Toward More Accurate Detection and Risk Stratification of Chronic Kidney Disease

Abstract

THE TERM CHRONIC KIDNEY DISEASE(CKD)WAS FIRST PROposedandsystematicallydefinedin2002,andthe5incrementalstages for thedegreeofseverityofCKDwere describedbasedontheestimatedglomerular filtration rate (GFR) (stage 1, 90; stage 2, 60-89; stage 3, 30-59; stage 4,15-29;andstage5, 15mL/min/1.73m).Stage1 is the least severeandstage5isclassifiedaskidneyfailure. Theestimated GFR (calculated from the Modification of Diet in Renal Disease [MDRD] Study equation) can be derived automatically from a single serum creatinine measurement, combined with theeasilyavailableageandsexdata,plusaqualifyingstatement on race, and without a need for patient weight. The automated estimated GFR calculation has rapidly becomearoutinecomponentofvirtually every laboratory report ofserumcreatinineconcentration.Thishasoccurredeventhough estimated GFR is not based on an accurate timed urine specimen, is only a rough estimate of a patient’s actual GFR, and is more applicable to the population than to the individual. An estimatedGFRlowerthan60mL /min/1.73m hasbeenflagged asindicatingmoderatetoseverekidneydisease andphysicians, followingtheguidelines,sometimesinformpatientsofthisfinding. The prevalence of CKD using the MDRD equation in nationally representative surveys has been estimated at 10% to 12% of the population, with CKD stage 3 (estimated GFR 3059mL/min/1.73m)comprisingthelargestcategory.Populationbasedstudieshaveconsistentlyreportedastrongandincremental association between CKD stages and risk of cardiovascular events and death, suggesting that an individual with low estimated GFR (ie, stage 3, 4, or 5) might be at increased risk. The use of the term “kidney” along with the new CKD staging and its expanded spectrum based on estimated GFR of less than 60 mL /min/1.73 m has increased awareness about and the apparent prevalence of a once underappreciated and confusingdisease state. Consequently,nephrologistshavehadan unprecedented increase in consultations to verify the diagnosis of “CKD stage 3 ” primarily because of a calculated estimatedGFRoflessthan60mL /min/1.73m.Manypatientswith thisallegeddiagnosisareanxiousuntil theyseeanephrologist, whereas thespecialist feels compelled,perhaps inpartbecause of concerns of litigation, to perform extensive and expensive workupstomoreaccuratelyassessrenal function.Someofthese patients have been stigmatized with a “preexisting condition” andhavebeendeniedinsurancecoverageuponreemployment. However, the diagnosis of stage 3 CKD for many patients cannot be substantiated other than with an estimated GFR of less than 60 mL /min/1.73 m according to the MDRD equation. Nephrologists have not adequately addressed the clinical and public health consequences of using the MDRD equation as a criterion for the detection and classification of CKD and have failed to acknowledge the many implications of the flaws in this approach. For instance, it is counterintuitive that more patients are classified as having stage 3 of a chronic disease than earlier stages, ie, stage 1 and 2 combined, in sharp contradistinction to other chronic disease states such as heart failure. The result has been that the nephrology community appears to have undermined its own important work in public health by overdiagnosing a nonexistent disease in millions of elderly persons as well as in women in whom the MDRD equation calculates a 25% worse kidney function by default, or in adults with larger muscle mass or other nutritional states associated with higher serum creatinine independent of kidney function. Use of the epidemiological classification of such an imperfect surrogate as estimated GFR does not square with the clinical reality of patient diagnosis and treatment. Many patients with so-called CKD stage 3 do not die of renal causes, and do not develop end-stage kidney disease over time, so there is a disconnect between classification based on estimated GFR equations and patients’ clinical course. At the same time, the diagnosis of true kidney disease may be missed in some persons with lower serum creatinine levels due to smaller skeletal muscle mass, low or no protein intake, or significant glomerular, tubular, or vascular kidney disease but with higher estimated GFR. As a result, and despite the overwhelming data on the association of kidney disease with cardiovascular events and death, the cardiology community has generally not considered CKD based on estimated GFR alone as a credible cardiovascular risk fac-