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National Kidney Foundation® KDOQI® Kidney Disease Outcomes Quality Initiative KDOQI CLINICAL PRACTICE GUIDELINE FOR HEMODIALYSIS ADEQUACY: 2015 UPDATE Abstract The National Kidney Foundation's Kidney Disease Outcomes Quality Initiative (KDOQI) has provided evidence-based guidelines for all stages of chronic kidney disease (CKD) and related complications since 1997. The 2015 update of the KDOQI Clinical Practice Guideline for Hemodialysis Adequacy is intended to assist practitioners caring for patients in preparation for and during hemodialysis. The literature reviewed for this update includes clinical trials and observational studies published between 2000 and March 2014. New topics include high-frequency hemodialysis and risks; prescription flexibility in initiation timing, frequency, duration, and ultrafiltration rate; and more emphasis on volume and blood pressure control. Appraisal of the quality of the evidence and the strength of recommendations followed the Grading of Recommendation Assessment, Development, and Evaluation (GRADE) approach. Limitations of the evidence are discussed and specific suggestions are provided for future research. Keywords: Hemodialysis; Clinical Practice Guideline; hemodialysis prescription; hemodialysis frequency; initiation; adequacy; treatment time; hemofiltration; urea modeling; evidence-based recommendation; KDOQI. In citing this document, the following format should be used: National Kidney Foundation. KDOQI clinical practice guideline for hemodialysis adequacy: 2015 update. Am J Kidney Dis. 2015;66(5):884-930. Am J Kidney Dis. 2015;66(5):884-930 Work Group Membership Work Group Chairs John T. Daugirdas, MD University of Illinois College of Medicine Chicago, IL Thomas A. Depner, MD University of California, Davis Sacramento, CA Work Group Members Jula Inrig, MD, MHS Duke University Medical Center Yorba Linda, CA Rajnish Mehrotra, MD University of Washington Division of Nephrology, Harborview Medical Center Seattle, WA Michael V. Rocco, MD, MSCE Wake Forest School of Medicine Winston Salem, NC Rita S. Suri, MD, MSc, FRCPC University of Montreal Montreal, Quebec Daniel E. Weiner, MD, MS Tufts Medical Center Boston, MA Evidence Review Team University of Minnesota Department of Medicine Minneapolis VA Center for Chronic Disease Outcomes Research, Minneapolis, MN, USA Nancy Greer, PhD, Health Science Specialist Areef Ishani, MD, MS, Chief, Section of Nephrology, Associate Professor of Medicine Roderick MacDonald, MS, Senior Research Assistant Carin Olson, MD, MS, Medical Editor and Writer Indulis Rutks, BS, Trials Search Coordinator and Research Assistant Yelena Slinin, MD, MS, Assistant Professor of Medicine Timothy J. Wilt, MD, MPH, Professor of Medicine and Project Director Am J Kidney Dis. 2015;66(5):884-930 KDOQI Leadership Michael Rocco, MD, MSCE KDOQI Chair Holly Kramer, MD Vice Chair, Research Michael J. Choi, MD Vice Chair, Education Milagros Samaniego-Picota, MD Vice Chair, Policy Paul J. Scheel, MD, MBA Vice Chair, Policy KDOQI Guideline Development Staff Kerry Willis, PhD, Chief Scientific Officer Jessica Joseph, MBA, Vice President, Scientific Activities Laura Brereton, MSc, KDOQI Project Director Am J Kidney Dis. 2015;66(5):884-930 NOTICE SECTION I: USE OF THE CLINICAL PRACTICE GUIDELINE This Clinical Practice Guideline document is based upon the best information available as of June 2015. It is designed to provide information and assist decision making. It is not intended to define a standard of care, and should not be construed as one, nor should it be interpreted as prescribing an exclusive course of management. Variations in practice will inevitably and appropriately occur when clinicians take into account the needs of individual patients, available resources, and limitations unique to an institution or type of practice. Every health care professional making use of these recommendations is responsible for evaluating the appropriateness of applying them in the setting of any particular clinical situation. The recommendations for research contained within this document are general and do not imply a specific protocol. SECTION II: DISCLOSURE Kidney Disease Outcomes Quality Initiative (KDOQI) makes every effort to avoid any actual or reasonably perceived conflicts of interest that may arise as a result of an outside relationship or a personal, professional, or business interest of a member of the Work Group. All members of the Work Group are required to complete, sign, and submit a disclosure and attestation form showing all such relationships that might be perceived or actual conflicts of interest. This document is updated annually and information is adjusted accordingly. All reported information is on file at the National Kidney Foundation (NKF). Am J Kidney Dis. 2015;66(5):884-930 Table of Contents Contents Figures 889 Abbreviations and Acronyms 890 Current CKD Nomenclature Used by KDOQI 891 Executive Summary 892 Gathering the Evidence 892 Initiating HD 892 Frequency and Duration of Dialysis 892 Membranes and Hemodiafiltration Versus HD 893 Small-Solute Clearance 893 Adverse Effects of Dialysis 893 Limitations of “Adequacy” 893 Structure of the Work Group 893 Methods 893 ERT Study Selection and Outcomes of Interest 894 Guideline Statements 895 Guideline 1: Timing of Hemodialysis Initiation 896 Rationale for Guideline 1.1 896 Research Recommendations 897 Rationale for Guideline 1.2 897 Guideline 2: Frequent and Long Duration Hemodialysis 902 Background and Definitions 902 Evidence Overview 902 Rationale for Guidelines 2.1 and 2.2 903 Research Recommendations 905 Rationale for Guidelines 2.3 and 2.4 905 Research Recommendations 907 Rationale for Recommendation 2.5 907 Research Recommendations 907 Guideline 3: Measurement of Dialysis—Urea Kinetics 908 Rationale 908 Target Dose (Guideline 3.1) 908 Adjustments for Kru (Guideline 3.2) 909 HD Schedules Other Than Thrice Weekly (Guideline 3.3) 910 Limitations of the Guidelines 910 Research Recommendations 911 Appendix to Guideline 3 911 Guideline 4: Volume and Blood Pressure Control—Treatment Time And Ultrafiltration Rate ..... 913 Rationale for Guideline 4.1 913 Rationale for Guideline 4.2 914 Research Recommendations 916 Guideline 5: Hemodialysis Membranes 917 Rationale 917 Hemodiafiltration 918 Research Recommendations 918 Acknowledgements 919 Biographic and Disclosure Information 920 References 924 Am J Kidney Dis. 2015;66(5):884-930 Tables Table 1. Grade for Strength of Recommendation 895 Table 2. Summary Data From Observational Studies That Assessed the Association Between Serum Creatinine-Based Estimates of Kidney Function at the Time of Initiation of Dialysis and Risk for Death 899 Table 3. Summary Data From Observational Studies That Assessed the Association Between Measured Kidney Function at the Time of Initiation of Dialysis and Risk for Death ..... 900 Table 4. Commonly Used Validated GFR Estimating Equations in Adults 900 Table 5. Clinical Settings Affecting Creatinine Generation 901 Table 6. Descriptive Nomenclature for Various HD Prescriptions 903 Table 7. Summary: Randomized Trials of More Frequent HD 904 Table 8. Published Clinical Studies on the Effect of Lowering Dialysate Sodium on Subsequent BP 915 Figures Figure 1. Systematic errors from 2 commonly used linear formulas based on percent reduction in urea concentration. 909 Figure 2. Data from the Netherlands Cooperative Study showing a marked increase in risk of death in patients with no residual native kidney function. 910 Figure 3. Delivered dialysis doses in the HEMO Study. 912 Am J Kidney Dis. 2015;66(5):884-930 Abbreviations and Acronyms <table><tr><td>ACTIVE</td><td>Advanced Cognitive Training for Independent and Vital Elderly</td></tr><tr><td>AV</td><td>Arteriovenous</td></tr><tr><td>avCpre</td><td>Average predialysis blood urea nitrogen</td></tr><tr><td>BP</td><td>Blood pressure</td></tr><tr><td>BSA</td><td>Body surface area</td></tr><tr><td>BUN</td><td>Blood urea nitrogen</td></tr><tr><td>CANUSA</td><td>Canadian-USA Study on Adequacy of Peritoneal Dialysis</td></tr><tr><td>CI</td><td>Confidence interval</td></tr><tr><td>Ci</td><td>Dialysate inlet conductivities</td></tr><tr><td>CKD</td><td>Chronic kidney disease</td></tr><tr><td>CKD-EPI</td><td>Chronic Kidney Disease Epidemiology Collaboration</td></tr><tr><td>$ CL_{cr} $</td><td>Creatinine clearance</td></tr><tr><td>Co</td><td>Dialysate outlet conductivities</td></tr><tr><td>CV</td><td>Cardiovascular</td></tr><tr><td>D</td><td>Dialysance</td></tr><tr><td>DRIP</td><td>Dry Weight Reduction Intervention</td></tr><tr><td>ECV</td><td>Extracellular volume</td></tr><tr><td>eGFR</td><td>Estimated glomerular filtration rate</td></tr><tr><td>eKt/V</td><td>Equilibrated Kt/V</td></tr><tr><td>ERT</td><td>Evidence Review Team</td></tr><tr><td>ESA</td><td>Erythropoiesis-stimulating agent</td></tr><tr><td>ESHOL</td><td>Estudio de Supervivencia de Hemodiafiltración On-Line</td></tr><tr><td>ESRD</td><td>End-stage renal disease</td></tr><tr><td>FHN</td><td>Frequent Hemodialysis Network</td></tr><tr><td>G</td><td>Urea generation</td></tr><tr><td>GFAC</td><td>G-factor</td></tr><tr><td>GFR</td><td>Glomerular filtration rate</td></tr><tr><td>GRADE</td><td>Grading of Recommendations Assessment, Development, and Evaluation</td></tr><tr><td>HD</td><td>Hemodialysis</td></tr><tr><td>HEMO</td><td>NIH study of HD dose and membrane flux</td></tr><tr><td>HR</td><td>Hazard ratio</td></tr><tr><td>IDEAL</td><td>Initiating Dialysis Early and Late</td></tr><tr><td>KDIGO</td><td>Kidney Disease: Improving Global Outcomes</td></tr><tr><td>KDOQI</td><td>Kidney Disease Outcomes Quality Initiative</td></tr><tr><td>Kru</td><td>Residual kidney function</td></tr><tr><td>KRT</td><td>Kidney replacement therapy</td></tr><tr><td>LVH</td><td>Left ventricular hypertrophy</td></tr><tr><td>MDRD</td><td>Modification of Diet in Renal Disease</td></tr><tr><td>mGFR</td><td>Measured glomerular filtration rate</td></tr><tr><td>MPO</td><td>Membrane Permeability Outcome</td></tr><tr><td>Na</td><td>Sodium</td></tr><tr><td>NCDS</td><td>National Cooperative Dialysis Study</td></tr><tr><td>NECOSAD</td><td>Netherlands Cooperative Study on the Adequacy of Dialysis</td></tr><tr><td>NIH</td><td>National Institutes of Health</td></tr><tr><td>NKF</td><td>National Kidney Foundation</td></tr><tr><td>NS</td><td>Not specified</td></tr><tr><td>PCR</td><td>Protein catabolic rate</td></tr><tr><td>PD</td><td>Peritoneal dialysis</td></tr><tr><td>PIDI</td><td>Preceding interdialysis interval</td></tr><tr><td>Pru</td><td>Percent reduction in urea concentration</td></tr><tr><td>Qb</td><td>Blood flow rate</td></tr><tr><td>Qd</td><td>Dialysate flow rate</td></tr><tr><td>Qf</td><td>Ultrafiltration flow</td></tr><tr><td>R</td><td>Ratio of postdialysis to predialysis BUN</td></tr><tr><td>RAAS</td><td>Renin-angiotensin-aldosterone system</td></tr><tr><td>RCT</td><td>Randomized controlled trial</td></tr><tr><td>RR</td><td>Relative risk</td></tr><tr><td>SA-sdtKt/V</td><td>Surface area-adjusted standard Kt/V</td></tr><tr><td>Scr</td><td>Serum creatinine</td></tr><tr><td>Scys</td><td>Serum cystatin C</td></tr><tr><td>sp</td><td>Single-pool (Kt/V)</td></tr><tr><td>std</td><td>Standard (Kt/V)</td></tr><tr><td>T</td><td>Treatment time in hours</td></tr><tr><td>TiME</td><td>Time to Reduce Mortality in End-Stage Renal Disease trial</td></tr><tr><td>Uf</td><td>Ultrafiltration rate</td></tr><tr><td>URR</td><td>Urea reduction ratio</td></tr><tr><td>USRDS</td><td>US Renal Data System</td></tr><tr><td>V</td><td>Urea volume</td></tr></table> Am J Kidney Dis. 2015;66(5):884-930 Current CKD Nomenclature Used by KDOQI <table><tr><td>CKD Categories</td><td>Definition</td></tr><tr><td>CKD</td><td>CKD of any stage (1-5), with or without a kidney transplant, including both non-dialysis-dependent CKD (CKD 1-5ND) and dialysis-dependent CKD (CKD 5D)</td></tr><tr><td>CKD ND</td><td>Non-dialysis-dependent CKD of any stage (1-5), with or without a kidney transplant (ie, CKD excluding CKD 5D)</td></tr><tr><td>CKD T</td><td>Non-dialysis-dependent CKD of any stage (1-5) with a kidney transplant</td></tr><tr><td colspan="2">Specific CKD Stages</td></tr><tr><td>CKD 1, 2, 3, 4</td><td>Specific stages of CKD, CKD ND, or CKD T</td></tr><tr><td>CKD 3-4, etc</td><td>Range of specific stages (eg, both CKD 3 and CKD 4)</td></tr><tr><td>CKD 5D</td><td>Dialysis-dependent CKD 5</td></tr><tr><td>CKD 5HD</td><td>Hemodialysis-dependent CKD 5</td></tr><tr><td>CKD 5PD</td><td>Peritoneal dialysis-dependent CKD 5</td></tr></table> Am J Kidney Dis. 2015;66(5):884-930 AJKD KDOQI HD Adequacy Guideline: 2015 Update Executive Summary When hemodialysis (HD) was introduced as an effective workable treatment in 1943, $ ^{1} $ the outlook for patients with advancing kidney failure suddenly changed from anticipation of impending death to indefinite survival. Since then, implementation of dialysis has advanced from an intensive bedside therapy to a more streamlined treatment, sometimes self-administered in the patient's home, using modern technology that has simplified dialysis treatment by reducing the time and effort required by the patient and caregivers. Standards have been established to efficiently care for large numbers of patients with a balance of resources and patient time. However, simplified standards can lead to inadequate treatment, so guidelines have been developed to assure patients, caregivers, and financial providers that reversal of the uremic state is the best that can be offered and complications are minimized. The National Kidney Foundation (NKF) continues to sponsor this forum for collaborative decision making regarding the aspects of HD that are considered vital to achieve these goals. Over 400,000 patients are currently treated with HD in the United States, with Medicare spending approaching $90,000 per patient per year of care in 2012.$ ^{2} $ Unfortunately, although mortality rates are improving (30% decline since 1999), they remain several-fold higher than those of age-matched individuals in the general population, and patients experience an average of nearly 2 hospital admissions per year.$ ^{3} $ Interventions that can improve outcomes in dialysis are urgently needed. Attempts to improve outcomes have included initiating dialysis at higher glomerular filtration rates (GFRs), increasing dialysis frequency and/or duration, using newer membranes, and employing supplemental or alternative hemofiltration. Efforts to increase the dose of dialysis administered 3 times weekly have not improved survival, indicating that something else needs to be addressed. GATHERING THE EVIDENCE The literature reviewed for this adequacy update includes observational studies and clinical trials published from 2000 to 2014. In some cases, high-quality data have been presented to support conclusions, but in most cases, clinicians are left with incomplete or inadequate data. In these situations, as in many aspects of general medical care, decisions about treatments must be based on logic and observation. A major goal of the Work Group and Evidence Review Team (ERT) was to compile and evaluate as much information as possible to arrive at a reasonable answer to the questions posed in Box 1, not all of which can be answered definitively with support from controlled clinical trials. Initiating HD Despite lack of evidence from randomized controlled trials (RCTs) about the optimal time to start kidney replacement therapy (KRT), there has been a trend, which has leveled off since 2010, in the United States toward earlier initiation of dialysis at higher levels of kidney function. $ ^{2,3} $ If earlier dialysis is ineffective, this trend would lead to greater resource utilization without clinical benefit. Published in 2010, results of the IDEAL (Initiating Dialysis Early and Late) trial explored this issue, and data from this trial constitute the best evidence regarding timing of dialysis initiation, motivating the update of this guideline. $ ^{4} $ Frequency and Duration of Dialysis Observational and controlled nonrandomized studies had suggested that more frequent and/or longer dialysis improves the patient's quality of life, controls hyperphosphatemia, reduces hypertension, and results in regression of left ventricular hypertrophy (LVH).$ ^{5,6} $ Box 1. Questions Posed at the Start of the Update Initiative In patients with CKD, does starting dialysis earlier improve outcomes? What harms result from starting dialysis earlier? In patients with end-stage kidney disease, does more frequent hemodialysis (>3 times a week) improve outcomes compared to less frequent hemodialysis? What harms result from more frequent hemodialysis? In patients with end-stage kidney disease, does extended-duration hemodialysis improve outcomes compared to usual-length hemodialysis? What harms result from extended hemodialysis? Do patients with high interdialytic weight gains and high ultrafiltration rates have worse outcomes compared with patients with lower interdialytic weight gains and low ultrafiltration rates? Do patients with extended (longer) or more frequent hemodialysis have greater blood pressure and volume control compared with patients with shorter or less frequent dialysis? Is improvement of blood pressure and volume control associated with improved clinical outcomes according to length or frequency of dialysis sessions? In patients with stage 5 CKD, do high-flux membranes improve patient outcomes when compared to hemodialysis with low-flux membranes? In patients with stage 5 CKD, does hemodiafiltration improve patient outcomes when compared to high-flux hemodialysis? What harms result from use of high-flux membranes compared to low-flux membranes or from use of hemodiafiltration? Abbreviation: CKD, chronic kidney disease. Am J Kidney Dis. 2015;66(5):884-930 KDOQI HD Adequacy Guideline: 2015 Update AJKD Based on these findings, more frequent and longer dialysis sessions have become more common. Since the previous KDOQI (Kidney Disease Outcomes Quality Initiative) update, $ ^{7} $ several RCTs that compared more frequent or extended dialysis to conventional dialysis have been completed. $ ^{8-11} $ This update reviews this evidence. Membranes and Hemodiafiltration Versus HD Cardiovascular (CV) disease is the leading cause of death in patients with CKD stage 5, $ ^{7} $ with uremic toxins and the kidney failure milieu including volume expansion likely important contributing factors. Compared to low-flux dialysis, high-flux dialysis and convective therapies such as hemofiltration and hemodiafiltration provide higher clearance of larger solutes, removal of which might improve CV outcomes. This update reviews the evidence for use of high-flux compared to low-flux dialyzer membranes, as well as convective modes of KRT compared to conventional HD. Small-Solute Clearance This update addresses only the dialysis treatment while acknowledging that there are limits to what dialysis can accomplish. Assessment of dialysis requires measurement of the dialysis dose. Included herein are the current recommended methods for measuring what dialysis does best, the purging of small dialyzable solutes, with the assumption that this function is the essence of the life-prolonging effect of dialysis. However, while optimization of small-solute removal should be considered the first priority, assessment of dialysis adequacy should not stop there as the absence of native kidneys entails loss of many vital functions, only one of which is small-solute removal. Adverse Effects of Dialysis Early investigators postulated that exposure of the blood to a large foreign surface for several hours would cause an inflammatory response in the patient and deplete vital constituents of the blood, such as platelets and clotting factors. Removal of low-molecular-weight hormones, vitamins, and other vital molecules was also a concern. Membranes were developed to be “biocompatible,” causing less interaction with blood constituents. While the postulated depletion syndromes apparently never materialized, in recent years, concern has been raised about transient intra- and postdialysis alkalosis and dialysis-associated reductions in blood pressure (BP), serum potassium, and serum phosphorus and changes in other electrolytes and proteins that may amount to a “perfect storm” of stress potentially responsible for acute cardiac events, as well as long-term effects on the brain and CV system. $ ^{12-14} $ More frequent and more prolonged dialysis, while improving solute clearance and volume removal, could enhance blood-membrane interaction, add to the burden on patients and caregivers, $ ^{15} $ and even accelerate loss of native kidney function and vascular access damage. $ ^{16,17} $ The current guideline update includes a listing and recommendations regarding potential benefits and adverse effects associated with more frequent dialysis. Limitations of "Adequacy" The ultimate goal of treatment for patients with CKD stage 5 is improvement in quality of life, with prolongation of life often an additional goal. This requires more than the dialysis treatment itself. In recent literature, adequacy of dialysis is sometimes confused with adequacy of other aspects of patient management, with the erroneous assumption that having achieved dialysis adequacy, the goal of dialysis has been accomplished. In the opinion of the Work Group, this is incorrect: it is important to distinguish adequacy of the dialysis from adequacy of patient care. Dialysis-dependent patients require a number of treatments independent of or only partially dependent on the dialysis itself, many of which were implemented long before the patient's dialysis started. Guidelines for some of these are addressed in other publications by DQOQI, including management of anemia, nutrition, metabolic bone disease, diabetes, and CV disease.$^{18-22}$ STRUCTURE OF THE WORK GROUP The volunteer members of the Work Group were selected for their clinical experience, as well as experience with clinical trials and familiarity with the literature, especially regarding the issues surrounding dialysis adequacy. All are practicing nephrologists who have many years of experience with care of patients dependent on KRT. METHODS In consultation with the DQOQI Hemodialysis Adequacy Clinical Practice Guidelines Update Work Group, the Minnesota ERT developed and followed a standard protocol for all steps of the review process. The guideline update effort was a multidisciplinary undertaking that included input from NKF scientific staff, the ERT from the Center for Chronic Disease Outcomes Research at the Minneapolis Veterans Affairs Medical Center, and the Work Group. The comprehensive findings from the systematic literature review prepared for this update are presented in detail in the accompanying article from Slinin et al. $ ^{23} $ Briefly, MEDLINE (Ovid) was searched from 2000 to March 2014 for English-language studies in populations of all ages. Additional searches included reference lists of recent systematic reviews and studies eligible for inclusion to identify relevant studies not identified in Am J Kidney Dis. 2015;66(5):884-930 AJKD KDOQI HD Adequacy Guideline: 2015 Update Box 2. Summary of Recommendation Statements Guideline 1: Timing of Hemodialysis Initiation 1.1 Patients who reach CKD stage 4 (GFR < 30 mL/min/1.73 m$ ^{2} $), including those who have imminent need for maintenance dialysis at the time of initial assessment, should receive education about kidney failure and options for its treatment, including kidney transplantation, PD, HD in the home or in-center, and conservative treatment. Patients' family members and caregivers also should be educated about treatment choices for kidney failure. (Not Graded) 1.2 The decision to initiate maintenance dialysis in patients who choose to do so should be based primarily upon an assessment of signs and/or symptoms associated with uremia, evidence of protein-energy wasting, and the ability to safely manage metabolic abnormalities and/or volume overload with medical therapy rather than on a specific level of kidney function in the absence of such signs and symptoms. (Not Graded) Guideline 2: Frequent and Long Duration Hemodialysis In-center Frequent HD 2.1 We suggest that patients with end-stage kidney disease be offered in-center short frequent hemodialysis as an alternative to conventional in-center thrice weekly hemodialysis after considering individual patient preferences, the potential quality of life and physiological benefits, and the risks of these therapies. (2C) 2.2 We recommend that patients considering in-center short frequent hemodialysis be informed about the risks of this therapy, including a possible increase in vascular access procedures (1B) and the potential for hypotension during dialysis. (1C) Home Long HD 2.3 Consider home long hemodialysis (6-8 hours, 3 to 6 nights per week) for patients with end-stage kidney disease who prefer this therapy for lifestyle considerations. (Not Graded) 2.4 We recommend that patients considering home long frequent hemodialysis be informed about the risks of this therapy, including possible increase in vascular access complications, potential for increased caregiver burden, and accelerated decline in residual kidney function. (1C) Pregnancy 2.5 During pregnancy, women with end-stage kidney disease should receive long frequent hemodialysis either in-center or at home, depending on convenience. (Not Graded) Guideline 3: Measurement of Dialysis: Urea Kinetics 3.1 We recommend a target single pool Kt/V (spKt/V) of 1.4 per hemodialysis session for patients treated thrice weekly, with a minimum delivered spKt/V of 1.2. (1B) 3.2 In patients with significant residual native kidney function (Kru), the dose of hemodialysis may be reduced provided Kru is measured periodically to avoid inadequate dialysis. (Not Graded) 3.3 For hemodialysis schedules other than thrice weekly, we suggest a target standard Kt/V of 2.3 volumes per week with a minimum delivered dose of 2.1 using a method of calculation that includes the contributions of ultrafiltration and residual kidney function. (Not Graded) Guideline 4: Volume and Blood Pressure Control: Treatment Time and Ultrafiltration Rate 4.1 We recommend that patients with low residual kidney function (< 2 mL/min) undergoing thrice weekly hemodialysis be prescribed a bare minimum of 3 hours per session. (1D) 4.1.1 Consider additional hemodialysis sessions or longer hemodialysis treatment times for patients with large weight gains, high ultrafiltration rates, poorly controlled blood pressure, difficulty achieving dry weight, or poor metabolic control (such as hyperphosphatemia, metabolic acidosis, and/or hyperkalemia). (Not Graded) 4.2 We recommend both reducing dietary sodium intake as well as adequate sodium/water removal with hemodialysis to manage hypertension, hypervolemia, and left ventricular hypertrophy. (1B) 4.2.1 Prescribe an ultrafiltration rate for each hemodialysis session that allows for an optimal balance among achieving euvolemia, adequate blood pressure control and solute clearance, while minimizing hemodynamic instability and intradialytic symptoms. (Not Graded) Guideline 5: New Hemodialysis Membranes 5.1 We recommend the use of biocompatible, either high or low flux hemodialysis membranes for intermittent hemodialysis. (1B) MEDLINE and ClinicalTrials.gov to identify any recently completed studies. ERT Study Selection and Outcomes of Interest Studies were included if they were randomized or controlled clinical trials in people treated with, initiating, or planning to initiate maintenance HD for CKD. To be included, studies needed to report the effects of an intervention on all-cause mortality, CV mortality, myocardial infarction, stroke, all-cause hospitalization, quality of life, depression or cognitive performance, BP or BP treatment, left ventricular mass, interdialytic weight gain, dry weight, or harms or complications related to vascular access or the process of dialysis. Observational studies considered by the Work Group that were not selected by the evidence Am J Kidney Dis. 2015;66(5):884-930 KDOQI HD Adequacy Guideline: 2015 Update AJKD Table 1. Grade for Strength of Recommendation <table><tr><td rowspan="2">Gradea</td><td colspan="3">Implications</td></tr><tr><td>Patients</td><td>Clinicians</td><td>Policy</td></tr><tr><td>Level 1 (strong recommendation): “We Recommend”</td><td>Most people in your situation would want the recommended course of action and only a small proportion would not.</td><td>Most patients should receive the recommended course of action.</td><td>The recommendation can be adopted as policy in most situations.</td></tr><tr><td>Level 2 (conditional recommendation/ suggestion): “We Suggest”</td><td>The majority of people in your situation would want the recommended course of action, but many would not.</td><td>Different choices will be appropriate for different patients. Each patient needs help to arrive at a management decision consistent with her or his values and preferences.</td><td>The recommendation is likely to require substantial debate and involvement of stakeholders before policy can be determined.</td></tr></table> Based on Uhlig et al. $ ^{24} $ $ ^{a} $ The additional category “Not Graded” was used, typically to provide guidance based on common sense or where the topic does not allow adequate application of evidence. The most common examples include recommendations regarding monitoring intervals, counseling, and referral to other clinical specialists. The ungraded recommendations are generally written as simple declarative statements, but are not meant to be interpreted as being stronger recommendations than Level 1 or 2 recommendations. team and are not included in the Evidence Report by the ERT include those evaluating mortality, hard outcomes, and pregnancy-related outcomes with frequent dialysis. For frequency and duration of HD sessions, trials that assigned individuals to more frequent HD (>3 times a week) or longer (>4.5 hours) dialysis versus conventional HD were included. For studies that compared high-flux to low-flux dialysis membranes or hemofiltration or hemodiafiltration to conventional HD, the ERT included trials that enrolled at least 50 participants with a minimum of 12 months' follow-up in each treatment arm. GUIDELINE STATEMENTS The Work Group distilled these answers in the form of 5 guidelines, some of which are similar to the previous guidelines published in 2006 $ ^{7} $ but have been re-emphasized or reinterpreted in light of new data (Box 2). For each of the guidelines, the quality of the evidence and the strength of the recommendations were graded separately using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach criteria $ ^{24} $: scales of A to D for quality of the evidence and 1 or 2 for strength of the recommendation, including its potential clinical impact (Table 1; Box 3). The guideline statements were based on a consensus within the Work Group that the strength of the evidence was sufficient to make definitive statements about appropriate clinical practice. When the strength of the evidence was not sufficient to make such statements, the Work Group offered recommendations based on the best available evidence and expert opinion. In cases in which controversy exists but data are sparse, the guideline is ungraded, based on consensus opinion of the Work Group. For a few of the guidelines, not all of the Work Group members agreed, and in such cases, the reasons for disagreement are spelled out in the rationale that follows the guideline statement. For all guidelines, clinicians should be aware that circumstances may appear that would require straying from the recommendations of the Work Group. Box 3. Grade for Quality of Evidence <table><tr><td>A: High quality of evidence. We are confident that the true effect lies close to that of the estimate of the effect.</td></tr><tr><td>B: Moderate quality of evidence. The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.</td></tr><tr><td>C: Low quality of evidence. The true effect may be substantially different from the estimate of the effect.</td></tr><tr><td>D: Very low quality of evidence. The estimate of effect is very uncertain and often will be far from the truth.</td></tr></table> Am J Kidney Dis. 2015;66(5):884-930 AJKD KDOQI HD Adequacy Guideline: 2015 Update Guideline 1: Timing of Hemodialysis Initiation 1.1 Patients who reach CKD stage 4 (GFR < 30 mL/min/1.73 m$ ^{2} $), including those who have imminent need for maintenance dialysis at the time of initial assessment, should receive education about kidney failure and options for its treatment, including kidney transplantation, PD, HD in the home or in-center, and conservative treatment. Patients' family members and caregivers also should be educated about treatment choices for kidney failure. (Not Graded) 1.2 The decision to initiate maintenance dialysis in patients who choose to do so should be based primarily upon an assessment of signs and/or symptoms associated with uremia, evidence of protein-energy wasting, and the ability to safely manage metabolic abnormalities and/or volume overload with medical therapy rather than on a specific level of kidney function in the absence of such signs and symptoms. (Not Graded) RATIONALE FOR GUIDELINE 1.1 Recent KDIGO (Kidney Disease: Improving Global Outcomes) and prior KDOQI guidelines recommend referral of all individuals with GFR < 30 mL/min/1.73 m$ ^{2} $ to a nephrologist, stressing that timely nephrology referral maximizes the likelihood of adequate planning for KRT to optimize decision making and outcomes.$^{7,25,26}$ While determining the rate of progression and precise timing of referral is beyond the scope of this guideline, the implication is clear—that patients, their families, and caregivers should have ample time to make informed decisions regarding KRT and to implement these decisions successfully.$^{27}$ Multiple dialysis modalities are available for KRT, including modalities performed in the home and modalities in dialysis facilities, none of which is conclusively demonstrated to be superior to the others. $ ^{28,29} $ Additionally, conservative nondialysis care may be the appropriate decision for many older or more infirm individuals, $ ^{30} $ while pre-emptive or early transplantation may be the best for many other patients. In patients considering maintenance dialysis, it is important to acknowledge that each KRT modality adds a unique burden of treatment to the already high burden of disease. In this context, patients, their families, and their caregivers are best positioned to determine which tradeoffs they are willing to make, particularly given the lack of definitive evidence for the superiority of one dialysis modality over the other and the possibility that conservative care may be the option that best fits some individual patients' goals. Morton and colleagues$^{31}$ recently provided a thematic synthesis of 18 qualitative studies that reported the experience of 375 patients and 87 caregivers. They identified 4 major themes central to treatment choices: confronting mortality (choosing life or death, being a burden, living in limbo), lack of choice (medical decision, lack of information, constraints on resources), gaining knowledge about options (peer influence, timing of information), and weighing alternatives (maintaining lifestyle, family influence, maintaining status quo). However, none of the essential decisions can be made in an informed manner without adequate time for education and contemplation. As illustrated by Morton and colleagues' systematic review, electing conservative therapy rather than dialysis or kidney transplantation is an important option for many people with kidney failure. In one study of 584 patients with CKD stages 4 and 5, a total of $61\%$ of the patients who had started HD regretted this decision,$^{30}$ and when asked why they chose dialysis, $52\%$ attributed this decision to their physician. While this study is limited by a homogeneous population, it is apparent that education prior to dialysis regarding treatment options was insufficient in many, and that this led to dissatisfaction with KRT decisions. The limited ability of care providers to predict patient choice was illustrated by a recent study reporting on focus groups and interviews with 11 nephrologists and 29 patients older than 65 years with advanced CKD.$^{32}$ Both patients and nephrologists acknowledged that discussions about prognosis are rare and patients cope most often with their diagnosis through avoidance, while nephrologists expressed concern over evoking negative reactions if they challenge this coping strategy. The Work Group recognizes that the experiences reported in this study are not unique to these patients and physicians; accordingly, we stress the need for patient-centered education to begin early; to involve patients, their families, and their caregivers, if possible; and to be continually reinforced in a positive and patient-sensitive manner.$^{27,31}$ Further, given the high prevalence of cognitive impairment$^{33}$ and delirium$^{34}$ among patients with kidney failure, as well as acknowledged difficulties predicting the rate of progression to kidney failure among patients with advanced CKD,$^{35-38}$ it is imperative that patients' informants and proxy decision makers be involved in this decision-making process. Few clinical trials have evaluated the potential benefits of referral and education prior to the need for dialysis $ ^{39,40} $ ; accordingly, statements made on this Am J Kidney Dis. 2015;66(5):884-930 KDOQI HD Adequacy Guideline: 2015 Update AJKD topic are based on opinion and observational reports. In one US setting where predialysis education was evaluated, individuals participating in an educational program were more than 5 times more likely than patients who did not receive such education to initiate peritoneal dialysis (PD) and twice as likely to initiate HD with an arteriovenous (AV) fistula or a graft. Notably, in this observational study, the mortality rate among those participating in the educational program was half that seen in controls. $ ^{41} $ However, even with timely education, many CKD patients may not initiate dialysis with their chosen modality; the reasons for this remain uncertain. $ ^{42} $ Studies over the last 2 decades indicate that most patients starting maintenance dialysis in the United States are unaware of options for KRT other than in-center HD. $ ^{43,44} $ Despite the introduction of a Medicare benefit for CKD education over 5 years ago, $ ^{45} $ many nephrology practices have not implemented structured education programs for stage 4 CKD patients and their families $ ^{46} $ ; it is the hope of this Work Group that this gap in availability of patient education will be eventually bridged. Acknowledging that the course of many dialysis initiations may be suboptimal, quality improvement initiatives suggest that intensive education should continue even following the initiation of dialysis. $ ^{47,48} $ Guideline 1.1 specifically includes those who have an imminent need for KRT. Whenever possible, the timing of presentation should not limit the treatment options for kidney failure. Although logistically, HD is easiest to implement, PD and conservative care are important options. $ ^{27,49-51} $ In the recent Choosing Wisely campaign, the American Society of Nephrology proposed that dialysis should not be initiated without ensuring a shared decision-making process among patients, their families and caregivers, and their physicians. $ ^{52} $ In the opinion of the Work Group, this statement is appropriate for both planned and urgent dialysis initiations. The Work Group acknowledges that there is tremendous heterogeneity in kidney disease progression. There are people with CKD stage 3 who may be rapid progressors who will benefit from earlier multidisciplinary education, while there also are many people with CKD stage 4 who ultimately will not receive dialysis. Accordingly, we acknowledge that there is no perfect threshold for all patients at which multidisciplinary education and preparation for kidney failure should be initiated. For those who do not end up progressing to kidney failure, education and preparation for dialysis may result in costs and stresses that may not have otherwise been incurred; however, in generating this recommendation, the Work Group believed strongly that patient empowerment, which is enabled by providing timely knowledge both of prognosis and of treatment options followed by sufficient time and ability to assess these options, outweighed these potential disadvantages. In this context, the Work Group noted that the purpose of dialysis is not solely prolongation of life but rather promotion of living. Accordingly, it is essential that dialysis initiation or the decision to forgo KRT be an individualized process and that this process incorporates eliciting patient goals and life preferences, prognosis, and expected benefits and burdens associated with kidney failure and its treatment, followed by guidance and decision support regarding the therapies that can offer the patient the greatest likelihood of achieving their goals within their preference structure. Research Recommendations Although improvements have been made in this area, as demonstrated by Tangri and colleagues, $ ^{53} $ better predictive instruments for determining when, if ever, an individual is likely to require KRT are important for optimizing patient preparation, including timely creation of vascular access, PD catheter placement, and pre-emptive transplantation, while minimizing unnecessary procedures such as vascular access surgeries and donor and recipient transplantation evaluations. Additionally, research regarding how to conduct patient education and to facilitate the decision-making process when challenged with the need for KRT has the potential to enhance individualized patient care. RATIONALE FOR GUIDELINE 1.2 The balance among the benefits, risks, and disadvantages of initiating or not initiating dialysis should be evaluated, taking into account education received and preferences expressed by the patients and/or their caregivers. Symptoms of uremia are nonspecific, and attempts should be made to evaluate for other, sometimes reversible, causes of symptoms. Moreover, uremic symptoms can be subtle, and patients may adapt to lower levels of functioning or well-being without clearly expressing symptoms. The decision to initiate KRT should not be based on estimated GFR (eGFR) level alone, in large part reflecting the imprecision of measurement, regardless of the method of assessment of kidney function. Although not included in the guideline statement, the Work Group noted that there likely is a floor GFR below which KRT is required, conveying the point that despite the lack of data regarding a specific GFR threshold and difficulties inherent in precisely determining GFR, there is a level at which electing for KRT initiation versus electing for conservative care becomes imperative. Am J Kidney Dis. 2015;66(5):884-930 AJKD KDOQI HD Adequacy Guideline: 2015 Update While there is a need to estimate kidney function in patients with CKD and the level of kidney function should be considered when determining the timing of dialysis initiation, the Work Group thought that sufficient data exist to discourage reliance on a specific eGFR level. In patients with advanced CKD, serum creatinine-based estimating equations are substantially influenced by muscle mass, making eGFR both a marker of sarcopenia and kidney function. Consistent with this, while most cohort studies assessing the association between eGFR at initiation of dialysis and mortality have shown a higher risk for death with higher eGFR (Table 2), the same association is not demonstrable with measured clearances (Table 3). $ ^{54} $ Currently, serum creatinine-based estimating equations are the most commonly used method to estimate GFR (Table 4); however, serum creatinine has limitations as a filtration marker because generation of creatinine may vary, most notably reflecting different levels of muscle mass, as noted above (Box 3). $ ^{55} $ Most commonly, in patients with advanced kidney disease, low muscle mass may result in overestimation of GFR (Table 5). To assist the decision-making process and better align clinical symptoms with GFR, in selected cases, direct measurement of GFR, measurement of filtration markers in the urine, and measures of serum cystatin C and other serum biomarkers of kidney function that are not dependent on muscle mass may yield more precise estimates in people with advanced kidney disease. $ ^{55,56} $ Ongoing investigations of existing and novel biomarkers ultimately may lead to improved estimates of GFR that can optimize the timing of dialysis initiation. Accordingly, although favoring eGFR rather than serum creatinine as an indicator of kidney function, the Work Group elected not to recommend a specific GFR estimating equation for use in advanced CKD as this is a rapidly evolving field with increasing use of novel biomarkers that may improve predictions. Additionally, the Work Group favored not recommending routine 24-hour urine collections of filtration markers, but recognizes the potential utility of this in clinical situations in which symptoms of uremia appear discordant with the level of kidney function. Despite the larger body of evidence that has accumulated since the prior KDOQI guideline, the recommendation for timing of dialysis initiation in this update does not markedly differ from the prior KDOQI guideline. The most important study that informs this guideline is the IDEAL Study. $ ^{4} $ In this clinical trial conducted in 32 centers in Australia and New Zealand, 828 adult patients with creatinine clearance of 10 to 15 mL/min/1.73 m $ ^{2} $ were randomized to begin dialysis treatment earlier (10-14 mL/min/1.73 m $ ^{2} $ ; n = 404) or later (5-7 mL/min/1.73 m $ ^{2} $ ; n = 424). Upon follow-up, 19% of participants assigned to start dialysis early started later, and 76% of participants assigned to start dialysis late started early. Hence, mean creatinine clearance at the time of initiation of dialysis in the early and late groups was 12.0 and 9.8 mL/min (eGFR, 9.0 vs 7.8 mL/min/1.73 m $ ^{2} $ ), and the median difference in time to dialysis initiation was 5.6 months. There was no significant difference in time to death, CV or infectious events, or complications of dialysis. $ ^{57} $ These results did not differ even when the analyses were restricted to individuals who started treatment with PD. Furthermore, the trend for higher total health care costs in individuals assigned to start dialysis early was not significantly different, $ ^{58} $ and in a substudy, there was no difference in cardiac structure or function between earlier and later start groups. $ ^{59} $ One limitation of the IDEAL Study was that the targeted degree of separation in creatinine clearance at the time of dialysis initiation was not achieved; this most often was due to earlier-than-planned initiation of dialysis due to symptoms of uremia in individuals randomized to a late start. Of note, IDEAL contrasts with many observational studies as there was no signal of harm with initiation of dialysis at higher levels of kidney function in IDEAL. By design, IDEAL participants were healthier than seen in routine clinical practice; most IDEAL participants had extensive pre-existing nephrology care and only 6% of IDEAL participants had a history of congestive heart failure as compared to one-third of the incident dialysis population in the United States. $ ^{60} $ Despite these limitations, the Work Group recognizes that IDEAL was an exceedingly difficult trial to conduct and notes that it is unlikely that another clinical trial of dialysis initiation will be undertaken in the near future. The results of the IDEAL Study and observational studies allowed the Work Group to make a few key conclusions. First, there is no compelling evidence that initiation of dialysis based solely on measurement of kidney function leads to improvement in clinical outcomes, including overall mortality. Additionally, in individuals with advanced CKD, particularly the elderly or those with multiple comorbid conditions, the most widely used measure of kidney function, serum creatinine-based eGFR, may be misleading due to the dependence of serum creatinine on creatinine generation from muscle mass. Accordingly, in otherwise asymptomatic individuals, there is no reason to begin maintenance dialysis solely based on a serum creatinine or eGFR value. Rather, in patients with advanced CKD without clear uremic symptoms, efforts should be directed at preparing patients for a seamless and safe transition to KRT. This includes determining Am J Kidney Dis. 2015;66(5):884-930 Am J Kidney Dis. 2015;66(5):884-930 Table 2. Summary Data From Observational Studies That Assessed the Association Between Serum Creatinine-Based Estimates of Kidney Function at the Time of Initiation of Dialysis and Risk for Death <table><tr><td>Study</td><td>Sample Size</td><td>Study Site</td><td>Study Period</td><td>Measure of Kidney Function</td><td>HR (95% CI) for Association of Kidney Function at Time of Dialysis Initiation With Death Risk</td></tr><tr><td>$ Fink^{64} $ (1999)</td><td>5,388</td><td>Veterans Affairs, Maryland, USA</td><td>04/1995-12/1996</td><td>Scr</td><td>For every 1-mg/dL higher Scr: 0.96 (0.93-0.99)</td></tr><tr><td>$ Traynor^{65} $ (2002)</td><td>235</td><td>Glasgow, UK</td><td>1987-2000</td><td>$ Cockcroft-Gault CL_{cr} $</td><td>For every 1-mL/min higher $ CL_{cr} $: 1.11 (1.01-1.21)</td></tr><tr><td>$ Beddu^{66} $ (2003)</td><td>2,920</td><td>Dialysis Morbidity and Mortality Study, USA</td><td>1996-1997</td><td>eGFR by MDRD Study equation</td><td>For every 5-mL/min/1.73 $ m^2 $ higher eGFR: 1.14 (1.06-1.22)</td></tr><tr><td>$ Kazmi^{67} $ (2005)</td><td>302,287</td><td>USRDS</td><td>1996-1999</td><td>eGFR by MDRD Study equation</td><td>For eGFR > 10 (reference, <5) mL/min/1.73 $ m^2 $: 1.42</td></tr><tr><td>$ Sawhney^{68} $ (2009)</td><td>7,299</td><td>Canada and Scotland</td><td>2000-2005</td><td>eGFR by MDRD Study equation</td><td>For eGFR > 15 and 10-15 (reference, 5-10) mL/min/1.73 $ m^2 $: 1.65 (1.39-1.95) and 1.37 (1.19-1.59), respectively</td></tr><tr><td>$ Stel^{69} $ (2009)</td><td>6,716</td><td>Europe</td><td>2003</td><td>eGFR by MDRD Study equation</td><td>For every 1-mL/min/1.73 $ m^2 $ higher eGFR: 1.02 (1.01-1.04)</td></tr><tr><td>$ Evans^{70} $ (2011)</td><td>901</td><td>Sweden</td><td>05/1996-05/1998</td><td>eGFR by MDRD Study equation</td><td>For eGFR > 7.5 (reference: <7.5) mL/min/1.73 $ m^2 $: 0.84 (0.64-1.10)</td></tr><tr><td>$ Hwang^{71} $ (2010)</td><td>23,551</td><td>Taiwan</td><td>07/2001-12/2004</td><td>eGFR by MDRD Study equation</td><td>For quintile 5 eGFR (>6.52 mL/min/1.73 $ m^2 $) (reference, quintile 1, <3.29 mL/min/1.73 $ m^2 $): 2.44 (2.11-2.81)</td></tr><tr><td>$ Lassalle^{72} $ (2010)</td><td>11,685</td><td>France</td><td>2002-2006</td><td>eGFR by MDRD Study equation</td><td>For every 5-mL/min/1.73 $ m^2 $ higher eGFR: 1.09 (1.05-1.14)</td></tr><tr><td>$ Wright^{73} $ (2010)</td><td>895,293</td><td>USRDS</td><td>01/1995-09/1996</td><td>eGFR by MDRD Study equation</td><td>For eGFR > 15 and 10-15 (reference, 5-10) mL/min/1.73 $ m^2 $: 1.44 (1.43-1.45) and 1.15 (1.15-1.16), respectively</td></tr><tr><td>$ Grootendorst^{74} $(2011)</td><td>569</td><td>Netherlands Cooperative Study on the Adequacy of Dialysis (NECOSAD)</td><td>1997-2005</td><td>eGFR by MDRD Study equation</td><td>For highest tertile of eGFR (reference: lowest tertile): 1.4 (1.0-1.9)</td></tr><tr><td>$ Rosansky^{75} $(2011)</td><td>81,176</td><td>USRDS (nondiabetics, aged 45-64 y)</td><td>1995-2006</td><td>eGFR by MDRD Study equation</td><td>For $ eGFR > 15.0 $ and 10.0-14.9 (reference, < 5) mL/min/1.73 $ m^2 $: 1.74 and 1.47, respectively</td></tr><tr><td>$ Crews^{76} $(2014)</td><td>84,654; propensity-matched: 61,930</td><td>USRDS (aged ≥ 67 y, ≥2 y of prior Medicare coverage)</td><td>2006-2008</td><td>eGFR by MDRD Study equation</td><td>For $ eGFR \geq 10 $ (reference, <10) mL/min/1.73 $ m^2 $: 1.11 (1.08-1.14) for propensity-matched analyses</td></tr><tr><td>$ Crews^{77} $(2014)</td><td>652 (187 initiating dialysis)</td><td>Cleveland Clinic</td><td>2005-2009</td><td>eGFR by MDRD Study equation</td><td>For $ eGFR \geq 10 $ (reference, <10) mL/min/1.733 $ m^2 $: OR, 0.85 (0.65-1.11) for inverse probability-weighted analyses</td></tr><tr><td>$ Jain^{78} $(2014)</td><td>8,047 initiating PD</td><td>Canadian Organ Replacement Register</td><td>2001-2009</td><td>eGFR by MDRD Study equation</td><td>For $ eGFR > 10.5 $ and 7.5-10.5 (reference, <7.5) mL/min/1.733 $ m^2 $: adjusted HRs of 1.08 (0.96-1.23) and 0.96 (0.86-1.09), respectively</td></tr></table> Abbreviations: CI, confidence interval; $ CL_{cr} $ , creatinine clearance; eGFR, estimated glomerular filtration rate; HR, hazard ratio; MDRD, Modification of Diet in Renal Disease; OR, odds ratio; PD, peritoneal dialysis; Scr, serum creatinine; UK, United Kingdom; USA, United States; USRDS, US Renal Data System. Kooi HD Adepouy Gueline: 2015 Update AKD AJKD KDOQI HD Adequacy Guideline: 2015 Update Table 3. Summary Data From Observational Studies That Assessed the Association Between Measured Kidney Function at the Time of Initiation of Dialysis and Risk for Death <table><tr><td>Study</td><td>Sample Size</td><td>Study Site</td><td>Study Period</td><td>Measure of Kidney Function</td><td>HR (95% CI) for Association of Kidney Function at Time of Dialysis Initiation With Death Risk</td></tr><tr><td>$ Bonomini^{79} $ (1985)</td><td>340</td><td>Single Italian center</td><td></td><td>$ CL_{cr} $</td><td>12-y survival in early dialysis group: (mean $ CL_{cr} $, 12.9 mL/min), 77%; late dialysis group (mean $ CL_{cr} $, 2.1 mL/min): 51%; no adjustment made for differences in patient characteristics</td></tr><tr><td>$ Tattersal^{80} $ (1995)</td><td>63</td><td>Single UK center</td><td>1991-1992</td><td>Renal $ Kt/V_{urea} $</td><td>Mean renal $ Kt/V_{urea} $ lower in 6 individuals who died; no adjustment made for differences in patient characteristics</td></tr><tr><td>$ Churchill^{81} $ (1997)</td><td>680</td><td>Canadian-USA Study on Adequacy of Peritoneal Dialysis (CANUSA)</td><td>9/1990-12/1992</td><td>24-h mean of urinary urea clearance and $ CL_{cr} $</td><td>For every 5-L/wk higher mGFR: 0.95 (0.91-0.99)</td></tr><tr><td>$ Beddhu^{66} $ (2003)</td><td>1,072</td><td>Dialysis Morbidity and Mortality Study, USA</td><td>1996-1997</td><td>Assumed 24-h urinary $ CL_{cr} $</td><td>For every 5-mL/min higher $ CL_{cr} $: 0.98 (0.86-1.14)</td></tr><tr><td>$ Grootendorst^{74} $(2011)</td><td>569</td><td>Netherlands Cooperative Study on the Adequacy of Dialysis (NECOSAD)</td><td>1997-2005</td><td>24-h mean of urinary urea clearance and $ CL_{cr} $</td><td>Highest tertile of mGFR (reference: lowest tertile of mGFR): 1.0 (0.7-1.3)</td></tr></table> Abbreviations: CI, confidence interval; $ CL_{cr} $ , creatinine clearance; HR, hazard ratio; mGFR, measured glomerular filtration rate; UK, United Kingdom; USA, United States. whether the individual is an appropriate candidate for kidney transplantation and/or maintenance dialysis, providing education about different dialysis therapies, offering decision support for selection of dialysis modality (including conservative care without dialysis), facilitating placement of permanent access, and starting dialysis in a timely manner. $ ^{27} $ Second, maintenance dialysis should not be denied to individuals with kidney failure who may potentially benefit from KRT, such as Table 4. Commonly Used Validated GFR Estimating Equations in Adults <table><tr><td rowspan="2">Coefficient</td><td colspan="2">MDRD Study Equation82,83</td><td colspan="3">CKD-EPI Equations</td></tr><tr><td>Scr</td><td>Scr(Levey et al,84 2009)</td><td>Scys(Inker et al,85 2012)</td><td>Scr and Scys(Inker et al,85 2012)</td><td></td></tr><tr><td>Scr</td><td>$ Scr^{-1.154} $</td><td>—</td><td>—</td><td>—</td><td></td></tr><tr><td>Scr, when >0.9 mg/dL for men or >0.7 mg/dL for women</td><td>—</td><td>$ Scr^{-1.209} $ if male</td><td>—</td><td>$ Scr^{-0.601} $</td><td></td></tr><tr><td>Scr, when ≤0.9 mg/dL for men or ≤0.7 mg/dL for women</td><td>—</td><td>$ Scr^{-0.329} $ if male</td><td>—</td><td>$ Scr^{-0.248} $ if male</td><td></td></tr><tr><td>Scys, when >0.8 mg/dL</td><td>—</td><td>$ Scr^{-0.411} $ if female</td><td></td><td>$ Scr^{-0.247} $ if female</td><td></td></tr><tr><td>Scys, when ≤0.8 mg/dL</td><td>—</td><td>—</td><td>$ SCysC^{-1.328} $</td><td>$ Scys^{-0.711} $</td><td></td></tr><tr><td>Age, in years</td><td>$ Age^{-0.203} $</td><td>$ 0.993^{age} $</td><td>$ SCysC^{-0.499} $</td><td>$ Scys^{-0.375} $</td><td></td></tr><tr><td>Female sex</td><td>0.742</td><td>1.018</td><td>$ 0.992^{age} $</td><td>$ 0.995^{age} $</td><td></td></tr><tr><td>Black race</td><td>1.212</td><td>1.159</td><td>—</td><td>0.969</td><td></td></tr><tr><td>Note: For the MDRD Study equation, the coefficient of -1.154 for the exponent of Scr indicates that estimated GFR is 1.154% lower for each 1% higher Scr. For any value of Scr, older age and female sex are associated with lower Scr-based estimated GFR, and African American race is associated with higher Scr-based estimated GFR. For the CKD-EPI equations, Scr is modeled as a 2-slope spline with sex-specific knots; Scys is modeled as a 2-slope spline with the same knot for both sexes. The slopes are steeper above than below the knots. Because of the sex-specific knots for the Scr coefficients, the sex coefficients in the CKD-EPI Scr and Scr-Scys equations are not comparable to the MDRD Study equation and the Scys-based CKD-EPI equation. The corresponding sex coefficients for the CKD-EPI Scr and Scr-Scys equations would be 0.75 and 0.83 for Scr values ≥ 0.9 mg/dL, respectively. Conversion factor for Scr in mg/dL to mmol/L, ×388.4.Abbreviations: CKD-EPI, Chronic Kidney Disease Epidemiology Collaboration; GFR, glomerular filtration rate; MDRD, Modification of Diet in Renal Disease; Scr, serum creatinine (in mg/dL); Scys, serum cystatin C (in mg/dL).Adapted with permission of the National Kidney Foundation from Levey et al.$^{55}$</td></tr></table> Am J Kidney Dis. 2015;66(5):884-930 KDOQI HD Adequacy Guideline: 2015 Update AJKD Table 5. Clinical Settings Affecting Creatinine Generation <table><tr><td>Setting</td><td>Effect on Serum Creatinine</td></tr><tr><td colspan="2">Demographic characteristics</td></tr><tr><td>Older age</td><td>Decreased</td></tr><tr><td>Female sex</td><td>Decreased</td></tr><tr><td>African Americana</td><td>Increased</td></tr><tr><td>Hispanica</td><td>Decreased</td></tr><tr><td>Asiana</td><td>Decreased</td></tr><tr><td colspan="2">Clinical characteristics</td></tr><tr><td>Muscular habitus</td><td>Increased</td></tr><tr><td>Rhabdomyolysis</td><td>Increased</td></tr><tr><td>Loss of muscle (amputation, neuromuscular diseases, cachexia)</td><td>Decreased</td></tr><tr><td>Cirrhosis/advanced liver disease</td><td>Decreasedb</td></tr><tr><td>Protein-energy wasting/inflammation</td><td>Decreased</td></tr><tr><td colspan="2">Dietary character …(140,959 more chars)