dialysis at higher levels of eGFR versus starting
dialysis at lower levels of eGFR (hazard ratio for the
early-start group: 1.04; 95% CI, 0.83–1.30; P = 0.75) [7].
However, the relatively small difference in initial eGFR at
which patients actually started dialysis in this study (mean
eGFR according to Cockcroft–Gault: 12.0 mL/min versus
9.8 mL/min in the early- and late-start group respectively)
may have contributed to the lack of difference in patient
survival. From the available evidence, therefore, the level
of kidney function at which patient survival and quality
of life are improved by starting dialysis remains unknown
[17] and the possibility that harm may be done by starting
dialysis at higher levels of eGFR cannot be excluded
[9, 13]. The mechanisms proposed for the potential harm
induced by starting haemodialysis at higher levels of renal
function include the more rapid loss of endogenous renal
function and the clinically significant hypotension
induced by this treatment as shown by Jansen et al. [18].
Furthermore, the recurrent episodes of myocardial ischaemia and ‘stunning’ as demonstrated by McIntyre may be
contributory [19].
We therefore support the conclusion of O’Hare et al.
that, in the absence of strong evidence of benefit from
earlier initiation of chronic dialysis, the trend to start
dialysis earlier in the process of deterioration of renal
function calls for a careful evaluation of contemporary
dialysis initiation practices [2]. As EQUAL investigators
we would also like to stress the importance of studying
the link between contemporary dialysis initiation practices
and patient prognosis.
Uraemic signs and symptoms
Knowledge of the development of uraemic signs and
symptoms during the progression of chronic kidney
disease (CKD) towards the start of dialysis is limited.
Both the IDEAL study and some observational studies
confirmed previous data showing that in starting dialysis
for ESRD nephrologists consider such signs and symptoms at least as important as the level of residual renal
function [7, 20–22]. For example in the late-start group of
the IDEAL study, 76% of the patients started dialysis
earlier than planned, mainly because of uraemia. A
similar variation in the timing of start of dialysis as
shown for the eGFR may exist for the presence and severity of signs and symptoms of uraemia. To the best of our
knowledge, data on the variation in signs and symptoms
at the start of dialysis, on their relative importance for the
decision to start dialysis as well as on their association
with patient prognosis are lacking. Studies in this area are
therefore needed.
Measuring renal function
The counterintuitive results from the observational studies
investigating the relationship between the eGFR at the
start of dialysis and patient survival and the negative
IDEAL trial have raised considerable doubts as to
whether the eGFR is suitable as an indicator of renal
function in this very low range of renal function when the
decision to start dialysis is made. The eGFR based on the
modification of diet in renal disease (MDRD) equation
and other serum creatinine-based measures of renal function have been shown to be inaccurate and imprecise indicators of residual renal function and to have a different
association with patient survival than the measured GFR
[20, 23, 24]. Some of the apparent adverse effects of starting dialysis at higher eGFR levels may be due to the dependency of the eGFR on muscle mass [24]. On the other
hand, the most valid methods to measure renal function in
advanced CKD in routine clinical practice are not known.
This leaves us with the problem of not knowing which
measure of residual renal function can be used to determine the best moment to start dialysis in relation to
patient outcomes.
Preferences of patients and caregivers regarding
the decision on when to start dialysis
Qualitative studies about medical decision making on
when and whether to start dialysis from the perspective of
patients and carers are extremely scarce [25, 26]. The few
studies performed indicate that indeed some elderly
patients themselves are not prepared to make the necessary changes to their lifestyle associated with dialysis [25].
The only study from Europe [26] provides some anecdotal
evidence that although such patients enjoy life and
express a desire to live for as long as possible, they are
not prepared to do so at any price. In this small study, the
age-associated decrease in vitality and loss of autonomy
were important reasons for these patients to decline dialysis. Data from the dialysis outcomes and practice patterns
study (DOPPS) [27] suggest that nephrologists take other
factors into account. The medical directors of centers
The EQUAL study
participating in that study were asked about their agreement not to start haemodialysis in patients with specific
conditions like dementia or multiple medical problems or
in the very elderly and ‘not independent’ patients (nursing
home residents). On average, they were hesitant not to
start dialysis in these patients, but there was a huge variation across countries with UK nephrologists more often
agreeing not to start dialysis than those from other
countries. Nephrologists tended to agree more if patients
were demented, but in the case of very elderly or dependent patients (nursing home residents), they usually disagreed with not starting dialysis. Recent data from the
USA show that the dialysis outcomes in nursing home residents are not very good [1] and therefore suggest that it
may not be possible to prolong life and increase the
quality of life by dialysis in all patients with ESRD.
Benefit or burden
Nephrology is increasingly dominated by problems traditionally considered to be geriatric issues. As a result,
there is an increasing debate whether dialysis in elderly
patients should be considered a benefit or a burden and
whether ‘non-aggressive renal care’ with prescription of
relevant medication and diet should not deserve a more
prominent place in ESRD [28]. Treatments to minimize
the effects of uraemia and therefore postpone the need for
dialysis may include erythropoietin, dietary restrictions,
anti-hypertensive drugs, phosphate binders, calcium and
vitamin D supplements. In theory, these interventions
without dialysis would control blood pressure, nutritional
status and uraemia and would avoid dialysis-related complications. Studies have shown that a strategy to postpone
dialysis is probably a viable option in elderly patients
with many comorbidities and a limited life expectancy
[29–34]. From this perspective, the recently revised clinical practice guideline Shared Decision-Making in the Appropriate Initiation of and Withdrawal from Dialysis [35]
is important. This guideline, however, is primarily based
on the US data concerning options within US renal practice which may not reflect renal practice in Europe.
The increasing prevalence of dialysis patients results in
higher costs of dialysis. At the same time, there is an increasing awareness that rational treatment does not need
to be the same as ‘rationing’. In this context, it is important to determine and characterize in a multinational European study the fraction of ESRD patients attending a
nephrology clinic who are postponing or not starting
dialysis and instead receive relevant medication and diet
(as a result of their own preference or based on their physician’s advice) and to compare their outcomes with
similar patients starting dialysis.
Dialysis or the prescription of relevant medication and
diet to postpone or not to start dialysis may affect patient
survival and quality of life in potentially important, different ways. Therefore, in analogy with clinical trials investigating treatments with a major impact on day-to-day life,
it is crucial to consider both survival and quality of life in
any comparison of outcomes between dialysis start with a
iii29
high renal function versus a low renal function, a high
number of uraemic signs and symptoms versus a low
number of uraemic signs and symptoms and starting
dialysis versus not starting dialysis. In the future, this will
support patients and nephrologists in making better informed choices.
Summary
In conclusion, there are limited data on how renal function, and uraemic signs and symptoms can be used to determine when dialysis should be initiated in elderly
patients in order to optimize the quantity and quality of
life. Furthermore, it is unknown to which extent residual
renal function, these uraemic signs and symptoms and
patients preference contribute to medical decision making
in the daily practice of starting dialysis and how they
affect the subsequent patient outcomes. Finally, it is
unknown which are valid methods to measure renal function in advanced CKD which may be used for the
decision making on the start of dialysis. The international
EQUAL study intends to address these issues.
The EQUAL study
EQUAL has received funding from the European Renal
Association–European Dialysis and Transplant Association (ERA–EDTA) and co-funding from the Dutch
Kidney Foundation and the Italian Society of Nephrology
to conduct an international prospective multi-centre
cohort study in CKD patients >65 years progressing
towards ESRD. Patients at the nephrology clinic with an
eGFR of 20 mL/min/1.73 m2 or lower (first ever and
those who are referred with a kidney function already
below this level) will be recruited.
Table 1. Synopsis of data collected within the EQUAL study
History and physical examination
Decision making
• Demographics
• Renal history
• Lifestyle
• Comorbidities
• Anthropometry
• Uraemic signs and symptoms
• Nephrologist’s reasons for
starting or not starting dialysis
• Patient’s opinion on information
received, involvement in
decision making on therapy and
satisfaction with treatment
Lab and other investigations
Therapy
• Blood: creatinine, urea, albumin,
haemoglobin, haematocrit, mean
corpuscular volume (MCV),
electrolytes, parathyroid hormone
(PTH) and cholesterol
• 24-h urine: volume, creatinine,
urea and protein
• Tracer studies in a subset of
patients to determine renal
function
• Dietary prescription
• Medication
• Dialysis therapy characteristics
Outcomes
• Dialysis treatment complications
• Quality of life
• Patients’ satisfaction
• Hospitalization
• Death
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K.J. Jager et al.
Fig. 1. Study flow.
The research questions to be addressed include:
• How do uraemic signs and symptoms develop during
the progression of CKD towards the start of dialysis?
• After accounting for biases such as lead-time bias and
selection bias, how do the outcomes––in terms of
patient survival and quality of life––compare between
the start of dialysis with a higher renal function versus
that with a lower renal function and the start of dialysis
with fewer uraemic signs and symptoms versus that
with more signs and symptoms?
• Which method of measuring renal function best informs
the decision to start dialysis in advanced CKD?
• What is the best moment to start dialysis in terms of
renal function and uraemic signs and symptoms in
relation to subsequent outcomes?
• How does decision making of nephrologists and
patients and their carers take place to decide if and
when to start dialysis and by which factors is this
affected?
• Are patients satisfied with decision making around the
start or postponement of dialysis?
Baseline and follow-up data will include routine clinical
data like demographics, lifestyle, comorbidities, uraemic
signs and symptoms, data derived from physical examination (for example, nutritional status), routine blood and
urine biochemistry, medication and other treatment
characteristics as well as hospitalization and mortality
(Table 1). In addition, data collection will comprise
quality of life data, information on decision making including patients preferences and patients satisfaction. Individual participating countries may collect additional data
for specific topics of interest and ancillary studies will be
implemented. Tracer studies for measuring renal function
using iohexol clearance in a subset of patients are included in this additional data collection both at patient
inclusion and at the initiation of dialysis. At the same
time points, blood and urine samples will be obtained
from all patients for biobanking and central analysis in
addition to standard clinical care.
Patients will be followed until death, discharge from
the nephrology clinic to primary care or until the end of
the study after 4 years of follow-up (Figure 1). Follow-up
visits will take place every 6 months until the eGFR falls
<10 mL/min/1.73 m2 or the patient commences dialysis
when the frequency will be increased to 3-month intervals. After 6 months on dialysis, the frequency of visits
will return to every 6 months.
Specific statistical techniques like marginal structural
modelling and inverse probability weighting will be employed to overcome selection bias which is inherent in observational studies. Such approaches have been successfully
adopted in other areas of medicine to overcome confounding by indication and selection bias [36, 37]. We strive to
include 3500 patients from five countries (Germany, Italy,
Sweden, The Netherlands and the UK). A pilot study has
been started in January 2012.
Conflict of interest statement. None declared.
References
1. Kurella Tamura M, Covinsky KE, Chertow GM et al. Functional
status of elderly adults before and after initiation of dialysis. N Engl
J Med 2009; 361: 1539–1547.
2. O’Hare AM, Choi AI, Boscardin WJ et al. Trends in timing of
initiation of chronic dialysis in the United States. Arch Intern Med
2011; 171: 1663–1669.
3. Rosansky SJ, Clark WF, Eggers P et al. Initiation of dialysis at
higher GFRs: is the apparent rising tide of early dialysis harmful or
helpful? Kidney Int 2009; 76: 257–261.
4. Stel VS, Tomson C, Ansell D et al. Level of renal function in
patients starting dialysis: an ERA-EDTA registry study. Nephrol
Dial Transplant 2010; 25: 3315–3325.
5. Traynor JP, Simpson K, Geddes CC et al. Early initiation of dialysis
fails to prolong survival in patients with end stage renal failure. J
Am Soc Nephrol 2002; 13: 2125–2132.
The EQUAL study
6. Lassalle M, Labeeuw M, Frimat L et al. Age and comorbidity may
explain the paradoxical association of an early dialysis start with
poor survival. Kidney Int 2010; 77: 700–707.
7. Cooper BA, Branley P, Bulfone L et al. A randomized, controlled
trial of early versus late initiation of dialysis. N Engl J Med 2010;
363: 609–619.
8. Termorshuizen F, Korevaar JC, Dekker FW et al. Time trends in
initiation and dose of dialysis in end-stage renal disease patients in
the Netherlands. Nephrol Dial Transplant 2003; 18: 552–558.
9. Clark WF, Na Y, Rosansky SJ et al. Association between estimated
glomerular filtration rate at initiation of dialysis and mortality. CMAJ
2011; 183: 47–53.
10. Stel VS, Dekker FW, Ansell D et al. Residual renal function at the
start of dialysis and clinical outcomes. Nephrol Dial Transplant
2009; 24: 3175–3182.
11. Hwang SJ, Yang WC, Lin MY et al.; Taiwan Society of Nephrology.
Impact of the clinical conditions at dialysis initiation on mortality in
incident haemodialysis patients: a national cohort study in Taiwan.
Nephrol Dial Transplant 2010; 25: 2616–2624.
12. Wright S, Klausner D, Baird B et al. Timing of dialysis initiation
and survival in ESRD. Clin J Am Soc Nephrol 2010; 5: 1828–1835.
13. Rosansky SJ, Eggers P, Jackson K et al. Early start of hemodialysis
may be harmful. Arch Intern Med 2011; 171: 396–403.
14. Beddhu S, Samore MH, Roberts MS et al. Impact of timing of
initiation of dialysis on mortality. J Am Soc Nephrol 2003; 14:
2305–2312.
15. Sawhney S, Djurdjev O, Simpson K et al. Survival and dialysis
initiation: comparing British Columbia and Scotland registries.
Nephrol Dial Transplant 2009; 24: 3186–3192.
16. Sjölander A, Nyrén O, Bellocco R et al. Comparing different strategies for timing of dialysis initiation through inverse probability
weighting. Am J Epidemiol 2011; 174: 1204–1210.
17. Korevaar JC, Jansen MAM, Dekker FW et al.; for the NECOSADStudy Group. When to initiate dialysis––effect of proposed US
guideline on survival. Lancet 2001; 358: 1046–1050.
18. Jansen MA, Hart AA, Korevaar JC et al.; NECOSAD Study Group.
Predictors of the rate of decline of residual renal function in incident
dialysis patients. Kidney Int 2002; 62: 1046–1053.
19. McIntyre CW. Effects of hemodialysis on cardiac function. Kidney
Int 2009; 76: 371–375.
20. Tattersall J, Dekker F, Heimbürger O et al.; on behalf of the ERBP
Advisory Board. When to start dialysis: updated guidance following
publication of the initiating dialysis early and late (IDEAL) study.
Nephrol Dial Transplant 2011; 26: 2082–2086.
21. Ledebo I, Kessler M, Van Biesen W et al. Initiation of dialysis––
opinions from an international survey: report on the dialysis opinion
symposium at the ERA-EDTA Congress, 18 September 2000, Nice.
Nephrol Dial Transplant 2001; 16: 1132–1138.
22. Stel VS, Jager KJ. Glomerular filtration rate and initiation of
dialysis. CMAJ 2011; 183: 24–25.
23. Grootendorst DC, Michels WM, Richardson JD et al. The MDRD
formula does not reflect GFR in ESRD patients. Nephrol Dial
Transplant 2011; 26: 1932–1937.
iii31
24. Krediet RT, Dekker FW. Dialysis: can plasma creatinine levels guide
initiation of dialysis? Nat Rev Nephrol 2010; 6: 563–564.
25. Morton RL, Tong A, Howard K et al. The views of patients and
carers in treatment decision making for chronic kidney disease: systematic review and thematic synthesis of qualitative studies. BMJ
2010; 340: c112.
26. Visser A, Dijkstra GJ, Kuiper D et al. Accepting or declining dialysis: considerations taken into account by elderly patients with endstage renal disease. J Nephrol 2009; 22: 794–799.
27. Lambie M, Rayner HC, Bragg-Gresham JL et al. Starting and withdrawing haemodialysis––associations between nephrologist’s opinions,
patient characteristics and practice patterns (data from the dialysis outcomes and practice patterns study). Nephrol Dial Transplant 2006; 21:
2814–2820.
28. Jassal SV, Watson D. Dialysis in late life: benefit or burden. Clin J
Am Soc Nephrol 2009; 4: 2008–2012.
29. Di Micco L, Torraca S, Pota A et al. Setting dialysis start at 6.0 mL/
min/1.73 m2 eGFR––a study on safety, quality of life and economic
impact. Nephrol Dial Transplant 2009; 24: 3434–3440.
30. Murtagh FEM, Marsh JE, Donohoe P et al. Dialysis or not?
A comparative survival study of patients over 75 years with chronic
kidney disease stage 5. Nephrol Dial Transplant 2007; 22:
1955–1962.
31. Smith C, Da Silva-Gane M, Chandna S et al. Choosing not to
dialyse: evaluation of planned non-dialytic management in a cohort
of patients with end-stage renal failure. Nephron Clin Pract 2003;
95: c40–c46.
32. Carson RC, Juszczak M, Davenport A et al. Is maximum conservative management an equivalent treatment option to dialysis for
elderly patients with significant comorbid disease? Clin J Am Soc
Nephrol 2009; 4: 1611–1619.
33. Chandna SM, Da Silva-Gane M, Marshall C et al. Survival of
elderly patients with stage 5 CKD: comparison of conservative management and renal replacement therapy. Nephrol Dial Transplant
2011; 26: 1608–1614.
34. Brunori G, Viola BF, Parrinello G et al. Efficacy and safety of a
very-low-protein diet when postponing dialysis in the elderly: a prospective randomized multicenter controlled study. Am J Kidney Dis
2007; 49: 569–580.
35. Renal Physicians Association. Shared Decision-Making in the
Appropriate Initiation of and Withdrawal from Dialysis. Clinical
Practice Guideline. 2nd edn. Rockville, ML: Renal Physicians
Association, 2010.
36. Kitahata MM, Gange SJ, Abraham AG et al. Effect of early versus
deferred antiretroviral therapy for HIV on survival. N Engl J Med
2009; 360: 1815–1826.
37. HIV-CAUSAL Collaboration. When to initiate combined antiretroviral therapy to reduce mortality and AIDS-defining illness in HIVinfected persons in developed countries: an observational study. Ann
Intern Med 2011; 154: 509–515.
Received for publication: 31.12.11; Accepted in revised form: 19.5.12