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 ]. 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 ]. 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. 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 ]! 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 m 2 , while in the Framingham cohort a cut-off value of 59 ml/min/1.73 m 2 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 m 2 and albuminuria-negative group is used as a reference value. 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 m 2 . 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 m 2 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. 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 m 2 . 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 ]. 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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Jong et al. (2007) studied this question.