NEPHROLOGISTS face a critical challenge

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1 Meeting the Challenges of the New K/DOQI Guidelines Garabed Eknoyan, MD Substantial gains in the dialytic treatment of patients with end-stage renal disease have been made during the past several decades. However, inadequate attention has been given to the problem of chronic kidney disease (CKD) as a whole. CKD and its associated complications emerge years before patients develop kidney failure and become dialysis dependent. It now is evident that to improve dialysis outcomes, it is essential for practitioners to recognize the earlier stages of CKD, not only to retard disease progression, but also to prevent and treat its complications and comorbidities long before the need for dialysis arises. The recently published National Kidney Foundation Kidney Disease Outcomes Quality Initiative guidelines identify the broad-based problem of CKD in the general population and introduce action plans that can be used at the different stages of CKD. This article discusses the process behind the development of the CKD guidelines and highlights the disease evaluation, classification, and stratification system provided by the guidelines. It is hoped that widespread implementation of these recommendations will increase the understanding of CKD among both providers and patients and eliminate many of the obstacles that nephrologists have faced in providing optimal care to dialysis patients in particular and to patients with CKD in general. Am J Kidney Dis 41(S5):S3-S by the National Kidney Foundation, Inc. INDEX WORDS: Chronic kidney disease (CKD); end-stage renal disease (ESRD); glomerular filtration rate (GFR); clinical practice guidelines; preventive medicine. NEPHROLOGISTS face a critical challenge in the optimal management of patients on maintenance dialysis therapy. Beginning in 1945, when Kolff invented a practical artificial kidney and achieved the first successful hemodialysis in a human, 1 treatment of uremic patients has improved steadily. Survival increased sharply beginning in 1960, when Scribner devised the Teflon (DuPont, Wilmington, DE) external shunt, 2 which made chronic use of the artificial kidney feasible and changed kidney failure from a fatal to a treatable disease. Subsequent developments in technology and increased understanding of kidney failure and dialysis-associated problems have significantly improved the survival and care of patients with end-stage renal disease (ESRD). Unfortunately, the medical community has failed in the goal of achieving prolonged survival of patients with ESRD. Although hemodialysis patient mortality decreased in the late 1980s after improvements in the delivered dose of dialysis, it has stabilized and remained unacceptably high since the mid-1990s. Recent reports from the US Renal Data System, published in 2000 and encompassing 1988 through 1997, show that the first-year mortality rate is still higher than 20 deaths/100 dialysis patient-years (Fig 1). 3 More disturbing is the variation in patient survival among hemodialysis centers. Whereas some centers are performing better than the national average, other centers are experiencing annual mortality rates of approximately 30%. 3 The continuing high mortality and variations in outcomes were two of the driving forces behind the development of comprehensive clinical practice guidelines for the management of these patients. 4 The guidelines are systematically developed evidence-based statements designed to assist practitioner and patient decisions about appropriate health care for special conditions. They are not standards, which is a term with legal connotations. Rather, guidelines are designed to be tools used by two parties, the patient and the health care professional, to address special medical conditions and arrive at appropriate decisions. Apart from improving patient outcomes, a primary goal of guidelines is to reduce variability of care and provide greater uniformity in practice. The process of clinical practice guideline development by the National Kidney Foundation began in 1995 with the decision to develop different sets of guidelines under the auspices of the Dialysis Outcomes Quality Initiative (DOQI). Initial strategies were implemented to develop guidelines for dialysis adequacy, vascular access, and anemia, followed by nutrition and cardiovas- From Baylor College of Medicine, Houston, TX. Supported by an unrestricted educational grant from Watson Pharma, Inc. Address reprint requests to Garabed Eknoyan, MD, Professor of Medicine, Baylor College of Medicine, One Baylor Plaza, Houston, TX geknoyan@bcm.tmc.edu 2003 by the National Kidney Foundation, Inc /03/ $30.00/0 doi: /s (03) American Journal of Kidney Diseases, Vol 41, No 6, Suppl 5 (June), 2003: pp S3-S10 S3

2 S4 GARABED EKNOYAN Fig 1. Adjusted first-year patient death rates by treatment modality and year of incidence, 1988 to Reprinted with permission. 3 cular disease (CVD). As the DOQI process began to unfold, it became clear that to improve dialysis outcomes, it was necessary to improve the health status of patients entering a dialysis program. Stated otherwise, the focus of adequate care needed to expand beyond ESRD and address the full spectrum of chronic kidney disease (CKD). As shown in Fig 2, the complications of CKD, such as anemia, CVD, bone disease, and nutritional problems, begin years before patients present to a hemodialysis clinic, representing multiple missed opportunities for optimal intervention and improvement in outcomes. Nowhere is the need for early assessment and intervention in the care of patients with CKD more evident than in the area of CVD, which is discussed in greater detail by Dr Sarnak elsewhere in this supplement. Changes in cardiac structure related to CKD begin long before the start of hemodialysis therapy. Nearly one third of patients with only a mild reduction in kidney function (creatinine clearance, 50 to 75 ml/min [0.83 to 1.25 ml/s]) already show evidence of left ventricular hypertrophy (LVH), and the prevalence of LVH increases steadily as kidney function continues to decline, affecting approximately 75% of patients by the start of hemodialysis therapy (Fig 3). 5,6 By failing to address the problem of CVD during the course of progressive CKD, health care providers are inheriting dialysis patients who already have severe CVD. The issue of early intervention is especially critical because patients with CKD are more Fig 2. Diagram illustrating the relative points in time when problems related to CKD begin to develop. Many relevant health issues in patients with CKD, such as malnutrition, CVD, and anemia, begin to occur in the earliest stages of CKD. Failure to address these issues long before patients present for hemodialysis therapy may greatly increase the risk for adverse outcomes. Abbreviations: CRF, chronic renal failure; CRI, chronic renal insufficiency; PRF, progressive renal failure; RRT, renal replacement therapy; TX, transplant; HD, hemodialysis; PD, peritoneal dialysis; NKF-DOQI, National Kidney Foundation-Dialysis Outcomes Quality Initiative.

3 MEETING THE CHALLENGES OF THE NEW K/DOQI GUIDELINES S5 Fig 3. Prevalence of LVH by level of kidney function. LVH is already present in 30% of patients with mild renal insufficiency (creatinine clearance, 50 to 75 ml/min). To convert ml/min to ml/s multiply by Reprinted with permission. 5 likely to die of cardiovascular-related causes than of their kidney disease and long before they progress to ESRD. Secondary analysis of the data from the Hypertension Detection and Follow-Up Program showed that serum creatinine level at baseline was a major predictor of mortality during the 8-year course of the study. At 96 months, mortality in patients with a baseline serum creatinine level of 2.5 mg/dl or greater ( 221 mol/l) was greater than 50%, and these patients were significantly more likely to die of ischemic heart disease or cerebrovascular disease than of kidney disease or cancer. 7 By the same token, data from the Multiple Risk Factor Intervention Trial showed an approximately 75% increase in overall mortality of patients with kidney damage, evidenced by persistent proteinuria (positive dipstick on two occasions). 8 Patients surviving CVD who present with kidney failure for dialysis therapy already have established LVH and congestive heart failure, in addition to a host of other comorbidities. Consequently, the ability to improve survival on dialysis therapy is highly compromised. It would be simplistic, at the very least, to assume that any improvements in dialysis will alter significantly the outcome of established comorbidities. The magnitude of the problem posed by CKD can best be addressed using a public health approach to the progressive course of the disease. As shown in Fig 4, this model defines stages of CKD, as well as antecedent conditions (healthy individuals and individuals at increased risk for developing CKD) and outcomes (complications of CKD and its treatment, as well as death from any cause). 4 The model illustrates that in the general population, there is a group of individuals who are at increased risk for CKD, and early detection and risk-reduction measures can be implemented in this group. If riskreduction measures fail and patients progress to the point of kidney damage, additional interventions can be implemented, with the overall goal of preventing patients from progressing to kidney failure and death from CVD. Viewing CKD as a progressive disease that can be ameliorated or delayed, and not a disease that begins at hemodialysis, was a major paradigm shift reflected in the expansion of DOQI to encompass the entire spectrum of CKD and the change of its acronym to K/DOQI for Kidney Disease Outcomes Quality Initiative. THE GUIDELINES PROCESS The objective of the K/DOQI is to develop clinical practice guidelines for the care of all patients with CKD with scientific and methods rigor, providing a rational and evidentiary basis for each guideline. The work groups for each set Fig 4. Stages in progression of CKD and therapeutic strategies. Reprinted with permission. 4

4 S6 of guidelines are multidisciplinary and are overseen by an advisory board. The work groups operate independently and have responsibility for ultimate decision making. All guidelines are based on a structured analysis of the literature. When guidelines have an evidentiary basis, they are identified as having evidence to support them; when evidence is lacking but a recommendation must still be made, the recommendation is identified as an opinion. Before finalization, guidelines are subjected to review by professionals, providers, organizations, patients, and the public. A major advantage of this open review process is that it exposes the chain of reasoning of each guideline to open debate, with the final product reflecting a broader consensus of providers and consumers. The K/DOQI guidelines for CKD were completed and published in February 2002, and one for dyslipidemias was published in April Another for bone disease is anticipated for publication by mid- to late Additional guidelines are being developed for blood pressure management, CVD in dialysis, and kidney biopsy. After each set of guidelines is issued, an update is anticipated every 2 to 3 years. CKD GUIDELINES The work group charged with the development of the CKD guidelines was a multidisciplinary body consisting of experts in nephrology, pediatric nephrology, epidemiology, laboratory medicine, nutrition, social work, gerontology, GARABED EKNOYAN and family medicine. An evidence review team was responsible for assembling the evidence. Goals of the CKD Work Group were to define and classify the stages of CKD, irrespective of underlying causes of kidney disease; evaluate laboratory measurements for the clinical assessment of kidney disease; associate the level of kidney function with complications of CKD; and stratify the risk for loss of kidney function and development of CVD. 4 Classification of the stages of CKD was a primary goal because of the wide variety of terms used to define kidney disease. An examination of abstracts from the Meetings of the American Society of Nephrology from 1998 and 1999 found no less than two dozen terms that were used to describe states of reduced glomerular filtration rate (GFR), including chronic renal failure, chronic renal insufficiency, renal dysfunction, preuremia, renal failure, predialysis, and chronic renal disease. 9 A search of abstracts on chronic renal failure found that a wide range of terms associated with kidney function were included under this rubric, including differing serum creatinine level ranges and levels of creatinine clearance or just plain uremia, dialysis, and predialysis. 9 Clearly, there is a need to develop uniformity of terms, not only to enhance research efforts, but also to improve communication among clinical care providers and arrive at a consistent definition of CKD that the public can understand. For this reason, a decision was made to use the word kidney instead of renal in the Fig 5. Correlation of GFR with (A) creatinine clearance and (B) MDRD Study equation. Reprinted with permission. 10

5 MEETING THE CHALLENGES OF THE NEW K/DOQI GUIDELINES S7 Fig 6. Serum creatinine levels versus GFRs in 171 patients with glomerular disease. Solid circles joined by continuous line represent the hypothetical relationship between GFR and serum creatinine level when creatinine is excreted solely by glomerular filtration. The broken horizontal line represents the upper limit of normal for serum creatinine level in the laboratory that conducted the test (1.4 mg/dl [124 mol/l]). To convert mg/dl to mol/l, multiply by Reprinted with permission. 14 CKD guidelines to enhance communication with patients, their families, providers, legislators, and other health care professionals. 4 Two factors were used to determine the presence of CKD and stage of disease: the presence of kidney damage and level of kidney function. Based on these two factors, the guidelines recommend that the presence of CKD be established based on the presence of kidney damage and level of kidney function, determined by GFR, irrespective of diagnosis. In addition, among patients with CKD, the stage of disease should be assigned based on level of kidney function, determined by the GFR. 4 GFR was specifically chosen to classify CKD severity for a number of reasons. First, GFR is accepted as the best overall measure of kidney function in health and disease. It is an easy concept to learn because the public understands that the kidney is like a filter and allows for the ultimate expression of the complex functions of the kidney in a single number. Use of GFR values also can encourage the public and patients to know their number, in much the same way that they have become familiar with their blood pressure or cholesterol measurements. The guidelines specifically recommend that GFR be estimated from prediction equations that take into account serum creatinine concentration and some or all of the following variables: age, sex, race, and body size. In adults, the Modification of Diet in Renal Disease (MDRD) Study equation 10 and the Cockcroft-Gault equation 11 were recommended, whereas in children, the Schwartz formula 12 and Counahan-Barratt equation 13 were recommended. Although the most widely used measure of kidney function is serum creatinine concentration, this measure alone does not provide a sufficiently accurate assessment of the actual level of kidney function. Use of 24- hour creatinine clearance, although more accurate than just serum creatinine level, is still less than ideal, fraught with collection errors and highly inconvenient, if not punitive, for the patient. Actually, the MDRD Study equation shows a tighter correlation with measured GFR than 24-hour creatinine clearance (Fig 5). 10 Research also has shown that use of serum creatinine level alone results in gross and unpredictable overestimates of kidney function (Fig 6), 14 because some patients maintain seemingly normal creatinine levels (eg, 1.3 mg/dl [115 mol/l]) despite declining GFRs. Relying solely on serum creati- Table 1. Definition of CKD Criteria Kidney damage for 3 months, defined by structural or functional abnormalities of the kidney with or without decreased GFR, manifest by either Pathological abnormalities Markers of kidney damage, including abnormalities in the composition of blood or urine or abnormalities in imaging tests GFR 60 ml/min/1.73 m 2 for 3 months, with or without kidney damage Reprinted with permission. 4

6 S8 GARABED EKNOYAN Table 2. Definition and Stages of CKD With Kidney Damage Without Kidney Damage GFR (ml/min/1.73 m 2 ) With HBP Without HBP With HBP Without HBP Increased BP Normal Increased BP decreased GFR Decreased GFR* or dialysis NOTE. Numbers represent CKD stages. Markers of kidney damage include pathological abnormalities or abnormalities in blood or urine test results or imaging studies. High blood pressure is defined as greater than 140/90 mm Hg in adults and greater than the 90th percentile for height and sex in children. Abbreviation: HBP, high blood pressure. *May be normal for age. Reprinted with permission. 4 nine level can mask significantly reduced kidney function in many cases. Using the presence of kidney damage and level of kidney function, the Work Group arrived at the definition of CKD in Table 1. 4 CKD can be identified by either damage to the kidney or abnormal GFR; either factor, when present, should prompt the provider to make a diagnosis of CKD. Using these two factors, the Work Group developed five stages of CKD (Table 2). 4 Stages 1 and 2 include patients with evidence of damage to the kidney (eg, proteinuria, structural changes on biopsy, or cysts on ultrasound), but with a normal GFR. After GFR decreases to less than 60 ml/min/1.73 m 2, the patient is classified as having CKD regardless of evidence of kidney damage. Classifying CKD according to these stages highlights the magnitude of the problem of the disease in the United States. Under these guidelines, approximately 20 million persons in the United States are in stages 1 through 4 of CKD, far more than the 300,000 hemodialysis patients who have heretofore been addressed. Because of the need for intervention at every stage of the disease, the guidelines provide an action plan for all five disease stages (Table 3). 4 Early stages of CKD primarily involve detection and CKD risk reduction, along with the treatment of comorbid conditions. As stage of CKD increases, the number of interventions increases to include an estimation of the degree of progression, evaluation and treatment of complications, and preparation of the patient for replacement therapy. GUIDELINES FOR CKD COMPLICATIONS Most of the CKD guidelines encompass classification, evaluation, and stratification of risk. However, many of the guidelines also focus on complications of CKD in adults, including hyper- Table 3. CKD: A Clinical Action Plan Stage Description GFR (ml/min/1.73 m 2 ) Action* At increased risk 90 (with CKD risk factors) Screening, CKD risk reduction 1 Kidney damage with normal or increased GFR 90 Diagnosis and treatment, treatment of comorbid conditions, slowing progression, CVD risk reduction 2 Kidney damage with mild Estimating progression decrease in GFR 3 Moderate decrease in GFR Evaluating and treating complications 4 Severe decrease in GFR Preparation for kidney replacement therapy 5 Kidney failure 15 (or dialysis) Replacement (if uremia present) *Each action plan includes action from the preceding stages. Reprinted with permission. 4

7 MEETING THE CHALLENGES OF THE NEW K/DOQI GUIDELINES S9 Fig 7. Prevalence of hypertension stratified according to GFR in the NHANES III population. Abbreviation: SBP, systolic blood pressure. 4 tension; anemia; nutrition; abnormalities of bone, calcium, and phosphorus; neurological changes; and functional well-being. 4 Each of these complications shows a substantial association with level of kidney function. Data from the Third National Health and Nutrition Examination Survey (NHANES III) show a significant association between increasing blood pressure and decreased GFR, with the prevalence of hypertension approaching 80% in those with stage 4 CKD according to the K/DOQI guidelines (Fig 7). 4 There also is a marked increase in the presence of anemia, defined by hemoglobin level, as GFR begins to decrease to less than 60 ml/min/1.73 m Additional NHANES III data show significant nutritional impairment, shown with decreasing albumin levels in patients with a GFR less than 60 ml/min/1.73 m 2. 4 Furthermore, the risk for having more than one of these abnormalities increases with decreasing GFR. As shown in Fig 8, the likelihood of having multiple abnormalities (including hypertension, difficulties in ambulation, anemia, hypoalbuminuria, and hyperphosphatemia) increases as GFR decreases to less than 30 ml/min/ 1.73 m 2. 4 At this stage of CKD, approximately 20% of patients have three or more of these abnormalities. CONCLUSIONS Until recently, the medical community has been looking at the tip of the iceberg (ie, patients with ESRD) and has not focused adequately on patients at all levels of CKD who are at increased Fig 8. Proportion of patients by number of abnormalities (Abn) by level of GFR in the NHANES III population. 4 risk for both progression of kidney disease and cardiovascular events. As a result, health care providers have inherited dialysis patients who are at an inherent disadvantage and for whom little effective long-term interventions can be provided. Now that clinical practice guidelines have been developed, it is essential that providers use them to improve patient outcomes through recognition of CKD, vigilant monitoring, and appropriate interventions. Implementation of clinical practice guidelines is not an easy process, and there are a number of barriers to provider and patient adherence of guidelines (Table 4). 15 In the case of CKD, efforts have been limited by the asymptomatic nature of early CKD, inappropriate use of measures of kidney function, poor models of care, and limited outcomes data, as well as provider time constraints and a poor reimbursement structure. Substantial improvements have been made in the care of Table 4. Barriers to Adherence to Clinical Practice Guidelines Knowledge Lack of awareness Lack of familiarity Attitude Lack of agreement (related to lack of awareness and familiarity) Lack of outcomes Lack of motivation (inertia) Behavior (external factors) Patient: preferences, compliance Guidelines: difficult, contradictory Environmental: time, resources Legal: liability, malpractice Data from Cabana et al. 15

8 S10 GARABED EKNOYAN patients with ESRD; now it is time to make substantial improvements in the care of all individuals with CKD. REFERENCES 1. Gottschalk CW, Fellner SK: History of the science of dialysis. Am J Nephrol 17: , Blagg CR: The early years of chronic dialysis: The Seattle contribution. Am J Nephrol 19: , US Renal Data System: Excerpts from the US Renal Data System 2000 Annual Data Report: Atlas of End-Stage Renal Disease in the United States. Am J Kidney Dis 36:S1-S239, 2000 (suppl 2) 4. National Kidney Foundation: K/DOQI Clinical Practice Guidelines for Chronic Kidney Disease: Executive Summary. New York, NY, National Kidney Foundation, Levin A, Thompson CR, Ethier J, et al: Left ventricular mass index increase in early renal disease: Impact of decline in hemoglobin. Am J Kidney Dis 34: , Foley RN, Parfrey PS, Harnett JD, et al: Clinical and echocardiographic disease in patients starting end-stage renal disease therapy. Kidney Int 47: , Shulman NB, Ford CE, Hall WD, et al, for the Hypertension Detection and Follow-Up Program Cooperative Group: Prognostic value of serum creatinine and effect of treatment of hypertension on renal function: Results from the Hypertension Detection and Follow-Up Program. Hypertension 13:SI80-SI93, 1989 (suppl I) 8. Grimm RH Jr, Svendsen KH, Kasiske B, et al, for the MRFIT Research Group: Proteinuria is a risk factor for mortality over 10 years of follow-up. Kidney Int Suppl 63:S10-S14, Hsu C-Y, Chertow GM: Chronic renal confusion: Insufficiency, failure, dysfunction, or disease. Am J Kidney Dis 36: , Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D, for the Modification of Diet in Renal Disease Study Group: A more accurate method to estimate glomerular filtration rate from serum creatinine: A new prediction equation. Ann Intern Med 130: , Cockcroft DW, Gault MH: Prediction of creatinine clearance from serum creatinine. Nephron 16:31-41, Schwartz GJ, Haycock GB, Edelmann CM Jr, Spitzer A: A simple estimate of glomerular filtration rate in children derived from body length and plasma creatinine. Pediatrics 58: , Counahan R, Chantler C, Ghazali S, Kirkwood B, Rose F, Barratt TM: Estimation of glomerular filtration rate from plasma creatinine concentration in children. Arch Dis Child 51: , Shemesh O, Golbetz H, Kriss JP, Myers BD: Limitations of creatinine as a filtration marker in glomerulopathic patients. Kidney Int 28: , Cabana MD, Rand CS, Powe NR, et al: Why don t physicians follow clinical practice guidelines? A framework for improvement. JAMA 282: , 1999