The European Chronic Kidney Disease Burden Consortium

Using the chronic kidney disease (CKD) definition provided in the KDIGO practice guideline, the European CKD Burden Consortium previously found that the prevalence of CKD stage 1-5 varied considerably across Europe, ranging from 3.3% in Norway to 17.3% in Northern Germany [5, 6]. Having gotten over 260 citations, the study of Brück et al. highlights the interest in CKD prevalence estimates across Europe. The KDIGO definition has provided a way to better standardize CKD diagnoses but it also has a potential pitfall. As there is a natural decline in kidney function with increasing age, many healthy older individuals have an estimated glomerular filtration rate (eGFR) below the KDIGO CKD classification threshold of 60 ml/min/1.73m2 [4, 7] without actually having the disease and without having an increased mortality risk [8]. As the eGFR at which the mortality risk increases decreases with age [8, 9], using the current KDIGO definition may lead to an over-diagnosis of CKD in older people, which has implications for the accuracy of estimates of CKD prevalence and subsequent public health policy. To this end, Delanaye et al. have proposed an age-adapted definition to estimate CKD prevalence [4].  
We would like to perform two new studies on behalf of the European CKD Burden Consortium. The results of the first study on eGFR reference values in healthy adults are needed to carry out analyses in the second study on the use of age-adapted definitions to estimate the prevalence of CKD. We will describe the content and rationale of these studies in more detail below. 
Study 1: eGFR reference values in healthy adults across Europe
There are challenges in comparing eGFR reference values across European countries due to variations across studies, such as measuring methods, ‘healthy’ individual definitions, and age range used. There are also inconsistent findings among studies. For example, studies of healthy populations have found eGFR to decline only after the age of 40 [10], eGFR to decline steadily with a more severe decline after the age of 50 [11], or eGFR to decline steadily with no change in slope across ages and no difference according to sex [12]. Melsom et al. found men to have a steeper decline in measured GFR (mGFR) compared to women and the presence of comorbidities or CKD risk factors to increase the rate of decline to the same extent in men and women [13].
The paper by Eriksen et al. best exemplifies the use of multiple studies to describe the trajectory of mGFR by age (in individuals above 50 years old ) and by sex in healthy European adults [7]. Ideally, a continuous age-adapted mGFR threshold should be created from mGFR reference values available for adults 20 years or older, preferably through clearance studies using isotopes. As the availability of such measurements is scarce, an alternative would be to use eGFR  (using the CKD-EPI 2009 equation), and accept this measurement bias in exchange for a better coverage across Europe and improved generalizability as the bias between eGFR and mGFR is seemingly small [7]. Once described, eGFR reference values can be used for the continuous age-adapted definitions to estimate CKD prevalence as described below. 
Study 2: Age-adapted definitions for CKD prevalence
Delanaye et al. have proposed an age-adapted definition using the eGFR thresholds of <75 ml/min per 1.73 m2 for individuals aged below 40 years, <60 ml/min per 1.73 m2 for those aged between 40 and 65 years, and <45 ml/min per 1.73 m2 for individuals aged above 65 years [4]. Only few publications have explored the prevalence of CKD using an age-adapted definition [14, 15]. Jonsson et al. recently found that in comparison to the KDIGO definition, the age-adapted definition resulted in a lower estimate of CKD prevalence in men (1.9% vs 3.9%) and women (2.8% vs 5.5%) with the largest decrease in CKD prevalence estimated in individuals over 65 years old [14]. 
While these suggested new thresholds incorporate age into the CKD diagnosis, an individual’s CKD status may change when the individual ages into the next age category without a change in their eGFR [16]. For example, a 65 year old with a persistant eGFR of 55 ml/min/1.73m2 might be diagnosed with CKD, but upon turning 66 years old the individual would no longer fulfill the criteria for a CKD diagnosis. An alternative to the categorical age-adapted definition could be a continuous age-adapted definition for eGFR. Creating these continous thresholds would require eGFR reference values in healthy (non-diseased) individuals from the general population across an entire adult age range. 
The use of a continuous age threshold would account for trends in kidney function decline by age and sex using eGFR thresholds derived from a percentile of the eGFR reference values. A threshold of an eGFR in the 5th percentile may be an appropriate threshold, as studies have shown that compared to individuals with an eGFR within the 5th-95th percentile, individuals with an eGFR in the 5th percentile have higher risks of cardiovascular events [17] and mortality [18]. Other thresholds may be considered.  
Providing comparable CKD prevalence estimates from European populations using KDIGO, categorical age-adapted, and continuous age-adapted definitions would provide an insight into the differences, feasibility, and ease of implementation of these various definitions used to estimate CKD prevalence. This study may spark conversations on the use of age-adapted definitions and inspire further research assessing the use and outcomes of age-adapted definitions in CKD prevalence estimates.