Nephrology Dialysis Transplantation 2008 23(4):1092-1095; doi:10.1093/ndt/gfn028
© The Author [2008]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org
Fact or fiction of the epidemic of chronic kidney disease—let us not squabble about estimated GFR only, but also focus on albuminuria
Paul E. de Jong and
Ron T. Gansevoort
Division of Nephrology, Department of Medicine, University Medical Centre Groningen, University of Groningen, Groningen, The Netherlands
Paul E. de Jong, Division of Nephrology, Department of Medicine, University Medical Centre Groningen, University of Groningen, Hanzeplein 1, 9713 EZ Groningen, The Netherlands. Tel: +31-50-3613434; Fax: +31-50-3619310; E-mail: p.e.de.jong{at}int.umcg.nl
Keywords: albuminuria; chronic kidney disease; glomerular filtration rate; proteinuria; screening
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Introduction
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In this issue of the journal, Glassock and Winearls question
the need to conclude that there is an epidemic of chronic kidney
disease (CKD) [
1], while Coresh
et al. emphasize in their response
that there definitely is a need to study glomerular filtration
rate (GFR) estimates [
2]. This is an important debate since
after the publication of the KDOQI guidelines on the classification
of CKD in 2002, many programs have been started to screen subjects
for CKD, in an attempt towards preventing complications in the
subjects involved. In this respect, it is important to note
that CKD is not only associated with an enhanced risk of developing
ESRD, but also with an increased risk of cardiovascular events
[
3].
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The definition of the five stages of chronic kidney disease
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The detection of subjects with CKD is facilitated by clear definitions
on what we should screen for and who we should screen. For this
purpose, the KDOQI classification has a great value. This classification
is based upon two manifestations of renal damage: first, the
presence of either micro- and macro-albuminuria, erythrocyturia
or abnormalities on renal ultrasound and second, an impaired
eGFR [
4]. In fact, an impaired eGFR is the only characteristic
needed to define a subject as having a stage 3, 4 or 5 CKD (eGFR
30–59, 15–29 or <15 ml/min/1.73 m
2, respectively).
The presence of other signs of renal damage is not required
for the definition of stages 3–5. These are mandatory
for the definition of the stage 1 and 2 CKD, while measurement
of the eGFR in these earlier stages is required only to distinguish
between stages 1 and 2 (increased albuminuria, erythrocyturia
or abnormal ultrasound, together with the eGFR >90 or 60–
89 ml/min/1.73 m
2, respectively).
For assessing renal damage besides an impaired eGFR, most surveys use a well-defined measure of micro-albuminuria [5–8] or dipstick-positive proteinuria [9–11]. A dipstick test is easy to apply and cheap. Many patients with dipstick positivity appear to have micro-albuminuria during confirmation. Of the subjects that were trace, 1+ or 2+ positive on a protein dipstick, 61, 71 and 41% had micro-albuminuria, whereas only 1, 7 and 50% had macro-albuminuria, thus showing that the submaximal categories of dipstick positivity are more indicative of micro- than macro-albuminuria [12]. However, these data also show that dipsticks are often false positive, limiting their applicability for screening purposes. In this respect, it seems more prudent for population screening to use a quantitative and more accurate measurement of urinary albumin by nephelometry in a laboratory or a point-of-care device [13].
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The risks associated with elevated albuminuria and impaired GFR
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Interestingly, micro-albuminuria, similar to an impaired GFR,
has been found to be associated with an increased risk for cardiovascular
events [
14,15]. This risk is independent of the risk induced
by an impaired GFR [
8,
10]. In this respect, it is disappointing
that both papers on the pro-con debate in this journal only
focus on the impact of a correct eGFR measurement for the definition
of CKD, thus limiting the discussion to CKD stages 3–5
[
1,2]. Remarkably, in the paper by Coresh
et al., the importance
of micro-albuminuria or proteinuria in the CKD definition is
acknowledged only by arguing that papers are being published
on this topic [
2]. They then refer to two papers that are in
press in late 2007 or early 2008, but do not discuss the numerous
papers that have been published on this topic in the last decade
and have recently been reviewed [
16]. The pro-con debate, as
it now stands, thus mainly discusses the pros and cons of taking
care of stage 3 CKD patients. It is emphasized by Glassock and
Winearls that the female to male ratio of stage 3 patients is
1.75:1, while the opposite is seen in treated ESRD (0.6:1),
suggesting that the definition of stage 3 patients is not appropriate
[
1]. It has also been shown that most of the patients with an
impaired GFR have fairly stable renal function during follow-up
[
17]. It is thus not unexpected that Glassock and Winearls question
whether we should redefine stage 3 CKD. They propose a lower
cut-off value for defining CKD in the absence of other signs
of kidney damage (such as micro- and macro-albuminuria), for
example an eGFR of <45 ml/min/1.73 m
2, or to use age- and
sex-specific normal values [
1]. The latter, however, may make
implementation of guidelines more difficult. Interestingly,
US data show that only 24% of the individuals classified as
having stage 3 CKD had micro- or macro-albuminuria [
18]. This
is fairly comparable to the 18% in the European PREVEND study.
In the PREVEND cohort, moreover, only 4% of the stage 3 CKD
subjects had a GFR of 30–44 ml/min/1.73 m
2 (van der Velde,
personal communication). Taking these data together, it is desirable
to reconsider the present definition for stage 3 CKD. We suggest
more to focus on the micro- and macro-albuminuric subjects.
With respect to subjects without micro- and macro-albuminuria:
we could then better focus on subjects with an eGFR in the range
of 30–44 ml/min/1.73 m
2. Such an approach will limit considerably
the number of subjects that we designate as having CKD. This
meets the concerns expressed by Glassock and Winearls that we
presently define too many subjects as having CKD. Furthermore,
as explained below, this will probably result in a better targeting
of reno- and cardio-protective efforts.
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The renal and cardiovascular risk of stages 1 and 2 versus that of stage 3
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Unfortunately, the debate on the epidemic of CKD limits itself
to the better definition of stage 3 subjects. The attention
that this debate gets entails the danger that we forget to pay
attention to stage 1 and 2 CKD patients; the patients with signs
of renal damage, but with still normal or only modestly impaired
eGFR. As we lack an optimal measure for renal function in this
higher eGFR range, it is questionable whether there is a real
need to know exactly whether a subject has CKD stage 1 or 2.
It has been shown that the incidence rate of a new CV event
was equally increased in stage 1 and 2 CKD patients (21 per
1000 person years) and stage 3 CKD patients (21 per 1000 person
years), compared to the normal population (7 per 1000 person
years). The same held true for developing a renal event (defined
as need for renal replacement therapy): 0.5 per 1000 person
years in stage 1 and 2 and 0.8 in stage 3 CKD compared to 0.02
in the normal population [
19]. Some studies evaluated the risks
of elevated albuminuria and impaired GFR separately. Both in
a study in subjects with pre-existing coronary heart disease
[
10] as in a general population cohort [
8], the risk of developing
a CV event is higher in stage 1 and 2 subjects (GFR > 60,
but micro- and macro-albuminuria positive) than in subjects
without CKD (GFR > 60, Alb–) (
Figure 1). Interestingly,
however, the risk was not increased in subjects with stage 3
CKD without increased albuminuria (GFR < 60, Alb–).
Only in stage 3 CKD subjects with albuminuria (GFR < 60,
Alb+) was the CV risk elevated (see
Figure 1) [
8,
10]. In the
MRFIT study it was similarly shown that the risk of developing
a renal event (the need to start renal replacement therapy)
was elevated
12-fold in stage 1 and 2 subjects with micro-albuminuria
as compared to subjects with no CKD (
Figure 2), while the risk
was only increased 2.4-fold in stage 3 subjects who did not
have micro-albuminuria. The increase was most pronounced in
stage 3 subjects with micro-albuminuria: 33-fold [
11]!
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Fig. 1 The age- and sex-adjusted hazard ratio (HR) for the development of a cardiovascular event in the 4098 participants of the Cholesterol and Recurrent Events Trial (left panel) (10) and in the 2966 subjects of the Framingham Offspring Cohort (right panel) (8). In the CARE trial, subjects are divided into groups with an estimated GFR above or below 60 ml/min/1.73 m2, while in the Framingham cohort a cut-off value of 59 ml/min/1.73 m2 for women and 64 for men was used. In the CARE study, albuminuria was defined as positive in the case of one or more positive on dipstick tests, while this was measured by an albumin creatinine ratio in the Framingham cohort and was considered positive when >30 mg/g. In both studies, the HR of the GFR >60 ml/min/1.73 m2 and albuminuria-negative group is used as a reference value.
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Fig. 2 The hazard ratio in a fully adjusted model for the development of end-stage renal disease in the 12 866 men participating in the Multiple Risk Factor Intervention Trial (MRFIT) (ref 11). Estimated GFR values are divided into groups of >75, 60–75 and <60 ml/min/1.73 m2. Albuminuria is defined as negative in the case of a negative or trace-positive dipstick test, and as positive when two or more are positive. The HR of the GFR >75 ml/min/1.73 m2 and albuminuria-negative group is used as a reference value. Note that data are presented on a log scale. * Statistically significantly different from GFR >75 and Alb-group.
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Screening only for an impaired GFR or also for elevated albuminuria?
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These data emphasize that it is prudent to look not only for
the level of an eGFR, but at least as important, also for the
presence of micro- or macro-albuminuria. We recently discussed
the differences in approach to screen for CKD in various parts
of the world [
19]. Some favour targeted screening, that is,
a screening of specific groups such as subjects with known diabetes
or with hypertension, or the elderly. This option has been argued
to be more cost-effective [
20,21]. This, however, is dependent
on the expected number of diabetic and hypertensive subjects
in a population, which is different in various parts of the
world. Moreover, we should realize that for every subject with
known hypertension or diabetes, there is one subject in the
population in which this diagnosis has not yet been made, but
who can have already considerable associated end-organ damage
[
22,23]. It has even been shown that the presence of micro-albuminuria
may even precede the diagnosis of hypertension [
24] and diabetes
[
25]. Finally, subjects with known diabetes or hypertension
frequently are already instituted on renoprotective and cardioprotective
regimens. Lastly, it is important to realize that when we focus
screening on these target groups, we most likely will have to
screen >50% of the population.
Another approach has been advocated in the UK [17,26,27]. These studies used centralized laboratory databases to select subjects with an eGFR <60 ml/min/ 1.73 m2. This database approach offers the advantage that we may limit the screening especially to those with a repeated measure of an impaired eGFR, to be sure it is a chronic problem. Another advantage of this approach is that one may limit more precise measurements of CV and renal risk factors to the less than 5% of the population that has an impaired GFR. However, disadvantages of such screening on known eGFR values in databases have been extensively discussed in the paper by Glassock and Winearls [1]. Moreover, as argued above, by not screening for albuminuria we will overlook all patients with stage 1 and 2 CKD, who are at greater risk than subjects in stage 3 without micro- and macroalbuminuria.
Since there are far more subjects with elevated albuminuria than with a seriously impaired eGFR, and since most subjects with a seriously impaired eGFR have also increased albuminuria, we advocate an approach of first screening for the presence of elevated albuminuria. That can be done by a simple dipstick test as described above [9,12], with the limitation of low specificity. In the PREVEND study a more specific approach was tested. The entire adult population of the city of Groningen was invited to send by post a vial containing a sample of the first morning urine void to a central laboratory facility for precise albumin measurement by nephelometry. In this way, information on the urinary albumin concentration and albumin creatinine ratio was obtained from about half of the population [28]. The procedure of sending urine vials by post is less expensive than drawing blood for screening on an eGFR in a large number of subjects. All subjects with a urinary albumin concentration >10 mg/l were next invited for confirmation of increased albumin excretion and further evaluation of renal and CV risk factors. This approach, followed by a 4-year treatment with an ACE inhibitor in those who were found to be micro-albuminuric, was shown to be cost-effective in preventing CV events [29].
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Conclusions
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Though the KDOQI classification of CKD in stages gave an enormous
impetus to the screening of CKD, the pro-con debate in this
issue of the journal shows that there is presently an increasing
unwillingness to diagnose the many subjects with stage 3 CKD
as being at risk, especially since most do not show progressive
renal nor cardiovascular disease. We agree that there is need
to improve the definitions of stage 3 CKD. We favour doing so
by including the presence of kidney damage as manifested from
an elevated albuminuria in stage 3. We, moreover, want to emphasize
that the stage 1 and 2 patients with elevated albuminuria, but
with a (fairly) normal eGFR, have a worse prognosis than the
present stage 3 patients without elevated albuminuria. We therefore
suggest focussing the screening practice also on the measurement
of albuminuria, instead of looking only for an impaired eGFR.
Conflict of interest statement. None declared.
(See related article by Richard J. Glassock et al. An epidemic of chronic kidney disease: fact or fiction? Nephrol Dial Transplant 2008; 23: 1117–1121.)
(See related article by Josef Coresh et al. Chronic kidney disease is common: What do we do next? Nephrol Dial Transplant 2008; 23: 1122–1125.)
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Received for publication: 9. 1.08
Accepted in revised form: 16. 1.08
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Introduction
The definition of the...