A Rebuttal to “The CKD Classification System in the Precision Medicine Era”

Introduction We were surprised to read the recent Clinical Journal of the American Society of Nephrology commentary by Hall and Himmelfarb (1), “The CKD classification system in the precision medicine era,” in which they conclude that “the current CKD classification system is antithetical to the Precision Medicine Initiative.” We believe that this viewpoint reflects misunderstandings and misrepresentations of the current guidelines. Instead, we contend that the current classification provides the foundation on which further refinements achieved by precision medicine should build (2). We are pleased that Hall and Himmelfarb (1) acknowledge that the CKD guidelines have provided a common language to relieve confusion (3), enabled description of disease burden (4), and promoted physician, patient, and public awareness. We agree that there are shortcomings of the classification system and that the discipline of nephrology has far to go to realize the potential benefits of precision medicine that have already begun to accrue in other disciplines, such as oncology. However, we disagree that the classification system fosters imprecision, fails to take into account individual variability, and limits training and innovation. Guidelines are not meant to substitute for clinical expertise and judgment. We would contend that poor implementation of the CKD classification system leads to oversimplification of the complexity in caring for patients with CKD and creates the problems that Hall and Himmelfarb (1) describe, not the classification system itself. Hall and Himmelfarb (1) characterize the current CKD guidelines as “lumping all kidney diseases together irrespective of etiology.” This is not correct. The guidelines recommend definition on the basis of abnormalities in structure and function; classification on the basis of cause of kidney disease (etiology), GFR, and albuminuria (Cause, GFR, Albuminuria [CGA]); and quantitative estimates of prognosis on the basis of CGA and other risk factors and comorbid conditions (5). The guidelines acknowledge that “CKD is a general term for heterogeneous disorders affecting kidney structure and function with variable clinical presentation, in part related to cause, severity and the rate of progression.” Indeed, CKD can vary in severity—from mild, requiring little intervention other than changes in drug dosing, to severe, requiring preparation for kidney replacement therapy. Recognizing this individual variation and the factors responsible for it is the aim of the CKD classification system as well as the Precision Medicine Initiative. Ignoring cause in the assessment and management of CKD is a failure of implementation of the guidelines, not of the guidelines themselves. What the Guidelines Recommend The 2012 Kidney Disease Improving Global Outcomes (KDIGO) Guidelines represent an update of the 2002 Kidney Disease Outcomes Quality Initiative Guidelines (5). The Guidelines contain five chapters. Chapter 1 describes the CKD definition, CGA classification, predicting prognosis, and evaluation. In particular, the description of the evaluation of cause of disease contrasts sharply with the reductionist approach described by Hall and Himmelfarb (1). The guidelines state that “CKD is not a diagnosis in and of itself, and that the assignment of cause is important for prognostication and treatment.” They recommend evaluation of the clinical context, including personal and family history, social and environmental factors, medications, physical examination, laboratory measures, imaging, and pathologic diagnosis, to determine the causes of kidney disease. They provide examples of a classification by cause (table 4 in the guidelines) and examples of the application of KDIGO nomenclature to some common and uncommon kidney diseases in children and adults (table 8 in the guidelines). We acknowledge that the current classification on the basis of CGA may not provide sufficient information about prognosis and treatment for many diseases, but the classification system does not limit the amount of information that can be used in determining cause of disease, and it does not limit further classification by new discoveries from precision medicine. Misunderstandings and Misrepresentations Throughout the guidelines, the limitations are discussed, with suggestions of where further evidence may help to resolve controversy and debate. However, the criticisms of Hall and Himmelfarb (1) are not about evidence but rather, reflects misunderstandings and misrepresentations of the content of the guidelines. We respectfully disagree with the following contentions by Hall and Himmelfarb (1). They state, “Unfortunately, confusion and questions about the utility of the CKD classification system in caring for individual patients are growing” (1). We contend that there are no data to support this statement. There remain those who would like to see modifications to the current system. However, despite early criticism, the CKD definition and classification system and its updates have been increasingly adopted by national and international organizations for use in clinical practice, research, and public health (6,7). They state, “Now, a deluge of ever-evolving GFR-estimating equations and conflicting declarations of the size of a CKD epidemic have confused policymakers, medical professionals, and patients alike” (1). We contend that this statement is also not evidence based. It is well accepted that estimating equations are more useful than serum creatinine alone for these purposes. Despite evolution in GFR-estimating equations, there is general agreement that the prevalence of CKD in the United States and worldwide is approximately 10%–15% of the adult population and higher in the elderly (4). They state, “In particular, the absence of age adjustments has cultivated growing frustration among clinicians about how best to advise their older patients—most with modest, stable reductions in eGFR—about their kidney disease” (1). We contend that this statement confuses diagnosis and prognosis. Like hypertension and diabetes, CKD is common in older people, but the criteria for the diagnosis of these conditions do not differ by age. As clinicians, we appreciate that the prognosis of these conditions varies substantially by age. Age is a key factor in predicting prognosis in patients with CKD (8,9). Younger age is more predictive of progression to kidney failure before death, whereas older age is more predictive of death before development of kidney failure. They state that the four hypothetical patient scenarios that they describe “would be classified as having stage 3 CKD with approximately the same eGFR” (1). We contend that this statement misrepresents the CGA classification system, which indeed captures the more detailed description of these four patients that they provide. It is disingenuous of Hall and Himmelfarb (1) to conclude from these examples that “[w]e fool ourselves by lumping these scenarios into the same disease category, and we sell ourselves short to the rest of the medical community by suggesting that care for highly complex patients can be reduced to simple one- or two-dimensional algorithms” (1). We contend that the three dimensions of cause, GFR, and albuminuria represent a minimal description and are not intended to be sufficient to guide care for complex patients. They state, “We now frequently ignore the diverse etiologies and types of kidney diseases in favor of the CKD terminology to the extent that many professionals now believe that CKD represents an actual diagnosis” (1). We contend that it is a failure of our medical education and training programs if patient presentations by trainees in an academic ambulatory clinic do not contain the information that the faculty believes are important. The guidelines do not recommend oversimplification of complex diseases. We contend that it is the responsibility of training program directors and faculty to rectify the deficiencies that Hall and Himmelfarb (1) describe. Why do Hall and Himmelfarb (1) blame the guidelines rather than encourage appropriate implementation of the guidelines in training programs? Similarly, why do they infer that guidelines are to blame for “our scientific community’s paucity of clinical trials and breakthrough studies compared with other disciplines” (1) rather than explore deeper issues that impede innovation in discovery and application in nephrology research (10)? Finally, they conclude by proposing that we “reconsider our approach” (1). What alternatives do they propose? We contend that it is potentially irresponsible to propose reconsideration of an approach with acknowledged benefits without proposing an alternative. In academic debate, it may be easier to disagree with an established idea than to propose a better alternative, but progress in medicine is not made by debates but by proposing and testing new ideas. Moving Forward We owe our patients and our colleagues more than empty debate. Hall and Himmelfarb (1) have not shown that the CKD classification system is “antithetical” to precision medicine. Instead, as in oncology, the CKD classification system provides a base on which to build from advances in precision medicine, In describing the Precision Medicine Initiative, Collins and Varmus (2) write, “Precision medicine’s more individualized, molecular approach to cancer will enrich and modify, but not replace, the successful staples of oncology—prevention, diagnostics, some screening methods, and effective treatments—while providing a strong framework for accelerating the adoption of precision medicine in other spheres.” We contend that, without the CKD classification system, we risk moving backward, sinking into the confusion that predated it and losing gains that we have achieved since then as acknowledged by Hall and Himmelfarb (1). However, instead of their lament, “[w]hether the all-encompassing term CKD now impoverishes our profession and frustrates development of a deeper understanding of kidney function in health and disease is a question that the nephrology community needs to consider” (1), we conclude that we should embrace the current classification system and move forward to prepare for further advances in our discipline. Disclosures A.S.L. was the Chair of the National Kidney Foundation Kidney Disease Outcomes Quality Initiative (NKF-KDOQI) Work Group for 2002 Guidelines and a member of the Kidney Disease Improving Global Outcomes (KDIGO) Work Group for 2012 Guidelines. A.S.L. was the Editor-in-Chief of the American Journal of Kidney Disease (2007–2016). A.L. was a member of the NKF-KDOQI Work Group for 2002 Guidelines and the Chair of the KDIGO Work Group for 2012 Guidelines. A.L. is the immediate past President of the International Society of Nephrology (2015–2017).

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