A Decade After the KDOQI CKD Guidelines: Impact on Research

Abstract

It is difficult to quantify impact on research, but still interesting to describe the major developments in chronic kidney disease (CKD) research during the past decade after publication of the KDOQI (Kidney Disease Outcomes Quality Initiative) clinical practice guidelines for CKD in 2002.1National Kidney FoundationK/DOQI Clinical Practice Guidelines for Chronic Kidney Disease: evaluation, classification, and stratification.Am J Kidney Dis. 2002; 39(2): S1-S266Google Scholar Standardization of terminology was one aspect that the guidelines focused on. Prior to 2000, a wide range of terminology was used (as nicely summarized in Hsu et al2Hsu C.Y. Chertow G.M. Chronic renal confusion: insufficiency, failure, dysfunction, or disease.Am J Kidney Dis. 2000; 36: 415-418Abstract Full Text Full Text PDF PubMed Scopus (114) Google Scholar), and the guidelines suggested use of the term CKD with a standardized definition and stages. Use of the term CKD in research papers increased dramatically since 2000 when the work group convened. The number of articles in the SCOPUS database retrieved by searching on CKD (June 10, 2012) increased from 188 in 2000 to 356 in 2002 and 4,035 in 2011; these are 0.7%, 1.6%, and 11.2% of all articles retrieved by searching the terms “kidney” or “renal” in these years. It is noteworthy that among the kidney/renal group of indexed articles, which includes nonhuman studies, the MDRD (Modification of Diet in Renal Disease) Study equation article for estimating glomerular filtration rate (GFR)3Levey A.S. Bosch J.P. Lewis J.B. Greene T. Rogers N. Roth D. A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation Modification of Diet in Renal Disease Study Group.Ann Intern Med. 1999; 130: 461-470Crossref PubMed Scopus (13049) Google Scholar ranks seventh by number of times cited (5,228 citations). The 2002 KDOQI CKD guidelines rank 19th (3,313 citations in SCOPUS; 6th when limited to publications since 2000). These results do not count related articles, such as the Levey et al4Levey A.S. Coresh J. Balk E. et al.National Kidney Foundation practice guidelines for chronic kidney disease: evaluation, classification, and stratification.Ann Intern Med. 2003; 139: 137-147Crossref PubMed Scopus (3687) Google Scholar article published by the Annals of Internal Medicine that summarized the guidelines, which was cited an additional 1,499 times. Notable among the other most cited articles are trials demonstrating the protective effect of angiotensin-converting enzyme (ACE) inhibitors on the kidney and the hypertension guidelines.5Brenner B.M. Cooper M.E. De Zeeuw D. et al.Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy.N Engl J Med. 2001; 345: 861-869Crossref PubMed Scopus (6180) Google Scholar, 6Lewis E.J. Hunsicker L.G. Clarke W.R. et al.Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes.N Engl J Med. 2001; 345: 851-860Crossref PubMed Scopus (5064) Google Scholar, 7Chobanian A.V. Bakris G.L. Black H.R. et al.The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: The JNC 7 Report.JAMA. 2003; 289: 2560-2572Crossref PubMed Scopus (16597) Google Scholar Recognizing the limitations of counting citations, my interpretation is that the KDOQI CKD guidelines were among the most influential publications in nephrology during the past decade. The main message of the guidelines can be simplified as follows: CKD is common, underdiagnosed, and treatable. This 3-part message is useful for outlining areas of research progress during the past decade, although the guidelines contain so much more. The guidelines quantified the prevalence of all stages of CKD in the United States, extending the US Renal Data System work of quantifying treated end-stage renal disease (ESRD). The inclusion of epidemiologists on the guidelines work group meant that the work group was informed by the quantitative implications of decisions about definitions and stages of CKD. Prevalence estimates for the United States were included in the guidelines in 2002 even before they were fully detailed separately in 20048Coresh J. Astor B.C. Greene T. Eknoyan G. Levey A.S. Prevalence of chronic kidney disease and decreased kidney function in the adult US population: Third National Health and Nutrition Examination Survey.Am J Kidney Dis. 2003; 41: 1-12Abstract Full Text Full Text PDF PubMed Scopus (2307) Google Scholar and updated in 2007.9Coresh J. Selvin E. Stevens L.A. et al.Prevalence of chronic kidney disease in the United States.JAMA. 2007; 298: 2038-2047Crossref PubMed Scopus (3899) Google Scholar Prevalence estimates relied on systematic calibration of serum creatinine, which was known to be problematic but tackled in force only after the guidelines and key articles pointed out its importance.10Coresh J. Astor B.C. McQuillan G. et al.Calibration and random variation of the serum creatinine assay as critical elements of using equations to estimate glomerular filtration rate.Am J Kidney Dis. 2002; 39: 920-929Abstract Full Text Full Text PDF PubMed Scopus (620) Google Scholar The National Kidney Disease Education Program (NKDEP) effectively worked with leaders in clinical chemistry to greatly improve the standardization of serum creatinine and implement automated reporting of estimated GFR (eGFR).11Myers G.L. Miller W.G. Coresh J. et al.Recommendations for improving serum creatinine measurement: a report from the Laboratory Working Group of the National Kidney Disease Education Program.Clin Chem. 2006; 52: 5-18Crossref PubMed Scopus (1011) Google Scholar Within a decade, nearly all serum creatinine assays were standardized to a gold-standard reference method, and 84% of 4,655 laboratories surveyed report eGFR as recommended by the NKDEP.12College of American PathologistsCurrent status of reporting estimated glomerular filtration rate (eGFR) for adults.http://www.cap.org/apps/docs/committees/chemistry/current_status_of_reporting_eGFR_2011.pdfGoogle Scholar The prevalence of CKD has been studied and shown to be high across the globe.13Levey A.S. Coresh J. Chronic kidney disease.Lancet. 2012; 379: 165-180Abstract Full Text Full Text PDF PubMed Scopus (1309) Google Scholar A global organization, KDIGO (Kidney Disease: Improving Global Outcomes), was formed and greater attention to CKD, partly due to influential concerns and criticism, led to unprecedented collaboration to address central questions. The CKD-EPI (CKD Epidemiology Collaboration) included 26 studies comprising 12,150 individuals with measured GFR to address concerns about bias in the MDRD Study equation at the higher GFR range. The new CKD-EPI equation using standardized serum creatinine to estimate GFR was published in 2009 and cited 760 times in less than 3 years!14Levey A.S. Stevens L.A. Schmid C.H. et al.A new equation to estimate glomerular filtration rate.Ann Intern Med. 2009; 150: 604-612Crossref PubMed Scopus (16218) Google Scholar Increasing recognition of the importance of serum cystatin C as a filtration marker, with demonstration of improved risk prediction spearheaded by Shlipak et al,15Shlipak M.G. Sarnak M.J. Katz R. et al.Cystatin C and the risk of death and cardiovascular events among elderly persons.N Engl J Med. 2005; 352: 2049-2060Crossref PubMed Scopus (1041) Google Scholar led to examination of population norms,16Kottgen A. Selvin E. Stevens L.A. Levey A.S. Van Lente F. Coresh J. Serum cystatin C in the United States: the Third National Health and Nutrition Examination Survey (NHANES III).Am J Kidney Dis. 2008; 51: 385-394Abstract Full Text Full Text PDF PubMed Scopus (124) Google Scholar preparation of reference material for cystatin C,17Grubb A. Blirup-Jensen S. Lindstrom V. Schmidt C. Althaus H. Zegers I. First certified reference material for cystatin C in human serum ERM-DA471/IFCC.Clin Chem Lab Med. 2010; 48: 1619-1621Crossref PubMed Google Scholar and a recently completed standardized cystatin C CKD-EPI equation for estimating GFR.18Inker L.A. Schmid C.H. Tighiouart H. et al.CKD-EPI InvestigatorsEstimating glomerular filtration rate from serum creatinine and cystatin C.N Engl J Med. 2012; 367: 20-29Crossref PubMed Scopus (2521) Google Scholar Standardized definitions of albuminuria using spot urine samples built on work in patients with diabetes and increased the emphasis of examining albuminuria and recognizing its high prevalence, as well as its strong relationship to risk despite substantial variability.19Levey A.S. de Jong P.E. Coresh J. et al.The definition, classification, and prognosis of chronic kidney disease: a KDIGO Controversies Conference report.Kidney Int. 2011; 80: 17-28Crossref PubMed Scopus (1527) Google Scholar Finally, studies have documented the low awareness of CKD, with its trends in the United States being tracked by the CKD Surveillance Program.20Tuot D.S. Plantinga L.C. Hsu C.Y. et al.Chronic kidney disease awareness among individuals with clinical markers of kidney dysfunction.Clin J Am Soc Nephrol. 2011; 6: 1838-1844Crossref PubMed Scopus (105) Google Scholar Reports on the cardiovascular risk associated with CKD,21Sarnak M.J. Levey A.S. Schoolwerth A.C. et al.Kidney disease as a risk factor for development of cardiovascular disease: a statement from the American Heart Association Councils on Kidney in Cardiovascular Disease, High Blood Pressure Research, Clinical Cardiology, and Epidemiology and Prevention.Hypertension. 2003; 42: 1050-1065Crossref PubMed Scopus (946) Google Scholar, 22Foley R.N. Parfrey P.S. Sarnak M.J. Clinical epidemiology of cardiovascular disease in chronic renal disease.Am J Kidney Dis. 1998; 32(5): S112-S119Abstract Full Text PDF Scopus (2974) Google Scholar which summarized the wealth of evidence that had accumulated in the years leading to the CKD guideline development, were highly influential. Since then, there has been a dramatic increase in the number and quality of prospective data looking at a wide range of complications of CKD. Most major cardiovascular studies examined CKD as a risk factor for cardiovascular disease (CVD), as well as for other outcomes that were measured. The National Institute of Diabetes and Digestive and Kidney Diseases funded the CRIC (Chronic Renal Insufficiency Cohort) Study, which recently showed the importance of mineral metabolism risk of mortality and ESRD.23Isakova T. Xie H. Yang W. et al.Fibroblast growth factor 23 and risks of mortality and end-stage renal disease in patients with chronic kidney disease.JAMA. 2011; 305: 2432-2439Crossref PubMed Scopus (813) Google Scholar Resourceful investigators assembled clinical populations of unprecedented size to examine risk. A Kaiser Permanente population was used to crystalize the association of eGFR with CVD risk in a million enrollees.24Go A.S. Chertow G.M. Fan D. McCulloch C.E. Hsu C.Y. Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization.N Engl J Med. 2004; 351: 1296-1305Crossref PubMed Scopus (9055) Google Scholar The Alberta Kidney Disease Network assembled data for eGFR, proteinuria, and clinical events in approximately one million province residents, producing a number of important reports.25James M.T. Hemmelgarn B.R. Wiebe N. et al.Glomerular filtration rate, proteinuria, and the incidence and consequences of acute kidney injury: a cohort study.Lancet. 2010; 376: 2096-2103Abstract Full Text Full Text PDF PubMed Scopus (243) Google Scholar, 26Hemmelgarn B.R. Zhang J. Manns B.J. et al.Nephrology visits and health care resource use before and after reporting estimated glomerular filtration rate.JAMA. 2010; 303: 1151-1158Crossref PubMed Scopus (135) Google Scholar, 27Hemmelgarn B.R. Manns B.J. Lloyd A. et al.Relation between kidney function, proteinuria, and adverse outcomes.JAMA. 2010; 303: 423-429Crossref PubMed Scopus (818) Google Scholar The number of outcomes to be examined is still being expanded. The dramatic increase in CKD prevalence with age led to a number of concerns, some of which were theoretical28Glassock R.J. Winearls C. An epidemic of chronic kidney disease: fact or fiction?.Nephrol Dial Transplant. 2008; 23: 1117-1121Crossref PubMed Scopus (176) Google Scholar and others based on the risk of ESRD decreasing among the very old.29O'Hare A.M. Choi A.I. Bertenthal D. et al.Age affects outcomes in chronic kidney disease.J Am Soc Nephrol. 2007; 18: 2758-2765Crossref PubMed Scopus (533) Google Scholar A 2009 KDIGO Controversies Conference that addressed the topics was noteworthy for a focus on summarizing nearly all prospective data on the topic as the key to moving forward. Data on more than 40 cohorts were analyzed for the meeting using a uniform analysis plan that allowed for nonlinear associations and interactions, as well as meta-analyses and meta-regressions across cohorts. Results showed impressive consistency in the importance of both eGFR and albuminuria, across the globe and different measurement methodologies, as risk factors for mortality, CVD mortality, ESRD, acute kidney injury, and CKD progression with relatively little effect modification by age dichotomized at 65 years.19Levey A.S. de Jong P.E. Coresh J. et al.The definition, classification, and prognosis of chronic kidney disease: a KDIGO Controversies Conference report.Kidney Int. 2011; 80: 17-28Crossref PubMed Scopus (1527) Google Scholar, 30Matsushita K. van der Velde M. Astor B.C. et al.Association of estimated glomerular filtration rate and albuminuria with all-cause and cardiovascular mortality in general population cohorts: a collaborative meta-analysis.Lancet. 2010; 375: 2073-2081Abstract Full Text Full Text PDF PubMed Scopus (2860) Google Scholar, 31van der Velde M. Matsushita K. Coresh J. et al.Lower estimated glomerular filtration rate and higher albuminuria are associated with all-cause and cardiovascular mortality A collaborative meta-analysis of high-risk population cohorts.Kidney Int. 2011; 79: 1341-1352Crossref PubMed Scopus (650) Google Scholar, 32Gansevoort R.T. Matsushita K. van der Velde M. et al.Lower estimated GFR and higher albuminuria are associated with adverse kidney outcomes A collaborative meta-analysis of general and high-risk population cohorts.Kidney Int. 2011; 80: 93-104Crossref PubMed Scopus (554) Google Scholar, 33Astor B.C. Matsushita K. Gansevoort R.T. et al.Lower estimated glomerular filtration rate and higher albuminuria are associated with mortality and end-stage renal disease A collaborative meta-analysis of kidney disease population cohorts.Kidney Int. 2011; 79: 1331-1340Crossref PubMed Scopus (521) Google Scholar The conference encouraged individual cohorts to increase the number of outcomes examined and work separately and with a new research group, the CKD Prognosis Consortium (CKD-PC), which continues to be productive.34Matsushita K. Tonelli M. Lloyd A. Levey A.S. Coresh J. Hemmelgarn B.R. Clinical risk implications of the CKD Epidemiology Collaboration (CKD-EPI) equation compared with the Modification of Diet in Renal Disease (MDRD) Study equation for estimated GFR.Am J Kidney Dis. 2012; 60: 241-249Abstract Full Text Full Text PDF PubMed Scopus (74) Google Scholar The 2002 CKD guidelines emphasized that benefits to the patients are the ultimate and central goals. They summarized increasing evidence that metabolic complications can be treated and adverse outcomes can be prevented or delayed. Review of treatment guidelines was left to later guidelines, but the concept that diagnosis, staging, and treatment are inextricably linked was emphasized. Clinical trial evidence was summarized recently.13Levey A.S. Coresh J. Chronic kidney disease.Lancet. 2012; 379: 165-180Abstract Full Text Full Text PDF PubMed Scopus (1309) Google Scholar ACE inhibitors and angiotensin receptor blockers are clearly effective for the treatment of CKD with proteinuria, but less effective for patients without proteinuria, whereas current anemia treatment strategies are now known not to reduce cardiovascular risk. Unfortunately, the number of trials conducted in patients with CKD has been too few. There is a need to fund such trials and avoid excluding patients with CKD from trials with other primary outcomes. It is noteworthy that SPRINT (Systolic Blood Pressure Intervention Trial, ClinicalTrials.gov identifier NCT01206062) is testing different blood pressure treatment goals, specifically oversamples patients with CKD, and includes measures of proteinuria, in marked contrast to many previous cardiovascular studies. Strategies for multidisciplinary management of CKD are being developed and evaluated, although such complex interventions are rarely tested in trials, with the notable exception of the CAN-PREVENT (Canadian Prevention of Renal and Cardiovascular Endpoints Trial) program, which showed no significant ESRD risk reduction, but showed improvements in risk-factor control and a decrease in the cost of care.35Hopkins R.B. Garg A.X. Levin A. et al.Cost-effectiveness analysis of a randomized trial comparing care models for chronic kidney disease.Clin J Am Soc Nephrol. 2011; 6: 1248-1257Crossref PubMed Scopus (44) Google Scholar, 36Barrett B.J. Garg A.X. Goeree R. et al.A nurse-coordinated model of care versus usual care for stage 3/4 chronic kidney disease in the community: a randomized controlled trial.Clin J Am Soc Nephrol. 2011; 6: 1241-1247Crossref PubMed Scopus (82) Google Scholar Lipid lowering has been examined more rigorously in a number of trials focusing on ESRD and CKD, with the largest, SHARP (Study of Heart and Renal Protection), showing protection on ischemic events.37Baigent C. Landray M.J. Reith C. et al.The effects of lowering LDL cholesterol with simvastatin plus ezetimibe in patients with chronic kidney disease (Study of Heart and Renal Protection): a randomised placebo-controlled trial.Lancet. 2011; 377: 2181-2192Abstract Full Text Full Text PDF PubMed Scopus (1898) Google Scholar Vitamin D and mineral metabolism disorders and correction strategies are drawing a great deal of interest for reduction of cardiovascular risk, but trial results are mixed.38Thadhani R. Appelbaum E. Pritchett Y. et al.Vitamin D therapy and cardiac structure and function in patients with chronic kidney disease: the PRIMO randomized controlled trial.JAMA. 2012; 307: 674-684Crossref PubMed Scopus (454) Google Scholar Reduction of inflammation through nuclear factor-kB blockade has shown promise39Pergola P.E. Raskin P. Toto R.D. et al.Bardoxolone methyl and kidney function in CKD with type 2 diabetes.N Engl J Med. 2011; 365: 327-336Crossref PubMed Scopus (715) Google Scholar and will be tested in the BEACON clinical trial (NCT01351675). In summary, the causal links between the 2002 KDOQI CKD guidelines and the many research developments in CKD during the past decade likely form a complex web that is not fully known. However, clinical research into CKD is more active than ever, with more, larger, and better conducted studies by a community with greater sophistication in clinical research methods and a willingness to work together to make improvements. What the next decade will bring is unknown, but the challenges are still great and the improved tools provided by standardized definitions, stages, and methods stimulated by clinical practice guidelines will help in making progress toward better recognition, prevention, and treatment of CKD. Financial Disclosure: Dr Coresh has consulted for Merck, Abbott, and Amgen.