NDT Advance Access originally published online on June 20, 2008
Nephrology Dialysis Transplantation 2008 23(8):2698-2699; doi:10.1093/ndt/gfn335
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Reply
E-mail: p.e.de.jong{at}int.umcg.nlSir,
We have read with interest the letter by Glassock and Winnearls on the debate on the epidemic of chronic kidney disease. They propose a new classification schema defining chronic kidney disease (CKD). We are happy to read that they agree with us that elevated albuminuria should get a more pronounced role in the classification of Stage 3. They, at the same time, argue to use age- and sex-specific cut-off values for eGFR instead of the presently used fixed cut-off value of <60 ml/min/1.73 m2 to define Stage 3. In their response, they also question whether an elevated albuminuria in the absence of a decline in eGFR should be regarded as a manifestation of chronic kidney disease.
The use of age- and sex-specific cut-off values defining abnormal renal function has been proposed before [1]. This statistical definition defines ‘abnormal’ as being outside two standard deviations of the age- and gender-specific mean. This is acceptable as a simple guide to the limits of what is common, but it is the question whether it should be given too much importance, because it fixes the frequency of abnormal values at 
5%. More importantly, what is ‘common’ is not necessarily good, and what is ‘uncommon’ is not necessarily bad. For instance, the disadvantage of such an approach is that 5% of young people are also identified as suffering from CKD, whereas from a clinical point of view this is very unlikely. Another argument against introduction of a CKD classification system based on age- and sex-specific cut-off values is that it is fully based on the shared feeling that the present CKD classification is not correct for Stage 3 CKD. However, how to define the other CKD stages in this system? Logically, they should be defined likewise on age- and gender-specific cut-off values. When this approach is adopted, a CKD classification system will result that is so basically different from the present system that it will be difficult to get it accepted by the medical community. Finally, would such a modification of the current classification scheme result in a better risk prediction? As yet there are no published data that such a CKD classification system performs better with respect to cardiovascular and renal risk stratification than the present CKD classification.
What is novel in the proposal by Glassock and Winnearls is that they want to define CKD Stage 3 not only by an eGFR level below the 5th percentile adjusted for age and gender, but also ask for true evidence of kidney injury. It is expected that only about one out of the four subjects in Stage 3 CKD will have elevated levels of albuminuria, thus clearly limiting the number of subjects defined to have CKD. Again, there is as yet no evidence that these two modifications of the classification system (age- and sex-specific eGFR cut-off values in combination with albuminuria) will lead to a better cardiovascular and renal risk prediction. On the other hand, there are now various papers showing that a refinement of the present classification of subjects with CKD Stage 3 using the advocated fixed cut-off eGFR levels of <60 ml/min/1.73 m2 together with elevated albuminuria results in identification of subjects at significantly increased risk to reach CV and renal endpoints compared to Stage 3 subjects without elevated albuminuria (discussed in reference [2]).
Glassock and Winnearls next question whether microalbuminuria in the absence of an impaired eGFR (Stage 1 and 2 CKD) should be regarded as a manifestation of chronic kidney disease rather than a reflection of chronic vascular disease in which the kidneys, along with other organs, are the victim rather than the culprit. We fully agree that this latter specific question is not yet settled scientifically, and that there are arguments that microalbuminuria should be considered as a manifestation of generalized endothelial damage. Though this is an important scientific question to tackle, in our opinion there is no reason to question the validity of screening for elevated albuminuria. First, it is difficult to imagine that the kidney will excrete more albumin if the renal endothelium is not damaged in a similar way to the endothelium elsewhere in the body. In that case it is more a question of semantics if the loss of albumin is a manifestation of kidney damage or not. Second, nowadays most subjects that reach end-stage renal disease do so because of diabetes and atherosclerosis-related renal disease. Considering that the kidneys in these patients are the victim of a generalized disease instead of the culprit does, in our opinion, not imply that screening should be limited to detect only patients in which the kidney is the culprit. Third, though the reason that one presently favours screening for CKD may be interpreted to be driven by ‘claiming an epidemic’ or by ‘setting nephrology on the political agenda’, in our opinion they are initiated ‘to promote health care, in particular preventive medicine’ [3]. This is not limited only to prevent end-stage renal disease, but also aims to prevent cardiovascular events. A final reason why we feel that screening for CKD should strongly focus on elevated albuminuria is that just focusing on Stages 3–5 will have a much smaller health care impact than the detection of Stages 1 and 2. Screening is intended not only to be able to prepare the patient early enough for renal replacement therapy, but—more importantly—to start reno- and cardioprotective treatment. The latter will be more successful when started early. As illustrated in Figure 1, the start of treatment in Stages 3–5 (as has been done in most ACEi and ARB studies in patients with known kidney disease) will at best delay the progression to start of renal replacement therapy a few years. There are arguments that the earlier start (at the time of a Stage 1 or 2 CKD) will offer more benefit in the long run. For example in the IRMA trial in diabetes it has been shown that early ARB treatment will prevent the progression of Stage 1 or 2 to Stage 3 CKD [4], an approach that in the long run will be more cost saving [5].
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We therefore suggest that we, in our activities to prevent end-stage renal and cardiovascular disease, should more clearly emphasize the impact of screening for albuminuria (as a manifestation of vascular and/or renal damage) instead of primarily emphasizing the impact of the level of eGFR as an indicator of (still) functioning renal mass.
Conflict of interest statement. None declared.
1 Division of Nephrology, Department of Internal Medicine, University Medical Centre, Groningen, PO Box 30-001 Hanzeplein 1, Groningen 9713 EZ 2 Department of Nephrology, University Medical Centre, Groningen, PO Box 30-001 Groningen, 9700 RB, The Netherlands
References
- Wetzels JF, Willems HL, den Heijer M. Age and gender-specific reference values of estimated glomerular filtration rate in a Caucasian population: results of the Nijmegen Biomedical Study. Kidney Int (2008) 73:657–658.[CrossRef][Web of Science][Medline]
- de Jong PE, Gansevoort RT. Fact or fiction of the epidemic of chronic kidney disease—let us not squabble about estimated GFR only, but also focus on albuminuria. Nephrol Dial Transplant (2008) 23:1092–1095.
[Free Full Text] - de Jong PE, Van Der Velde M, Gansevoort RT, et al. Screening for chronic kidney disease: where does Europe go? Clin J Am Soc Nephrol (2008) 3:616–623.
[Abstract/Free Full Text] - Parvin HH, Lehnert H, Brochner-Mortensen J. The effect of irbesartan on the development of diabetic nephropathy in patients with type 2 diabetes. N Engl J Med (2001) 345:870–878.
[Abstract/Free Full Text] - Palmer AJ, Annemans L, Roze S, et al. Cost-effectiveness of early irbesartan treatment versus control or late irbesartan treatment in patients with type 2 diabetes, hypertension and renal disease. Diabetes Care (2004) 27:1897–1903.
[Abstract/Free Full Text]
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