Lifetime Risk of CKD: What Does It Really Mean?

Life is inherently risky. Some individuals manage to avoid the consequences of these risks over many years, whereas others are not so fortunate. The lifetime risk of dying, of course, is 100%. However, the magnitude of the risk for acquiring a diagnosis of a specific disease or groupofdiseases overa lifetime (also called cumulative incidence of diseases) varies widely according to the frequency of the disease in the population as a whole, how the occurrence of the disease is spread over the lifetime of individuals, and how the disease is defined and ascertained. For example, the lifetime risk of developing cancer is 1 in 2; however, the lifetime risk for colon cancer specifically is 1 in 21.Diseases are often defined as a departure from a reference population of normal, healthy persons; however,making such a clear separation between disease and normality is often a difficult task (1). This is especially true in the case of identifying generic CKD, because clinical manifestations often occur late and frequently not even until RRT is needed (2,3). Thus, nephrologists have come to rely heavily on biomarkers, mainly eGFR and albuminuria (or proteinuria), for definition of generic CKD (2). Although measured GFR (mGFR; by inulin, iohexol, or iothalamate clearances) is the preferred method of assessing GFR when a high degree of precision is required in a given individual or in clinical trials, an eGFR using an equation based on serum creatinine or serum cystatin C concentrations or their combination is sufficient for many clinical and nearly all epidemiologic purposes (4,5). Albuminuria (or proteinuria) can be determined by qualitative or quantitative tests on untimed or timedurine samples. Applying the results of these biomarker assessments for diagnosing CKD and thus determining risk over time is a daunting task with numerous challenges. The issue of diagnosing CKD is central to understanding results of a study of lifetime risk of developing stage 3–5 CKD in a well characterized Icelandic population of men and women reported by Inker et al. in this issue of CJASN (6). The authors prospectively followed for 25 years (from 1967 to 2005) 3888 people in Iceland. At baseline, the mean age was 4767 years, both genders were equally represented, and all participants had an eGFR (calculated by the Chronic Kidney Disease Epidemiology Collaboration equation).60 ml/min per 1.73 m2. Such a long follow-up in a large sample of patients is quite unique in the nephrologic literature. The goal of the authors was to assess the lifetime risk (cumulative incidence) of generic CKD defined as (1) an eGFR of ,60 ml/min per 1.73 m2 on two consecutive measurements [equal to that utilized by the Kidney Disease Improving Global Outcomes clinical practice guidelines (2)], (2) kidney failure treated by dialysis or transplantation, (3) one measurement of eGFR,45 ml/min per 1.73 m2 if it was the last measurement, or (4) onemeasurement of eGFR,60ml/min per 1.73m2 if the patient died before the next measurement. Albuminuria (or proteinuria) was not assessed. Obviously, the lifetime risk of generic CKD was very dependent on the definition used for CKD. For example, the risk of CKD at 20 years for a 45-year-old woman was 8.6% if CKD was defined by two consecutive measurements of eGFR,60 ml/min per 1.73 m2 or 16.8% if CKD was defined by only one measurement of eGFR ,60 ml/min per 1.73 m2 (6). Because chronicity implies a notion of time by its nature, the first CKD definition (with a second confirmatory result) seems more relevant (2). In addition, the specific threshold of eGFR used in this analysis for separating CKD from non-CKD is arbitrary and absolute, rather than stratified by age. These results need tobe contrastedwithother studies that examined lifetime risk of CKD, including retrospective, simulation models in which CKDwas defined by only one value of eGFR (7,8). In their longitudinal analysis, Inker et al. clearly demonstrated that eGFR decreased progressively with aging; unsurprisingly, the diagnosis of CKD, using a single threshold, increased with aging (6). Unfortunately, the absence of data on eGFR slopes with aging makes it difficult to compare this study with other longitudinal studies on the decline of GFR with aging (9,10). In the context of the well established GFR decline with healthy aging, the reference base of normality is also very important. Cross-sectional datawith eGFRandmGFRhave clearly shown that otherwise healthy people demonstrate a decline in GFR to values ,60 ml/min per 1.73 m2 with aging, especially in women aged .65 years (3,11–14). Thus, it is not surprising that using the definitions of Inker et al., the lifetime risk (to age 85 years) of CKD is greater in women than in men; this is the opposite of what is seen from calculations of lifetime risk of treated ESRD, inwhichmen have a greater (about 1.5-fold) risk than women (15). Although many alternative schemas for defining CKD based on eGFR are possible, one that alters the threshold based on age is both plausible and desirable (16). For example, we have proposed that an isolated GFR ,45 ml/min per 1.73 m2 (CKD stage 3B) *Department of Nephrology, Dialysis Transplantation, University of Liège, Liège, Belgium; and David Geffen School of Medicine, University of California, Los Angeles, California