KDIGO 2012 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease

Figure 4. Relationship of albuminuria with mortality 23 Figure 5. Age-standardized rates of death from any cause, cardiovascular events, and hospitalization, according to the eGFR among 1,120,295 ambulatory adults 28 Figure 6. Summary of continuous meta-analysis for general population cohorts with ACR 29 Figure 7. Summary of categorical meta-analysis for general population cohorts with ACR 30 Figure 8. Prevalence of CKD in the USA by GFR and albuminuria 31 Figure 9. Prognosis of CKD by GFR and albuminuria category 34 Figure 10. Determinants of the serum level of endogenous filtration markers 39 Figure 11. Performance of the CKD-EPI and MDRD Study equations in estimating measured GFR in the external validation data set 43 Figure 12. Comparison of distribution of GFR and CKD prevalence by age (NHANES 1999-2004) 46 Figure 13. Meta-analysis of NRI for all-cause mortality, CVD mortality, and ESRD 47 Figure 14. Association of CKD definitions with all-cause mortality and ESRD 50 Figure 15. Performance of three equations for estimating GFR 53 Figure 16. Suggested protocol for the further investigation of an individual demonstrating a positive reagent strip test for albuminuria/proteinuria or quantitative albuminuria/proteinuria test 57 Figure 17. GFR and albuminuria grid to reflect the risk of progression 63 Figure 18. Distribution of the probability of nonlinearity with three example trajectories demonstrating different probabilities of nonlinearity 69 Figure 19. Summary estimates for risks of all-cause mortality and cardiovascular mortality associated with levels of serum phosphorus, PTH, and calcium 86 Figure 20. Prevalence of deficiency of 1,25(OH) 2 D3 , 25(OH)D3 , and secondary hyperparathyroidism by GFR intervals 88 Figure 21. Referral decision making by GFR and albuminuria 113 Figure 22. The CKD chronic care model 116 Additional information in the form of supplementary materials can be found online at http://www.kdigo.org/clinical_practice_guidelines/ckd.php vi Kidney International Supplements (2013) 3, vi c o n t e n t s http://www.kidney-international.org & 2013 KDIGO KDIGO Board Members Garabed Eknoyan, MD Norbert Lameire, MD, PhD Founding KDIGO Co-Chairs Kai-Uwe Eckardt, MD Immediate Past Co-Chair Bertram L Kasiske, MD KDIGO Co-Chair David C Wheeler, MD, FRCP KDIGO Co-Chair Omar I Abboud, MD, FRCP Sharon Adler, MD, FASN Rajiv Agarwal, MD Sharon P Andreoli, MD Gavin J Becker, MD, FRACP Fred Brown, MBA, FACHE Daniel C Cattran, MD, FRCPC Allan J Collins, MD, FACP Rosanna Coppo, MD Josef Coresh, MD, PhD Ricardo Correa-Rotter, MD Adrian Covic, MD, PhD Jonathan C Craig, MBChB, MM (Clin Epi), DCH, FRACP, PhD Angel LM de Francisco, MD Paul E de Jong, MD, PhD Ana Figueiredo, RN, MSc, PhD Mohammed Benghanem Gharbi, MD Gordon Guyatt, MD, MSc, BSc, FRCPC David Harris, MD Lai Seong Hooi, MD Enyu Imai, MD, PhD Lesley A Inker, MD, MS, FRCP Michel Jadoul, MD Simon Jenkins, MBE, FRCGP Suhnggwon Kim, MD, PhD Martin K Kuhlmann, MD Nathan W Levin, MD, FACP Philip K-T Li, MD, FRCP, FACP Zhi-Hong Liu, MD Pablo Massari, MD Peter A McCullough, MD, MPH, FACC, FACP Rafique Moosa, MD Miguel C Riella, MD Adibul Hasan Rizvi, MBBS, FRCP Bernardo Rodriquez-Iturbe, MD Robert Schrier, MD Justin Silver, MD, PhD Marcello Tonelli, MD, SM, FRCPC Yusuke Tsukamoto, MD Theodor Vogels, MSW Angela Yee-Moon Wang, MD, PhD, FRCP Christoph Wanner, MD Elena Zakharova, MD, PhD NKF-KDIGO GUIDELINE DEVELOPMENT STAFF Kerry Willis, PhD, Senior Vice-President for Scientific Activities Michael Cheung, MA, Guideline Development Director Sean Slifer, BA, Guideline Development Manager Kidney International Supplements (2013) 3, vii vii http://www.kidney-international.org & 2013 KDIGO ADULT GFR ESTIMATING EQUATIONS 2009 CKD-EPI creatinine equation: 141  min(SCr/k, 1)a  max(SCr/k, 1)1.209  0.993 Age [  1.018 if female] [  1.159 if black], where SCr is serum creatinine (in mg/dl), k is 0.7 for females and 0.9 for males, a is 0.329 for females and 0.411 for males, min is the minimum of SCr/k or 1, and max is the maximum of SCr/k or 1. 2012 CKD-EPI cystatin C equation: 133  min(SCysC/0.8, 1)0.499  max(SCysC/0.8, 1)1.328  0.996 Age [  0.932 if female], where SCysC is serum cystatin C (in mg/l), min indicates the minimum of SCysC/0.8 or 1, and max indicates the maximum of SCysC/0.8 or 1. Grade Quality of evidence Meaning A High We are confident that the true effect lies close to that of the estimate of the effect. B Moderate The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. C Low The true effect may be substantially different from the estimate of the effect. D Very low The estimate of effect is very uncertain, and often will be far from the truth. Implications Grade* Patients Clinicians Policy Level 1 ‘We recommend’ Most people in your situation would want the recommended course of action and only a small proportion would not. Most patients should receive the recommended course of action. The recommendation can be evaluated as a candidate for developing a policy or a performance measure. Level 2 ‘We suggest’ The majority of people in your situation would want the recommended course of action, but many would not. 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. The recommendation is likely to require substantial debate and involvement of stakeholders before policy can be determined. *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. NOMENCLATURE AND DESCRIPTION FOR RATING GUIDELINE RECOMMENDATIONS Within each recommendation, the strength of recommendation is indicated as Level 1, Level 2, or Not Graded, and the quality of the supporting evidence is shown as A, B, C, or D. Reference Keys Equations expressed for specified sex and serum creatinine level Gender Serum creatinine Equation for estimating GFR Female p0.7 mg/dl (p62 mmol/l) 144  (SCr/0.7)0.329  0.993 Age [  1.159 if black] Female 40.7 mg/dl (462 mmol/l) 144  (SCr/0.7)1.209  0.993 Age [  1.159 if black] Male p0.9 mg/dl (p80 mmol/l) 141  (SCr/0.9)0.411  0.993 Age [  1.159 if black] Male 40.9 mg/dl (480 mmol/l) 141  (SCr/0.9)1.209  0.993 Age [  1.159 if black] Equations expressed for serum cystatin C level Serum cystatin C Equation for estimating GFR Female or male p0.8 mg/l 133  (SCysC/0.8)0.499  0.996 Age [  0.932 if female] Female or male 40.8 mg/l 133  (SCysC/0.8)1.328  0.996 Age [  0.932 if female] viii Kidney International Supplements (2013) 3, viii http://www.kidney-international.org & 2013 KDIGO 2012 CKD-EPI creatinine–cystatin C equation: 135  min(SCr/k, 1)a  max(SCr/k, 1)0.601  min(SCysC/0.8, 1)0.375  max(SCysC/ 0.8, 1)0.711  0.995 Age [  0.969 if female] [  1.08 if black], where SCr is serum creatinine (in mg/dl), SCysC is serum cystatin C (in mg/l), k is 0.7 for females and 0.9 for males, a is 0.248 for females and 0.207 for males, min(SCr/k, 1) indicates the minimum of SCr/k or 1, and max(SCr/k, 1) indicates the maximum of SCr/k or 1; min(SCysC/0.8, 1) indicates the minimum of SCysC/0.8 or 1 and max(SCysC/ 0.8, 1) indicates the maximum of SCysC/0.8 or 1. PEDIATRIC GFR ESTIMATING EQUATIONS http://www.kidney-international.org & 2013 KDIGO Equations expressed for specified sex, serum creatinine, and serum cystatin C level Gender Serum creatinine Serum cystatin C Equation for estimating GFR Female p0.7 mg/dl (p62 mmol/l) p0.8 mg/l 40.8 mg/l 130  (SCr/0.7)0.248  (SCysC/0.8)0.375  0.995 Age [  1.08 if black] 130  (SCr/0.7)0.248  (SCysC/0.8)0.711  0.995 Age [  1.08 if black] Female 40.7 mg/dl (462 mmol/l) p0.8 mg/l 40.8 mg/l 130  (SCr/0.7)0.601  (SCysC/0.8)0.375  0.995 Age [  1.08 if black] 130  (SCr/0.7)0.601  (SCysC/0.8)0.711  0.995 Age [  1.08 if black] Male p0.9 mg/dl (p80 mmol/l) p0.8 mg/l 40.8 mg/l 135  (SCr/0.9)0.207  (SCysC/0.8)0.375  0.995 Age [  1.08 if black] 135  (SCr/0.9)0.207  (SCysC/0.8)0.711  0.995 Age [  1.08 if black] Male 40.9 mg/dl (480 mmol/l) p0.8 mg/l 40.8 mg/l 135  (SCr/0.9)0.601  (SCysC/0.8)0.375  0.995 Age [  1.08 if black] 135  (SCr/0.9)0.601  (SCysC/0.8)0.711  0.995 Age [  1.08 if black] Creatinine-based equations 41.3  (height/SCr) 40.7  (height/SCr) 0.64  (30/BUN) 0.202 BUN, blood urea nitrogen in mg/dl; height in meters; SCr, serum creatinine in mg/dl Cystatin C-based equations 70.69  (SCysC)0.931 SCysC, serum cystatin C in mg/l. Kidney International Supplements (2013) 3, ix ix CURRENT CHRONIC KIDNEY DISEASE (CKD) NOMENCLATURE USED BY KDIGO CKD is defined as abnormalities of kidney structure or function, present for 43 months, with implications for health and CKD is classified based on cause, GFR category, and albuminuria category (CGA). Persistent albuminuria categories Description and range A1 A2 A3 Normal to mildly increased Moderately increased Severely increased <30 mg/g <3 mg/mmol 30-300 mg/g 3-30 mg/mmol >300 mg/g >30 mg/mmol GFR categories (ml/min/ 1.73 m 2 ) Description and range G1 Normal or high ≥90 G2 Mildly decreased 60-89 G3a Mildly to moderately decreased 45-59 G3b Moderately to severely decreased 30-44 G4 Severely decreased 15-29 G5 Kidney failure <15 Prognosis of CKD by GFR and Albuminuria Categories: KDIGO 2012 Prognosis of CKD by GFR and albuminuria category Green: low risk (if no other markers of kidney disease, no CKD); Yellow: moderately increased risk; Orange: high risk; Red, very high risk. http://www.kidney-international.org & 2013 KDIGO x Kidney International Supplements (2013) 3, x CONVERSION FACTORS OF METRIC UNITS TO SI UNITS HbA1C CONVERSION CHART DCCT (%) IFCC (mmol/mol) DCCT (%) IFCC (mmol/mol) DCCT (%) IFCC (mmol/mol) DCCT (%) IFCC (mmol/mol) DCCT (%) IFCC (mmol/mol) 5.0 31 6.0 42 7.0 53 8.0 64 9.0 75 5.1 32 6.1 43 7.1 54 8.1 65 9.1 76 5.2 33 6.2 44 7.2 55 8.2 66 9.2 77 5.3 34 6.3 45 7.3 56 8.3 67 9.3 78 5.4 36 6.4 46 7.4 57 8.4 68 9.4 79 5.5 37 6.5 48 7.5 58 8.5 69 9.5 80 5.6 38 6.6 49 7.6 60 8.6 70 9.6 81 5.7 39 6.7 50 7.7 61 8.7 72 9.7 83 5.8 40 6.8 51 7.8 62 8.8 73 9.8 84 5.9 41 6.9 52 7.9 63 8.9 74 9.9 85 DCCT (%) IFCC (mmol/mol) DCCT (%) IFCC (mmol/mol) DCCT (%) IFCC (mmol/mol) DCCT (%) IFCC (mmol/mol) DCCT (%) IFCC (mmol/mol) 10.0 86 11.0 97 12.0 108 13.0 119 14.0 130 10.1 87 11.1 98 12.1 109 13.1 120 14.1 131 10.2 88 11.2 99 12.2 110 13.2 121 14.2 132 10.3 89 11.3 100 12.3 111 13.3 122 14.3 133 10.4 90 11.4 101 12.4 112 13.4 123 14.4 134 10.5 91 11.5 102 12.5 113 13.5 124 14.5 135 10.6 92 11.6 103 12.6 114 13.6 125 14.6 136 10.7 93 11.7 104 12.7 115 13.7 126 14.7 137 10.8 95 11.8 105 12.8 116 13.8 127 14.8 138 10.9 96 11.9 107 12.9 117 13.9 128 14.9 139 IFCC-HbA 1c (mmol/mol) ¼ [DCCT-HbA1c (%)2.15]  10.929 Abbreviations: DCCT, Diabetes Control and Complications Trial; IFCC, International Federation of Clinical Chemistry and Laboratory Medicine. Source: Diabetes UK, www.diabetes.org.uk. Parameter Metric units Conversion factor SI units Albumin (serum) g/dl 10 g/l Blood urea nitrogen (BUN) mg/dl 0.357 mmol/l Creatinine (serum) mg/dl 88.4 mmol/l Creatinine clearance ml/min 0.01667 ml/s Hemoglobin g/dl 10 g/l Phosphate (serum) mg/dl 0.323 mmol/l PTH (parathyroid hormone, serum) pg/ml 0.106 pmol/l Urea (plasma) mg/dl 0.167 mmol/l Uric acid mg/dl 59.485 mmol/l Vitamin D, 25-hydroxyvitamin D ng/ml 2.496 nmol/l Note: Metric unit  conversion factor ¼ SI unit. Kidney International Supplements (2013) 3, xi xi http://www.kidney-international.org & 2013 KDIGO Kidney International Supplements (2013) 3, xii xii Abbreviations and Acronyms 4C Cardiovascular Comorbidity in Children with CKD AASK African American Study of Kidney Disease and Hypertension ABPM Ambulatory blood pressure monitoring ACCORD Action to Control Cardiovascular Risk in Diabetes ACE-I Angiotensin-converting enzyme inhibitor ACR Albumin-to-creatinine ratio ACS Acute coronary syndrome ADVANCE Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation AER Albumin excretion rate AGREE Appraisal of Guidelines for Research and Evaluation AKD Acute kidney disease AKDN Alberta Kidney Disease Network AKI Acute kidney injury ANP Atrial natriuretic peptide APPROACH Alberta Provincial Project for Outcome Assess- ment in Coronary Heart Disease AusDiab Australian Diabetes, Obesity and Lifestyle study ARB Angiotensin-receptor blocker BMD Bone mineral density BMI Body mass index BNP B-type natriuretic peptide BP Blood pressure BSA Body surface area BUN Blood urea nitrogen CAD Coronary artery disease CAPRICORN Carvedilol Post-Infarct Survival Control in Left Ventricular Dysfunction CGA Cause, GFR and Albuminuria categories CHARM Candesartan in Heart Failure-Assessment of Reduction in Mortality and Morbidity CHF Congestive heart failure CHS Cardiovascular Health Study CI Confidence interval CIBIS II Cardiac Insufficiency Bisoprolol Study II CKD Chronic kidney disease CKD-EPI CKD Epidemiology Collaboration CKD-MBD Chronic Kidney Disease-Mineral and Bone Disorder CKiD Chronic Kidney Disease in Children COGS Conference on Guideline Standardization COPERNICUS Carvedilol Prospective Randomized Cumulative Survival COX-2 Cyclooxygenase-2 Cr-EDTA Chromium-ethylenediamine tetraacetic acid CREATE Cardiovascular Risk Reduction by Early Anemia Treatment with Epoetin Beta Trial CREDO Clopidogrel for Reduction of Events During Observation CrCl Creatinine clearance CRIC Chronic Renal Insufficiency Cohort CRP C-reactive protein cTnI Cardiac troponin I cTnT Cardiac troponin T CVD Cardiovascular disease DCCT/EDIC Diabetes Control and Complications Trial/ Epidemiology of Diabetes Interventions and Complications DIG Digitalis Intervention Group DPI Dietary protein intake DXA Dual-energy x-ray absorptiometry ECG Electrocardiography eGFR Estimated GFR EMU Early morning urine ERT Evidence review team ESA Erythropoiesis-stimulating agent ESCAPE Effect of Strict Blood Pressure Control and ACE-Inhibition on Progression of Chronic Renal Failure in Pediatric Patients ESRD End-Stage Renal Disease ESUR European Society of Urogenital Radiology FGF-23 Fibroblast growth factor-23 GBCA Gadolinium-based contrast agent GFR Glomerular filtration rate GN Glomerulonephritis GRADE Grading of Recommendations Assessment, Development and Evaluation Hb Hemoglobin HbA 1c Hemoglobin A1c HBV Hepatitis B virus HDL-C High-density lipoprotein cholesterol HOPE Heart Outcomes Prevention Evaluation HOT Hypertension Optimal Treatment HR Hazard ratio HR-pQCT High-resolution peripheral quantitative computed tomography HUNT 2 Nord-Trøndelag Health Study (1995-1997) ICD International Classification of Diseases ICU Intensive-care unit IDF International Diabetes Federation IDMS Isotope-dilution mass spectrometry IQR Interquartile range IRMM Institute for Reference Materials and Measure- ments ItalKid Italian Pediatric Registry of Chronic Renal Failure JCTLM Joint Committee for Traceability in Laboratory Medicine KDIGO Kidney Disease: Improving Global Outcomes KDOQI Kidney Disease Outcomes Quality Initiative LDL-C Low-density lipoprotein cholesterol LIFE Losartan Intervention For Endpoint Reduction in Hypertension LPD Low-protein diet LVH Left ventricular hypertrophy MAP Mean arterial pressure MDRD Modification of Diet in Renal Disease MESA Multi-Ethnic Study of Atherosclerosis http://www.kidney-international.org & 2013 KDIGO MI Myocardial infarction MRI Magnetic resonance imaging NAPRTCS North American Pediatric Renal Trials and Collaborative Studies NCEP III Third Report of the National Cholesterol Education Program NECOSAD Netherlands Cooperative Study on the Adequacy of Dialysis Study Group NHANES National Health and Nutrition Examination Survey NICE National Institute for Health and Clinical Excellence NIH National Institutes of Health NKDEP National Kidney Disease Education Program NKF National Kidney Foundation NSAID Nonsteroidal anti-inflammatory drug NSF Nephrogenic systemic fibrosis NT-proBNP N-terminal pro-BNP ONTARGET Ongoing Telmisartan Alone and in Combina- tion with Ramipril Global Endpoint trial OR Odds ratio PAD Peripheral arterial disease PCR Protein-to-creatinine ratio PER Protein excretion rate PICARD Program to Improve Care in Acute Renal Disease PICODD Population, Intervention or Predictor, Compa- rator, Outcome, study Design, and Duration of follow-up PREVEND Prevention of Renal and Vascular Endstage Disease PTH Parathyroid hormone QOL Quality of life RAAS Renin-angiotensin-aldosterone system RBC Red blood cell RCT Randomized controlled trial RENAAL Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan RR Relative risk RRT Renal replacement therapy SCORE Systematic COronary Risk Evaluation SCr Serum creatinine SCysC Serum cystatin C SD Standard deviation SEEK Study for the Evaluation of Early Kidney disease SHARP Study of Heart and Renal Protection SPECT Single photon emission computed tomography SUA Serum uric acid TREAT Trial to Reduce Cardiovascular Events with Aranesp Therapy UKPDS United Kingdom Prospective Diabetes Study USA-PRC USA–People’s Republic of China Collaborative Study of Cardiovascular and Cardiopulmonary Epidemiology USRDS US Renal Data System VADT Veterans Affairs Diabetes Trial Val-HeFT Valsartan Heart Failure Trial VLPD Very low-protein diet WBC White blood cell WHO World Health Organization http://www.kidney-international.org & 2013 KDIGO Kidney International Supplements (2013) 3, xiii xiii Notice Kidney International Supplements (2013) 3, 1; doi:10.1038/kisup.2012.73 SECTION I: USE OF THE CLINICAL PRACTICE GUIDELINE This Clinical Practice Guideline document is based upon systematic literature searches last conducted in June 2011, supplemented with additional evidence through November 2012. 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 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: Improving Global Outcomes (KDIGO) 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 as or are actual conflicts of interest. This document is updated annually and information is adjusted accordingly. All reported information is published in its entirety at the end of this document in the Work Group members’ Biographic and Disclosure Information section, and is kept on file at the National Kidney Foundation (NKF), former Managing Agent for KDIGO. http://www.kidney-international.org & 2013 KDIGO Copyright & 2012 by KDIGO. All rights reserved. Single photocopies may be made for personal use as allowed by national copyright laws. Special rates are available for educational institutions that wish to make photocopies for non-profit educational use. No part of this publication may be reproduced, amended, or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without explicit permission in writing from KDIGO. Details on how to seek permission for reproduction or translation, and further information about KDIGO’s permissions policies can be obtained by contacting Danielle Green, Managing Director, at danielle.green@kdigo.org To the fullest extent of the law, neither KDIGO, Kidney International Supplements, National Kidney Foundation (KDIGO’s former Managing Agent) nor the authors, contributors, or editors, assume any liability for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein. Kidney International Supplements (2013) 3, 1 1 Foreword Kidney International Supplements (2013) 3, 2; doi:10.1038/kisup.2012.74 It is our hope that this document will serve several useful purposes. Our primary goal is to improve patient care. We hope to accomplish this, in the short term, by helping clinicians know and better understand the evidence (or lack of evidence) that determines current practice. By providing comprehensive evidence-based recommendations, this guide- line will also help define areas where evidence is lacking and research is needed. Helping to define a research agenda is an often neglected, but very important, function of clinical practice guideline development. We used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system to rate the quality of evidence and the strength of recommendations. In all, there were 12 (17.1%) recommendations in this guideline for which the overall quality of evidence was graded ‘A,’ whereas 36 (51.4%) were graded ‘B,’ 17 (24.3%) were graded ‘C,’ and 5 (7.1%) were graded ‘D.’ Although there are reasons other than quality of evidence to make a grade 1 or 2 recommendation, in general, there is a correlation between the quality of overall evidence and the strength of the recommendation. Thus, there were 43 (62.3%) recommendations graded ‘1’ and 26 (37.7%) graded ‘2.’ There were 9 (13.0%) recommendations graded ‘1A,’ 23 (33.3%) were ‘1B,’ 10 (14.5%) were ‘1C,’ and 1 (1.4%) was ‘1D.’ There were 2 (2.9%) recommendations graded ‘2A,’ 13 (18.8%) were ‘2B,’ 7 (10.1%) were ‘2C,’ and 4 (5.8%) were ‘2D.’ There were 41 (37.3%) statements that were not graded. Some argue that recommendations should not be made when evidence is weak. However, clinicians still need to make decisions in their daily practice, and they often ask, ‘‘What do the experts do in this setting?’’ We opted to give guidance, rather than remain silent. These recommendations are often rated with a low strength of recommendation and a low quality of evidence, or were not graded. It is important for the users of this guideline to be cognizant of this (see Notice). In every case these recommendations are meant to be a place for clinicians to start, not stop, their inquiries into specific management questions pertinent to the patients they see in daily practice. We wish to thank the Work Group Co-Chairs, Drs. Adeera Levin and Paul Stevens, along with all of the Work Group members who volunteered countless hours of their time developing this guideline. We also thank the Evidence Review Team members and staff of the National Kidney Foundation who made this project possible. Finally, we owe a special debt of gratitude to the many KDIGO Board members and individuals who volunteered time reviewing the guideline, and making very helpful suggestions. Bertram L Kasiske, MD David C Wheeler, MD, FRCP KDIGO Co-Chair KDIGO Co-Chair http://www.kidney-international.org & 2013 KDIGO 2 Kidney International Supplements (2013) 3, 2 Work Group Membership Kidney International Supplements (2013) 3, 3; doi:10.1038/kisup.2012.75 http://www.kidney-international.org & 2013 KDIGO WORK GROUP CO-CHAIRS Adeera Levin, MD, FRCPC University of British Columbia Vancouver, Canada Paul E Stevens, MB, FRCP East Kent Hospitals University NHS Foundation Trust Canterbury, United Kingdom WORK GROUP EVIDENCE REVIEW TEAM Tufts Center for Kidney Disease Guideline Development and Implementation Tufts Medical Center, Boston, MA, USA: Katrin Uhlig, MD, MS, Project Director; Director, Guideline Development Dana Miskulin, MD, MS, Staff Nephrologist Amy Earley, BS, Project Coordinator Shana Haynes, MS, DHSc, Research Assistant Jenny Lamont, MS, Project Manager In addition, support and supervision were provided by: Ethan M Balk, MD, MPH; Program Director, Evidence Based Medicine Rudy W Bilous, MD Newcastle University and James Cook University Hospital Middlesbrough, United Kingdom Edmund J Lamb, PhD, FRCPath East Kent Hospitals University NHS Foundation Trust Canterbury, United Kingdom Josef Coresh, MD, PhD, MHS Johns Hopkins University Baltimore, USA Andrew S Levey, MD Tufts Medical Center Boston, USA Angel LM de Francisco, MD, PhD Hospital Universitario Valdecilla Santander, Spain Miguel C Riella, MD, PhD, FACP Evangelic University Hospital Curitiba, Brazil Paul E de Jong, MD, PhD University Medical Center Groningen Groningen, The Netherlands Michael G Shlipak, MD, MPH VA Medical Center, UCSF San Francisco, USA Kathryn E Griffith, BM, BS, MSc, MRCP, MRCGP University Health Centre, York University York, United Kingdom Haiyan Wang, MD Peking University First Hospital Beijing, China Brenda R Hemmelgarn, MD, PhD, FRCP(C) University of Calgary Alberta, Canada Colin T White, MD, FRCPC University of British Columbia Vancouver, Canada Kunitoshi Iseki, MD University Hospital of the Ryukyus Nishihara, Okinawa, Japan Christopher G Winearls, MB, DPhil, FRCP Oxford Radcliffe Hospitals NHS Trust Oxford, United Kingdom Kidney International Supplements (2013) 3, 3 3 Abstract Kidney International Supplements (2013) 3, 4; doi:10.1038/kisup.2012.76 The Kidney Disease: Improving Global Outcomes (KDIGO) 2012 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease (CKD) serves to update the 2002 KDOQI Clinical Practice Guidelines for Chronic Kidney Disease: Evaluation, Classification, and Stratification following a decade of focused research and clinical practice in CKD. The document aims to provide state-of-the-art guidance on the evaluation, management and treatment for all patients with CKD. Specifically, the guideline retains the definition of CKD but presents an enhanced classification framework for CKD; elaborates on the identification and prognosis of CKD; discusses the management of progression and complications of CKD; and expands on the continuum of CKD care: timing of specialist referral, ongoing management of people with progressive CKD, timing of the initiation of dialysis, and finally the implementation of a treatment program which includes comprehensive conservative management. The development of the guideline followed an explicit process of evidence review and appraisal. Treatment approaches are addressed in each chapter and guideline recommendations are based on systematic reviews of relevant trials. Practical comments or statements which serve as educational purposes are ungraded, but included as important information for the readership. Appraisal of the quality of the evidence and the strength of recommendations followed the GRADE approach. Ongoing areas of controversies, limitations of the evidence, and international relevance are discussed and additional suggestions are provided for future research. Keywords: Albuminuria; Chronic kidney disease; Classification; Clinical practice guideline; Evidence-based recommendation; GFR; Glomerular filtration rate; KDIGO; Proteinuria; Systematic review CITATION In citing this document, the following format should be used: Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group. KDIGO 2012 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease. Kidney inter., Suppl. 2013; 3: 1–150. http://www.kidney-international.org & 2013 KDIGO 4 Kidney International Supplements (2013) 3, 4 Summary of Recommendation Statements Kidney International Supplements (2013) 3, 5–14; doi:10.1038/kisup.2012.77 http://www.kidney-international.org & 2013 KDIGO Chapter 1: Definition and classification of CKD 1.1: DEFINITION OF CKD 1.1.1: CKD is defined as abnormalities of kidney structure or function, present for 43 months, with implications for health. (Not Graded) 1.2: STAGING OF CKD 1.2.1: We recommend that CKD is classified based on cause, GFR category, and albuminuria category (CGA). (1B) 1.2.2: Assign cause of CKD based on presence or absence of systemic disease and the location within the kidney of observed or presumed pathologic-anatomic findings. (Not Graded) 1.2.3: Assign GFR categories as follows (Not Graded): 1.2.4: Assign albuminuria* categories as follows (Not Graded): *note that where albuminuria measurement is not available, urine reagent strip results can be substituted (Table 7) 1.3: PREDICTING PROGNOSIS OF CKD 1.3.1: In predicting risk for outcome of CKD, identify the following variables: 1) cause of CKD; 2) GFR category; 3) albuminuria category; 4) other risk factors and comorbid conditions. (Not Graded) Criteria for CKD (either of the following present for 43 months) Markers of kidney damage (one or more) Albuminuria (AER Z30 mg/24 hours; ACR Z30 mg/g [Z3 mg/mmol]) Urine sediment abnormalities Electrolyte and other abnormalities due to tubular disorders Abnormalities detected by histology Structural abnormalities detected by imaging History of kidney transplantation Decreased GFR GFR o60 ml/min/1.73 m2 (GFR categories G3a–G5) Abbreviations: CKD, chronic kidney disease; GFR, glomerular filtration rate. GFR categories in CKD GFR category GFR (ml/min/1.73 m2 ) Terms G1 Z90 Normal or high G2 60–89 Mildly decreased* G3a 45–59 Mildly to moderately decreased G3b 30–44 Moderately to severely decreased G4 15–29 Severely decreased G5 o15 Kidney failure Abbreviations: CKD, chronic kidney disease; GFR, glomerular filtration rate. *Relative to young adult level In the absence of evidence of kidney damage, neither GFR category G1 nor G2 fulfill the criteria for CKD. Albuminuria categories in CKD AER ACR (approximate equivalent) Category (mg/24 hours) (mg/mmol) (mg/g) Terms A1 o30 o3 o30 Normal to mildly increased A2 30-300 3-30 30-300 Moderately increased* A3 4300 430 4300 Severely increased** Abbreviations: AER, albumin excretion rate; ACR, albumin-to-creatinine ratio; CKD, chronic kidney disease. *Relative to young adult level. **Including nephrotic syndrome (albumin excretion usually 42200 mg/24 hours [ACR 42220 mg/g; 4220 mg/mmol]). Kidney International Supplements (2013) 3, 5–14 5 1.3.2: In people with CKD, use estimated risk of concurrent complications and future outcomes to guide decisions for testing and treatment for CKD complications. (Not Graded) 1.3.3: In populations with CKD, group GFR and albuminuria categories with similar relative risk for CKD outcomes into risk categories. (Not Graded) 1.4: EVALUATION OF CKD 1.4.1: Evaluation of chronicity 1.4.1.1: In people with GFR o60 ml/min/1.73 m 2 (GFR categories G3a-G5) or markers of kidney damage, review past history and previous measurements to determine duration of kidney disease. (Not Graded) K If duration is 43 months, CKD is confirmed. Follow recommendations for CKD. K If duration is not 43 months or unclear, CKD is not confirmed. Patients may have CKD or acute kidney diseases (including AKI) or both and tests should be repeated accordingly. 1.4.2: Evaluation of cause 1.4.2.1: Evaluate the clinical context, including personal and family history, social and environmental factors, medications, physical examination, laboratory measures, imaging, and pathologic diagnosis to determine the causes of kidney disease. (Not Graded) 1.4.3: Evaluation of GFR 1.4.3.1: We recommend using serum creatinine and a GFR estimating equation for initial assessment. (1A) 1.4.3.2: We suggest using additional tests (such as cystatin C or a clearance measurement) for confirmatory testing in specific circumstances when eGFR based on serum creatinine is less accurate. (2B) 1.4.3.3: We recommend that clinicians (1B): K use a GFR estimating equation to derive GFR from serum creatinine (eGFR creat) rather than relying on the serum creatinine concentration alone. K understand clinical settings in which eGFRcreat is less accurate. 1.4.3.4: We recommend that clinical laboratories should (1B): K measure serum creatinine using a specific assay with calibration traceable to the international standard reference materials and minimal bias compared to isotope-dilution mass spectrometry (IDMS) reference methodology. K report eGFR creat in addition to the serum creatinine concentration in adults and specify the equation used whenever reporting eGFR creat. Persistent albuminuria categories Description and range A1 A2 A3 Normal to mildly increased Moderately increased Severely increased <30 mg/g <3 mg/mmol 30-300 mg/g 3-30 mg/mmol >300 mg/g >30 mg/mmol GFR categories (ml/min/ 1.73 m 2 ) Description and range G1 Normal or high ≥90 G2 Mildly decreased 60-89 G3a Mildly to moderately decreased 45-59 G3b Moderately to severely decreased 30-44 G4 Severely decreased 15-29 G5 Kidney failure <15 Prognosis of CKD by GFR and Albuminuria Categories: KDIGO 2012 Green: low risk (if no other markers of kidney disease, no CKD); Yellow: moderately increased risk; Orange: high risk; Red, very high risk. 6 Kidney International Supplements (2013) 3, 5–14 s u m m a r y o f r e c o m m e n d a t i o n s t a t e m e n t s K report eGFR creat in adults using the 2009 CKD-EPI creatinine equation. An alternative creatinine-based GFR estimating equation is acceptable if it has been shown to improve accuracy of GFR estimates compared to the 2009 CKD-EPI creatinine equation. When reporting serum creatinine: K We recommend that serum creatinine concentration be reported and rounded to the nearest whole number when expressed as standard international units (lmol/l) and rounded to the nearest 100 th of a whole number when expressed as conventional units (mg/dl). When reporting eGFRcreat : K We recommend that eGFR creat should be reported and rounded to the nearest whole number and relative to a body surface area of 1.73 m2 in adults using the units ml/min/1.73 m 2 . K We recommend eGFR creat levels less than 60 ml/min/1.73 m 2 should be reported as ‘‘decreased.’’ 1.4.3.5: We suggest measuring cystatin C in adults with eGFR creat 45–59 ml/min/1.73 m2 who do not have markers of kidney damage if confirmation of CKD is required. (2C) K If eGFR cys /eGFR creat-cys is also o60 ml/min/1.73 m 2 , the diagnosis of CKD is confirmed. K If eGFR cys /eGFR creat-cys is Z60 ml/min/1.73 m 2 , the diagnosis of CKD is not confirmed. 1.4.3.6: If cystatin C is measured, we suggest that health professionals (2C): K use a GFR estimating equation to derive GFR from serum cystatin C rather than relying on the serum cystatin C concentration alone. K understand clinical settings in which eGFRcys and eGFR creat-cys are less accurate. 1.4.3.7: We recommend that clinical laboratories that measure cystatin C should (1B): K measure serum cystatin C using an assay with calibration traceable to the international standard reference material. K report eGFR from serum cystatin C in addition to the serum cystatin C concentration in adults and specify the equation used whenever reporting eGFR cys and eGFR creat-cys. K report eGFR cys and eGFRcreat-cys in adults using the 2012 CKD-EPI cystatin C and 2012 CKD-EPI creatinine-cystatin C equations, respectively, or alternative cystatin C-based GFR estimating equations if they have been shown to improve accuracy of GFR estimates compared to the 2012 CKD-EPI cystatin C and 2012 CKD-EPI creatinine-cystatin C equations. When reporting serum cystatin C: K We recommend reporting serum cystatin C concentration rounded to the nearest 100 th of a whole number when expressed as conventional units (mg/l). When reporting eGFR cys and eGFR creat-cys : K We recommend that eGFR cys and eGFR creat-cys be reported and rounded to the nearest whole number and relative to a body surface area of 1.73 m 2 in adults using the units ml/min/1.73 m 2 . K We recommend eGFRcys and eGFR creat-cys levels less than 60 ml/min/1.73 m 2 should be reported as ‘‘decreased.’’ 1.4.3.8: We suggest measuring GFR using an exogenous filtration marker under circumstances where more accurate ascertainment of GFR will impact on treatment decisions. (2B) 1.4.4: Evaluation of albuminuria 1.4.4.1: We suggest using the following measurements for initial testing of proteinuria (in descending order of preference, in all cases an early morning urine sample is preferred) (2B): 1) urine albumin-to-creatinine ratio (ACR); 2) urine protein-to-creatinine ratio (PCR); 3) reagent strip urinalysis for total protein with automated reading; 4) reagent strip urinalysis for total protein with manual reading. 1.4.4.2: We recommend that clinical laboratories report ACR and PCR in untimed urine samples in addition to albumin concentration or proteinuria concentrations rather than the concentrations alone. (1B) 1.4.4.2.1: The term microalbuminuria should no longer be used by laboratories. (Not Graded) Kidney International Supplements (2013) 3, 5–14 7 s u m m a r y o f r e c o m m e n d a t i o n s t a t e m e n t s 1.4.4.3: Clinicians need to understand settings that may affect interpretation of measurements of albuminuria and order confirmatory tests as indicated (Not Graded): K Confirm reagent strip positive albuminuria and proteinuria by quantitative laboratory measurement and express as a ratio to creatinine wherever possible. K Confirm ACRZ30 mg/g (Z3 mg/mmol) on a random untimed urine with a subsequent early morning urine sample. K If a more accurate estimate of albuminuria or total proteinuria is required, measure albumin excretion rate or total protein excretion rate in a timed urine sample. 1.4.4.4: If significant non-albumin proteinuria is suspected, use assays for specific urine proteins (e.g., a1-micro- globulin, monoclonal heavy or light chains, [known in some countries as ‘‘Bence Jones’’ proteins]). (Not Graded) Chapter 2: Definition, identification, and prediction of CKD progression 2.1: DEFINITION AND IDENTIFICATION OF CKD PROGRESSION 2.1.1: Assess GFR and albuminuria at least annually in people with CKD. Assess GFR and albuminuria more often for individuals at higher risk of progression, and/or where measurement will impact therapeutic decisions (see figure below). (Not Graded) 2.1.2: Recognize that small fluctuations in GFR are common and are not necessarily indicative of progression. (Not Graded) 2.1.3: Define CKD progression based on one of more of the following (Not Graded): K Decline in GFR category (Z90 [G1], 60–89 [G2], 45–59 [G3a], 30–44 [G3b], 15–29 [G4], o15 [G5] ml/min/ 1.73 m2 ). A certain drop in eGFR is defined as a drop in GFR category accompanied by a 25% or greater drop in eGFR from baseline. K Rapid progression is defined as a sustained decline in eGFR of more than 5 ml/min/1.73 m 2 /yr. K The confidence in assessing progression is increased with increasing number of serum creatinine measurements and duration of follow-up. 2.1.4: In people with CKD progression, as defined in Recommendation 2.1.3, review current management, examine for reversible causes of progression, and consider referral to a specialist. (Not Graded) Guide to Frequency of Monitoring (number of times per year) by GFR and Albuminuria Category Persistent albuminuria categories Description and range A1 A2 A3 GFR categories (ml/min/1.73 m 2) Description and range G1 Normal or high ≥90 1 if CKD 1 2 G2 Mildly decreased 60–89 1 if CKD 1 2 G3a Mildly to moderately decreased 45–59 1 2 3 G3b Moderately to severely decreased 30–44 2 3 3 G4 Severely decreased 15–29 3 3 4+ G5 Kidney failure <15 4+ 4+ 4+ Normal to mildly increased Moderately increased Severely increased <30 mg/g <3 mg/mmol 30–300 mg/g 3–30 mg/mmol >300 mg/g >30mg/mmol GFR and albuminuria grid to reflect the risk of progression by intensity of coloring (green, yellow, orange, red, deep red). The numbers in the boxes are a guide to the frequency of monitoring (number of times per year). 8 Kidney International Supplements (2013) 3, 5–14 s u m m a r y o f r e c o m m e n d a t i o n s t a t e m e n t s 2.2: PREDICTORS OF PROGRESSION 2.2.1: Identify factors associated with CKD progression to inform prognosis. These include cause of CKD, level of GFR, level of albuminuria, age, sex, race/ethnicity, elevated BP, hyperglycemia, dyslipidemia, smoking, obesity, history of cardiovascular disease, ongoing exposure to nephrotoxic agents, and others. (Not Graded) Chapter 3: Management of progression and complications of CKD 3.1: PREVENTION OF CKD PROGRESSION BP and RAAS interruption 3.1.1: Individualize BP targets and agents according to age, coexistent cardiovascular disease and other comorbidities, risk of progression of CKD, presence or absence of retinopathy (in CKD patients with diabetes), and tolerance of treatment as described in the KDIGO 2012 Blood Pressure Guideline. (Not Graded) 3.1.2: Inquire about postural dizziness and check for postural hypotension regularly when treating CKD patients with BP-lowering drugs. (Not Graded) 3.1.3: Tailor BP treatment regimens in elderly patients with CKD by carefully considering age, comorbidities and other therapies, with gradual escalation of treatment and close attention to adverse events related to BP treatment, including electrolyte disorders, acute deterioration in kidney function, orthostatic hypotension and drug side effects. (Not Graded) 3.1.4: We recommend that in both diabetic and non-diabetic adults with CKD and urine albumin excretion o30 mg/ 24 hours (or equivalent*) whose office BP is consistently 4140 mm Hg systolic or 490 mm Hg diastolic be treated with BP-lowering drugs to maintain a BP that is consistently r140 mm Hg systolic and r90 mm Hg diastolic. (1B) 3.1.5: We suggest that in both diabetic and non-diabetic adults with CKD and with urine albumin excretion of Z30 mg/24 hours (or equivalent*) whose office BP is consistently 4130 mm Hg systolic or 480 mm Hg diastolic be treated with BP-lowering drugs to maintain a BP that is consistently r130 mm Hg systolic and r80 mm Hg diastolic. (2D) 3.1.6: We suggest that an ARB or ACE-I be used in diabetic adults with CKD and urine albumin excretion 30–300 mg/ 24 hours (or equivalent*). (2D) 3.1.7: We recommend that an ARB or ACE-I be used in both diabetic and non-diabetic adults with CKD and urine albumin excretion 4300 mg/24 hours (or equivalent*). (1B) 3.1.8: There is insufficient evidence to recommend combining an ACE-I with ARBs to prevent progression of CKD. (Not Graded) 3.1.9: We recommend that in children with CKD, BP-lowering treatment is started when BP is consistently above the 90 th percentile for age, sex, and height. (1C) 3.1.10: We suggest that in children with CKD (particularly those with proteinuria), BP is lowered to consistently achieve systolic and diastolic readings less than or equal to the 50 th percentile for age, sex, and height, unless achieving these targets is limited by signs or symptoms of hypotension. (2D) 3.1.11: We suggest that an ARB or ACE-I be used in children with CKD in whom treatment with BP-lowering drugs is indicated, irrespective of the level of proteinuria. (2D) *Approximate equivalents for albumin excretion rate per 24 hours—expressed as protein excretion rate per 24 hours, albumin-to-creatinine ratio, protein-to- creatinine ratio, and protein reagent strip results— are given in Table 7, Chapter 1. CKD and risk of AKI 3.1.12: We recommend that all people with CKD are considered to be at increased risk of AKI. (1A) 3.1.12.1: In people with CKD, the recommendations detailed in the KDIGO AKI Guideline should be followed for management of those at risk of AKI during intercurrent illness, or when undergoing investigation and procedures that are likely to increase the risk of AKI. (Not Graded) Kidney International Supplements (2013) 3, 5–14 9 s u m m a r y o f r e c o m m e n d a t i o n s t a t e m e n t s Protein intake 3.1.13: We suggest lowering protein intake to 0.8 g/kg/day in adults with diabetes (2C) or without diabetes (2B) and GFR o30 ml/min/ 1.73 m 2 (GFR categories G4-G5), with appropriate education. 3.1.14: We suggest avoiding high protein intake (41.3 g/kg/day) in adults with CKD at risk of progression. (2C) Glycemic control 3.1.15: We recommend a target hemoglobin A 1c (HbA 1c ) of B7.0% (53 mmol/mol) to prevent or delay progression of the microvascular complications of diabetes, including diabetic kidney disease. (1A) 3.1.16: We recommend not treating to an HbA 1c target of o7.0% (o53 mmol/mol) in patients at risk of hypoglycemia. (1B) 3.1.17: We suggest that target HbA 1c be extended above 7.0% (53 mmol/mol) in individuals with comorbidities or limited life expectancy and risk of hypoglycemia. (2C) 3.1.18: In people with CKD and diabetes, glycemic control should be part of a multifactorial intervention strategy addressing blood pressure control and cardiovascular risk, promoting the use of angiotensin-converting enzyme inhibition or angiotensin receptor blockade, statins, and antiplatelet therapy where clinically indicated. (Not Graded) Salt intake 3.1.19: We recommend lowering salt intake to o90 mmol (o2 g) per day of sodium (corresponding to 5 g of sodium chloride) in adults, unless contraindicated (see rationale). (1C) 3.1.19.1: We recommend restriction of sodium intake for children with CKD who have hypertension (systolic and/ or diastolic blood pressure 495th percentile) or prehypertension (systolic and/or diastolic blood pressure 490th percentile and o95th percentile), following the age-based Recommended Daily Intake. (1C) 3.1.19.2: We recommend supplemental free water and sodium supplements for children with CKD and polyuria to avoid chronic intravascular depletion and to promote optimal growth. (1C) Hyperuricemia 3.1.20: There is insufficient evidence to support or refute the use of agents to lower serum uric acid concentrations in people with CKD and either symptomatic or asymptomatic hyperuricemia in order to delay progression of CKD. (Not Graded) Lifestyle 3.1.21: We recommend that people with CKD be encouraged to undertake physical activity compatible with cardiovascular health and tolerance (aiming for at least 30 minutes 5 times per week), achieve a healthy weight (BMI 20 to 25, according to country specific demographics), and stop smoking. (1D) Additional dietary advice 3.1.22: We recommend that individuals with CKD receive expert dietary advice and information in the context of an education program, tailored to severity of CKD and the need to intervene on salt, phosphate, potassium, and protein intake where indicated. (1B) 3.2: COMPLICATIONS ASSOCIATED WITH LOSS OF KIDNEY FUNCTION Definition and identification of anemia in CKD 3.2.1: Diagnose anemia in adults and children 415 years with CKD when the Hb concentration is o13.0 g/dl (o130 g/l) in males and o12.0 g/dl (o120 g/l) in females. (Not Graded) 3.2.2: Diagnose anemia in children with CKD if Hb concentration is o11.0 g/dl (o110 g/l) in children 0.5–5 years, o11.5 g/dl (115 g/l) in children 5–12 years, and o12.0 g/dl (120 g/l) in children 12-15 years. (Not Graded) Evaluation of anemia in people with CKD 3.2.3: To identify anemia in people with CKD measure Hb concentration (Not Graded): K when clinically indicated in people with GFR Z60 ml/min/1.73 m 2 (GFR categories G1-G2); K at least annually in people with GFR 30–59 ml/min/1.73 m 2 (GFR categories G3a-G3b); K at least twice per year in people with GFRo30 ml/min/1.73 m 2 (GFR categories G4-G5). 10 Kidney International Supplements (2013) 3, 5–14 s u m m a r y o f r e c o m m e n d a t i o n s t a t e m e n t s 3.3: CKD METABOLIC BONE DISEASE INCLUDING LABORATORY ABNORMALITIES 3.3.1: We recommend measuring serum levels of calcium, phosphate, PTH, and alkaline phosphatase activity at least once in adults with GFR o45 ml/min/1.73 m 2 (GFR categories G3b-G5) in order to determine baseline values and inform prediction equations if used. (1C) 3.3.2: We suggest not to perform bone mineral density testing routinely in those with eGFR o45 ml/min/1.73 m 2 (GFR categories G3b-G5), as information may be misleading or unhelpful. (2B) 3.3.3: In people with GFR o45 ml/min/1.73 m 2 (GFR categories G3b-G5), we suggest maintaining serum phosphate concentrations in the normal range according to local laboratory reference values. (2C) 3.3.4: In people with GFR o45 ml/min/1.73 m 2 (GFR categories G3b-G5) the optimal PTH level is not known. We suggest that people with levels of intact PTH above the upper normal limit of the assay are first evaluated for hyperphosphatemia, hypocalcemia, and vitamin D deficiency. (2C) Vitamin D supplementation and bisphosphonates in people with CKD 3.3.5: We suggest not to routinely prescribe vitamin D supplements or vitamin D analogs, in the absence of suspected or documented deficiency, to suppress elevated PTH concentrations in people with CKD not on dialysis. (2B) 3.3.6: We suggest not to prescribe bisphosphonate treatment in people with GFR o30 ml/min/1.73 m2 (GFR categories G4-G5) without a strong clinical rationale. (2B) 3.4: ACIDOSIS 3.4.1: We suggest that in people with CKD and serum bicarbonate concentrations o22 mmol/l treatment with oral bicarbonate supplementation be given to maintain serum bicarbonate within the normal range, unless contraindicated. (2B) Chapter 4: Other complications of CKD: CVD, medication dosage, patient safety, infections, hospitalizations, and caveats for investigating complications of CKD 4.1:CKD AND CVD 4.1.1: We recommend that all people with CKD be considered at increased risk for cardiovascular disease. (1A) 4.1.2: We recommend that the level of care for ischemic heart disease offered to people with CKD should not be prejudiced by their CKD. (1A) 4.1.3: We suggest that adults with CKD at risk for atherosclerotic events be offered treatment with antiplatelet agents unless there is an increased bleeding risk that needs to be balanced against the possible cardiovascular benefits. (2B) 4.1.4: We suggest that the level of care for heart failure offered to people with CKD should be the same as is offered to those without CKD. (2A) 4.1.5: In people with CKD and heart failure, any escalation in therapy and/or clinical deterioration should prompt monitoring of eGFR and serum potassium concentration. (Not Graded) 4.2: CAVEATS WHEN INTERPRETING TESTS FOR CVD IN PEOPLE WITH CKD BNP/N-terminal-proBNP (NT-proBNP) 4.2.1: In people with GFR o60 ml/min/1.73 m2 (GFR categories G3a-G5), we recommend that serum concentrations of BNP/NT-proBNP be interpreted with caution and in relation to GFR with respect to diagnosis of heart failure and assessment of volume status. (1B) Troponins 4.2.2: In people with GFRo60 ml/min/1.73 m 2 (GFR categories G3a-G5), we recommend that serum concentrations of troponin be interpreted with caution with respect to diagnosis of acute coronary syndrome. (1B) Kidney International Supplements (2013) 3, 5–14 11 s u m m a r y o f r e c o m m e n d a t i o n s t a t e m e n t s Non-invasive testing 4.2.3: We recommend that people with CKD presenting with chest pain should be investigated for underlying cardiac disease and other disorders according to the same local practice for people without CKD (and subsequent treatment should be initiated similarly). (1B) 4.2.4: We suggest that clinicians are familiar with the limitations of non-invasive cardiac tests (e.g., exercise electrocardiography [ECG], nuclear imaging, echocardiography, etc.) in adults with CKD and interpret the results accordingly. (2B) 4.3: CKD AND PERIPHERAL ARTERIAL DISEASE 4.3.1: We recommend that adults with CKD be regularly examined for signs of peripheral arterial disease and be considered for usual approaches to therapy. (1B) 4.3.2: We suggest that adults with CKD and diabetes are offered regular podiatric assessment. (2A) 4.4: MEDICATION MANAGEMENT AND PATIENT SAFETY IN CKD 4.4.1: We recommend that prescribers should take GFR into account when drug dosing. (1A) 4.4.2: Where precision is required for dosing (due to narrow therapeutic or toxic range) and/or estimates may be unreliable (e.g., due to low muscle mass), we recommend methods based upon cystatin C or direct measurement of GFR. (1C) 4.4.3: We recommend temporary discontinuation of potentially nephrotoxic and renally excreted drugs in people with a GFR o60 ml/min/1.73 m2 (GFR categories G3a-G5) who have serious intercurrent illness that increases the risk of AKI. These agents include, but are not limited to: RAAS blockers (including ACE-Is, ARBs, aldosterone inhibitors, direct renin inhibitors), diuretics, NSAIDs, metformin, lithium, and digoxin. (1C) 4.4.4: We recommend that adults with CKD seek medical or pharmacist advice before using over-the-counter medicines or nutritional protein supplements. (1B) 4.4.5: We recommend not using herbal remedies in people with CKD. (1B) 4.4.6: We recommend that metformin be continued in people with GFR Z45 ml/min/1.73 m2 (GFR categories G1-G3a); its use should be reviewed in those with GFR 30–44 ml/min/1.73 m2 (GFR category G3b); and it should be discontinued in people with GFR o30 ml/min/1.73 m2 (GFR categories G4-G5). (1C) 4.4.7: We recommend that all people taking potentially nephrotoxic agents such as lithium and calcineurin inhibitors should have their GFR, electrolytes and drug levels regularly monitored. (1A) 4.4.8: People with CKD should not be denied therapies for other conditions such as cancer but there should be appropriate dose adjustment of cytotoxic drugs according to knowledge of GFR. (Not Graded) 4.5: IMAGING STUDIES 4.5.1: Balance the risk of acute impairment in kidney function due to contrast agent use against the diagnostic value and therapeutic implications of the investigation. (Not Graded) Radiocontrast 4.5.2: We recommend that all people with GFR o60 ml/min/1.73 m 2 (GFR categories G3a-G5) undergoing elective investigation involving the intravascular administration of iodinated radiocontrast media should be managed according to the KDIGO Clinical Practice Guideline for AKI including: K Avoidance of high osmolar agents (1B); K Use of lowest possible radiocontrast dose (Not Graded); K Withdrawal of potentially nephrotoxic agents before and after the procedure (1C); K Adequate hydration with saline before, during, and after the procedure (1A); K Measurement of GFR 48–96 hours after the procedure (1C). Gadolinium-based contrast media 4.5.3: We recommend not using gadolinium-containing contrast media in people with GFR o15 ml/min/1.73 m 2 (GFR category G5) unless there is no alternative appropriate test. (1B) 4.5.4: We suggest that people with a GFR o30 ml/min/1.73 m2 (GFR categories G4-G5) who require gadolinium- containing contrast media are preferentially offered a macrocyclic chelate preparation. (2B) Bowel preparation 4.5.5: We recommend not to use oral phosphate-containing bowel preparations in people with a GFR o60 ml/min/ 1.73 m 2 (GFR categories G3a-G5) or in those known to be at risk of phosphate nephropathy. (1A) 12 Kidney International Supplements (2013) 3, 5–14 s u m m a r y o f r e c o m m e n d a t i o n s t a t e m e n t s 4.6: CKD AND RISKS FOR INFECTIONS, AKI, HOSPITALIZATIONS, AND MORTALITY CKD and risk of infections 4.6.1: We recommend that all adults with CKD are offered annual vaccination with influenza vaccine, unless contraindicated. (1B) 4.6.2: We recommend that all adults with eGFR o30 ml/min/1.73 m 2 (GFR categories G4-G5) and those at high risk of pneumococcal infection (e.g., nephrotic syndrome, diabetes, or those receiving immunosuppression) receive vaccination with polyvalent pneumococcal vaccine unless contraindicated. (1B) 4.6.3: We recommend that all adults with CKD who have received pneumococcal vaccination are offered revaccination within 5 years. (1B) 4.6.4: We recommend that all adults who are at high risk of progression of CKD and have GFR o30 ml/min/1.73 m 2 (GFR categories G4-G5) be immunized against hepatitis B and the response confirmed by appropriate serological testing. (1B) 4.6.5: Consideration of live vaccine should include an appreciation of the patient’s immune status and should be in line with recommendations from official or governmental bodies. (Not Graded) 4.6.6: Pediatric immunization schedules should be followed according to official international and regional recommedations for children with CKD. (Not Graded) CKD and risk of AKI 4.6.7: We recommend that all people with CKD are considered to be at increased risk of AKI. (1A) 4.6.7.1: In people with CKD, the recommendations detailed in the KDIGO AKI Guideline should be followed for management of those at risk of AKI during intercurrent illness, or when undergoing investigation and procedures that are likely to increase the risk of AKI. (Not Graded) CKD and risk of hospitalization and mortality 4.6.8: CKD disease management programs should be developed in order to optimize the community management of people with CKD and reduce the risk of hospital admission. (Not Graded) 4.6.9: Interventions to reduce hospitalization and mortality for people with CKD should pay close attention to the management of associated comorbid conditions and cardiovascular disease in particular. (Not Graded) Chapter 5: Referral to specialists and models of care 5.1: REFERRAL TO SPECIALIST SERVICES 5.1.1: We recommend referral to specialist kidney care services for people with CKD in the following circumstances (1B): K AKI or abrupt sustained fall in GFR; K GFR o30 ml/min/1.73 m2 (GFR categories G4-G5)*; K a consistent finding of significant albuminuria (ACR Z300 mg/g [Z30 mg/mmol] or AER Z300 mg/ 24 hours, approximately equivalent to PCR Z500 mg/g [Z50 mg/mmol] or PER Z500 mg/24 hours); K progression of CKD (see Recommendation 2.1.3 for definition); K urinary red cell casts, RBC 420 per high power field sustained and not readily explained; K CKD and hypertension refractory to treatment with 4 or more antihypertensive agents; K persistent abnormalities of serum potassium; K recurrent or extensive nephrolithiasis; K hereditary kidney disease. 5.1.2: We recommend timely referral for planning renal replacement therapy (RRT) in people with progressive CKD in whom the risk of kidney failure within 1 year is 10–20% or higherw, as determined by validated risk prediction tools. (1B) *If this is a stable isolated finding, formal referral (i.e., formal consultation and ongoing care management) may not be necessary and advice from specialist services may be all that is required to facilitate best care for the patients. This will be health-care system dependent. wThe aim is to avoid late referral, defined here as referral to specialist services less than 1 year before start of RRT. Kidney International Supplements (2013) 3, 5–14 13 s u m m a r y o f r e c o m m e n d a t i o n s t a t e m e n t s 5.2: CARE OF THE PATIENT WITH PROGRESSIVE CKD 5.2.1: We suggest that people with progressive CKD should be managed in a multidisciplinary care setting. (2B) 5.2.2: The multidisciplinary team should include or have access to dietary counseling, education and counseling about different RRT modalities, transplant options, vascular access surgery, and ethical, psychological, and social care. (Not Graded) 5.3: TIMING THE INITIATION OF RRT 5.3.1: We suggest that dialysis be initiated when one or more of the following are present: symptoms or signs attributable to kidney failure (serositis, acid-base or electrolyte abnormalities, pruritus); inability to control volume status or blood pressure; a progressive deterioration in nutritional status refractory to dietary intervention; or cognitive impairment. This often but not invariably occurs in the GFR range between 5 and 10 ml/min/1.73 m 2 . (2B) 5.3.2: Living donor preemptive renal transplantation in adults should be considered when the GFR is o20 ml/min/ 1.73 m 2 , and there is evidence of progressive and irreversible CKD over the preceding 6–12 months. (Not Graded) 5.4: STRUCTURE AND PROCESS OF COMPREHENSIVE CONSERVATIVE MANAGEMENT 5.4.1: Conservative management should be an option in people who choose not to pursue RRT and this should be supported by a comprehensive management program. (Not Graded) 5.4.2: All CKD programs and care providers should be able to deliver advance care planning for people with a recognized need for end-of-life care, including those people undergoing conservative kidney care. (Not Graded) 5.4.3: Coordinated end-of-life care should be available to people and families through either primary care or specialist care as local circumstances dictate. (Not Graded) 5.4.4: The comprehensive conservative management program should include protocols for symptom and pain management, psychological care, spiritual care, and culturally sensitive care for the dying patient and their family (whether at home, in a hospice or a hospital setting), followed by the provision of culturally appropriate bereavement support. (Not Graded) Persistent albuminuria categories Description and range A1 A2 A3 Normal to mildly increased Moderately increased Severely increased GFR categories (ml/min/ 1.73 m 2 ) Description and range G1 Normal or high ≥90 Monitor Refer* G2 Mildly decreased 60–89 Monitor Refer* G3a 45–59 Monitor Monitor Refer G3b 30–44 Monitor Monitor Refer G4 Severely decreased 15–29 Refer* Refer* Refer G5 Kidney failure <15 Refer Refer Refer Mildly to moderately decreased Moderately to severely decreased <30 mg/g <3 mg/mmol 30–300 mg/g 3–30 mg/mmol >300 mg/g >30 mg/mmol Referral decision making by GFR and albuminuria. *Referring clinicians may wish to discuss with their nephrology service depending on local arrangements regarding monitoring or referring. 14 Kidney International Supplements (2013) 3, 5–14 s u m m a r y o f r e c o m m e n d a t i o n s t a t e m e n t s Introduction: The case for updating and context Kidney International Supplements (2013) 3, 15–18; doi:10.1038/kisup.2012.63 Justification for updating the guideline for CKD Definition, Evaluation, Classification, and Stratification from an international perspective In 2002, the US-based Kidney Disease Outcomes Quality Initiative (KDOQI) group published a guideline on defini- tion, classification and evaluation of chronic kidney disease (CKD). The guideline proposed uniform definitions of CKD together with a staging system 1 and described issues related to measurement of kidney function that had not previously been identified by the clinical community. This publication revolutionized the concept and management of CKD, generating substantial research and controversy, stimulating discussion, and influencing public policy and laboratory practice. The research generated has led to new insights which require contextualizing in the current era, providing the evidence drivers for updating guidance for defining, diagnosing, staging and managing CKD, and promoting improved care of those with early CKD. Successive interna- tional controversies conferences, under the direction of Kidney Disease: Improving Global Outcomes (KDIGO), have shaped the scope of this international update through: 1. Facilitating global implementation of the definition and classification of CKD, identifying areas of uncertainty, and developing a collaborative research agenda to improve the evidence base and facilitate implementation (November 2004). 2. Evaluating the definition and classification of CKD from a global public health perspective (October 2006). 3. Reviewing the definition and classification of CKD based on data on patient prognosis derived from a unique research collaboration on prognosis (October 2009). Given the international interest in understanding and improving the outcomes of people living with kidney disease and the tremendous amount of data generated since 2002, a need was identified to review, revise, and update the original 2002 KDOQI guideline. There has been a wealth of published data highlighting the risk of adverse consequences and outcomes in people with albumin excretion rate (AER) 430 mg/24 hours and/or glomerular filtration rate (GFR) o60 ml/min/1.73 m 2 (GFR categories G3a-G5), irrespective of the etiology or duration of reduced kidney function. Description of the relationship between GFR, albuminuria and prognosis has significantly improved the understanding of CKD in multiple popula- tions. 2–5 Internationally, the widespread use of albumin-to- creatinine ratio (ACR) and reagent strip urine testing to detect elevated albuminuria together with reporting of estimated GFR (eGFR) has led to easier identification of people with CKD. However elevated albuminuria or reduced GFR alone are not necessarily indicators of need for specialist referral. Clinicians and medical systems are still adjusting to the improved ‘‘identification’’ of CKD and guidance about appropriate stratification of risk and modified action plans for different subgroups of individuals regarding further evaluation, referral, or treatment is needed. The goal of this guideline is to clarify the definition and classification system of CKD, and to develop appropriate guidance as to the management and care of people with CKD. In addition, we present a framework which should foster an extended collaborative research agenda over the next decade and inform guidelines in the future. Kidney disease is an important problem worldwide Kidney disease is defined as an abnormality of kidney structure or function with implications for the health of an individual, which can occur abruptly, and either resolve or become chronic. CKD is a general term for heterogeneous disorders affecting kidney structure and function with variable clinical presentation, in part related to cause, severity and the rate of progression. The concept of CKD evolved after the recognition of the contribution of disordered kidney structure and function on the health of individuals across a wide range of severity. 1 The utility of the concept is that recognition of CKD will have implications for the individual and their care. Kidney failure is traditionally considered as the most serious outcome of CKD. Symptoms are usually due to complications of decreased kidney function and when severe, they can be treated only by dialysis or transplantation. Earlier stages of kidney disease are often asymptomatic, are detected during the evaluation of comorbid conditions, and may be reversible. Rapidly progressive diseases may lead to kidney failure within months but most diseases evolve over decades, and some patients do not progress during many years of follow-up. Figure 1 shows a conceptual model for the development, progression, and complications of CKD.1,6 The model includes antecedents associated with increased risk for development of CKD, stages of disease, and complications including death. Risks for development of CKD may be categorized either as susceptibility to kidney disease due to sociodemographic and genetic factors or exposure to factors that can initiate kidney disease. Abnormalities in kidney structure (damage) usually precede abnormalities in func- tion. Outcomes of CKD may be progression, as shown by the horizontal arrows, and complications, as shown by the diagonal arrows, or both. http://www.kidney-international.org i n t r o d u c t i o n & 2013 KDIGO Kidney International Supplements (2013) 3, 15–18 15 Although the need for treatment of chronic kidney failure with dialysis and/or kidney transplantation arises in only 1% of people with CKD, it remains the most expensive of chronic diseases and reduces lifespan significantly. The costs of dialysis and transplantation consume disproportionate amounts within the health-care budgets in all jurisdictions (5% of annual budgets consumed by less than 1% of the population). Failure to recognize CKD results in neglect of its consequences and complications, and late referral of people with advanced CKD resulting in worse renal replacement therapy (RRT) outcomes. In addition, there is a growing body of evidence that indicates people with CKD are at increased risk of acute kidney injury (AKI), which is also associated with poor outcomes and may accelerate progres- sion of CKD. Therefore, identification of people at earlier time points in the trajectory of CKD, with appropriate management and earlier referral of those who would benefit from specialist kidney services, should lead to both economic and clinical benefits. In those countries where access to dialysis and transplan- tation services may be limited or unavailable, the final consequence of progressive CKD is death. In all locations, irrespective of availability of dialysis and transplantation, early identification of CKD therefore assumes great im- portance, as delay or prevention of progression has the potential to prolong health and save lives for much lower cost than RRT. Although etiologies vary in frequency or absolute numbers in different countries, the proportion of people with important antecedents to CKD, such as diabetes, is growing alarmingly worldwide in both developed and developing countries. Complications of CKD affect all organ systems. Kidney failure leads to the commonly recognized symptoms of uremia. Less severe CKD has been recognized as an independent risk factor for cardiovascular disease (CVD) and other common conditions affecting the elderly, such as infection and impairments in physical function and cogni- tion. In addition, CKD is associated with increased risk from adverse effects of drugs, intravascular radiocontrast admin- istration, surgery and other invasive procedures. Altogether, these complications are associated with higher morbidity, mortality and cost. If CKD is detected early, the associated complications and the progression to kidney failure can be delayed or even prevented through appropriate interventions. Regular testing of high-risk groups (i.e., people with diabetes, hypertension, CVD, structural renal tract disease, multi- system diseases with potential kidney involvement such as systemic lupus erythematosus, family history of kidney failure, hereditary kidney disease, the elderly, those receiving potential nephrotoxic drugs or those opportunistically found to have hematuria or proteinuria) can give an early indication of kidney damage, thus permitting the introduc- tion of available interventions at an early stage, and the testing of novel interventions with potential added value. Factors associated with progression of CKD and with increased cardiovascular risk are overlapping to a large extent. Thus targeting of those risk factors that are modifiable may both reduce CVD in people with CKD and reduce progression of CKD to end-stage renal disease (ESRD). There is strong evidence that blockade of the renin-angiotensin- aldosterone system (RAAS) is a blood pressure (BP) lowering strategy which is more effective in reducing risk of kidney and cardiovascular disease in the presence of albuminuria. The development of guidance for health-care providers will provide opportunities to improve the care of people with kidney disease. We hope that this publication serves to stimulate strategic research initiatives from basic, translational, clinical and health outcome perspectives. General summary for the reader: what you will and will not find in this guideline 1. The guideline will offer best practice and evidence-based advice on the evaluation and approach to management of CKD. a. The target population for the guideline is all people identified with CKD who are not on RRT (i.e., not on dialysis or have not received a kidney transplant). b. The target population includes adults and children. The guideline will cover the spectrum of individuals with CKD, from children to the elderly who form important subgroups, underscoring current issues at the extremes of age with respect to the evidence base, especially in relation to implementation and manage- ment issues. Where the guideline does not apply to Figure 1 | Conceptual model of CKD. Continuum of development, progression, and complications of CKD and strategies to improve outcomes. Horizontal arrows between circles represent development, progression, and remission of CKD. Left-pointing horizontal arrowheads signify that remission is less frequent than progression. Diagonal arrows represent occurrence of complications of CKD, including drug toxicity, endocrine and metabolic complications, cardiovascular disease, and others such as infection, cognitive impairment, and frailty. Complications might also arise from adverse effects of interventions to prevent or treat the disease. CKD, chronic kidney disease; EOL, end-of-life care and/or conservative management; GFR, glomerular filtration rate. Adapted from Levey AS, Stevens LA, Coresh J. 6 Conceptual model of CKD: applications and implications. Am J Kidney Dis. 2009; 53:S4-16 with permission from the National Kidney Foundation; accessed http://download.journals. elsevierhealth.com/pdfs/journals/0272-6386/PIIS02726386080 17186.pdf 16 Kidney International Supplements (2013) 3, 15–18 i n t r o d u c t i o n children, statements to that effect will be made. It is beyond the scope of this guideline to address all issues related to children with CKD, given the heteroge- neous nature of this group of individuals who range from newborn to post-adolescents, with specific physiological differences within each of those groups. Specific evidence and rationale will be articulated as appropriate in each section. c. The target condition is CKD of any or unknown etiology. Identifying the cause of the CKD is strongly encouraged, both because treatment may need to be adjusted according to etiology and because it influences the prognosis and relative importance of risk factors associated with CKD. A comprehensive list of possible etiologies is not practical and guidance on detailed work-up for specific causes of CKD is beyond the scope of this document (readers will be referred to other pertinent sources). We will describe how knowledge of the etiology of CKD in an individual may be important in prognostication and management. d. The target audience of the guideline includes nephrologists, primary care physicians, non-nephro- logy specialists (e.g., cardiologists, diabetologists, etc), clinical chemists and other practitioners caring for adults and children with CKD. The guideline is also expected to be suitable for use in public policy and other health-care arenas. e. As a global guideline it is written for use in different health-care settings, but unavoidably its full imple- mentation relies on health-care resources that are not universally available. We recognize this overtly in some of the discussion sections within the guideline. f. The target health-care settings include primary, secondary, and tertiary care. 2. The guideline will provide information, advice, and education to support self-management for people with CKD and aid caregivers with the diagnosis and manage- ment of CKD. To avoid redundancy and potential for becoming outdated, the reader is asked to refer to existing KDIGO guidance on anemia, metabolic bone disease, BP, AKI, hepatitis C, lipid management, glomerulonephritis (GN) and other pertinent guidelines. 3. The guideline will provide a blueprint for an approach to CKD care in an international context. While the guideline will be sensitive to issues related to ethnicity and also geographical considerations, it is expected that subsequent regional adaptation will be required for specific health- care settings or contexts. 4. Research recommendations in general are described to inform a framework for ongoing research agendas in the international community. We have attempted to identify important study questions in need of answers. Through identification of gaps in knowledge, the reader will be better able to define methodologies, definitions of populations, and outcome measures of relevance to study designs in the future. Topics that will not be covered This document is not intended to provide enough detail to replace training and education in nephrology, nor is it intended to serve as a textbook of medicine or nephrology. Thus, there are some specific topics that will not be covered. Specifically we will not discuss: 1. Evaluation and management of people receiving RRT (management of kidney failure by dialysis or kidney transplantation). 2. Specific approaches to the diagnosis of people with AKI and other acute kidney diseases. This topic has been extensively reviewed in KDIGO Clinical Practice Guideline for Acute Kidney Injury. 7 3. Diagnostic work-up or treatment of specific causes of CKD, including GN. 8 4. Management of pregnancy in women with CKD or of pregnant women who develop kidney disease. 5. Detailed management of endocrine and metabolic com- plications of CKD. These are reviewed extensively by recent KDIGO guidelines on CKD-MBD, 9 management of BP10 and anemia 11 in CKD. 6. Detailed management of CVD and CVD risk factors in CKD. This is reviewed in a recent KDIGO publication. 12 7. Drug dosing in CKD. This topic has been addressed in a recent KDIGO publication. 13 8. Details of resource implications and barriers to imple- mentation are beyond the scope of this guideline. By virtue of its being international, the variability in these aspects by country, region, and even jurisdiction is vast. We look to the individual commentaries from around the world to inform those aspects more fully. Brief overview on methodology The Work Group included an international group of kidney specialists, primary care physicians, diabetologists, epide- miologists, clinical chemists, administrators, and a profes- sional Evidence Review Team (ERT) who provided support and guidance to the group. Details of the methods used by the ERT are described in Methods for Guideline Development, along with the systematic searches for areas identified by Work Group members and performed by the ERT. The recommendations and statements created herein will serve to direct both care and research in the next decade. Importantly, we expect the renewed classification system and risk stratification concepts to direct research and enrollment into trials which address test therapies to improve patient outcomes. Statement grading and wording. The methods for formu- lating recommendations were based on modified Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system, and have used the words Kidney International Supplements (2013) 3, 15–18 17 i n t r o d u c t i o n ‘recommend’ when the balance of evidence would support the notion that the majority of patients would benefit from the implementation of this recommendation. The words ‘suggest’ are used when the balance of evidence would support the notion that some patients would benefit from the implementation of the recommendation, but that individual patient, physician and health-care system considerations would be necessary to adopt the practice. There are also ungraded statements many of which are often key practice points or educational issues (Table 1). The Work Group had struggled whether to organize them differently or move them to the rationale section. Ultimately they remain here in the guideline statement format so that they are not overlooked by those wishing to understand the condition better. A significant proportion of statements in this guideline are ungraded because the grading system is most appropriate for statements of intervention. The international system, GRADE, allows for such statements which guide thoughts and attitude, and not specific actions. In the descriptive statements identifying, classifying, and defining the condition of CKD, grading is not possible. Since few studies have compared different methods of evaluation or care models, those statements too are difficult to grade. Thus, grading of specific statements is reserved for interventions or alternative diagnostic test strategies for which there is a substantial body of evidence. Consideration of health benefits, side effects, and risks. These have been considered when formulating the recom- mendations but given the paucity of data in many of the areas reviewed, this has been less consistent than the Work Group would have liked. We see this as an area of research and future study that will inform future updates. Review process. As with all KDIGO guidelines a two step process was used. This included a review by the Board of Directors, with feedback to the Work Group Chairs followed by revisions to the document. The public review, consisting of interested stakeholders from international communities, organizations and individuals, was then undertaken. The draft document was sent to a total of 2320 external reviewers, with 293 responses received and tabulated. The feedback was carefully reviewed and where appropriate, suggested changes were incorporated into the final document. In the interest of transparency, the Work Group prepared individual responses to each reviewer comment and these will be posted on the KDIGO website. Planned update. At the current time there is no official plan to update the guideline in its entirety. Given the breadth and depth of the current undertaking and with knowledge of new studies and applications of some of these recommenda- tions, the Work Group recommends that individual sections of this guideline be updated every 3-5 years as new evidence becomes available. We believe that this will be more practical for the readership. Table 1 | KDIGO nomenclature and description for grading recommendations Implications Grade* Patients Clinicians Policy Level 1 ‘‘We recommend’’ Most people in your situation would want the recommended course of action and only a small proportion would not. Most patients should receive the recommended course of action. The recommendation can be evaluated as a candidate for developing a policy or a performance measure. Level 2 ‘‘We suggest’’ The majority of people in your situation would want the recommended course of action, but many would not. 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. The recommendation is likely to require substantial debate and involvement of stakeholders before policy can be determined. *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. 18 Kidney International Supplements (2013) 3, 15–18 i n t r o d u c t i o n Chapter 1: Definition and classification of CKD Kidney International Supplements (2013) 3, 19–62; doi:10.1038/kisup.2012.64 1.1: DEFINITION OF CKD 1.1.1: CKD is defined as abnormalities of kidney struc- ture or function, present for 43 months, with implications for health (Table 2). (Not Graded) RATIONALE The definition of CKD remains intact, but we have clarified the classification and risk stratification as indicated below. The addition of ‘with implications for health’ is intended to reflect the notion that a variety of abnormalities of kidney structure or function may exist, but not all have implications for health of individuals, and therefore need to be contextualized. Kidney damage refers to a broad range of abnormalities observed during clinical assessment, which may be insensitive and non-specific for the cause of disease but may precede reduction in kidney function (Table 2). Excretory, endocrine and metabolic functions decline together in most chronic kidney diseases. GFR is generally accepted as the best overall index of kidney function. We refer to a GFR o60 ml/min/ 1.73 m 2 as decreased GFR (Table 2) and a GFR o15 ml/min/ 1.73 m 2 as kidney failure. AKI may occur in patients with CKD and hasten the progression to kidney failure.14 Complications include drug toxicity, metabolic and endocrine complications, increased risk for CVD, and a variety of other recently recognized complications, including infections, frailty, and cognitive impairment. 15–18 Complica- tions may occur at any stage, often leading to death without progression to kidney failure. Complications may also arise from adverse effects of interventions to prevent or treat the disease and associated comorbidity. Criteria for CKD Defining terms: The following section aims to define specific terms and concepts so as to ensure clarity among all users. In addition, the rationale for including these terms is included. Table 3 provides a justification for the criteria for CKD. The criteria for definition of CKD are objective and can be ascertained by means of simple laboratory tests without identification of the cause of disease, thereby enabling detection of CKD by non-nephrologist physicians and other health professionals. Duration 43 Months Kidney diseases may be acute or chronic. We explicitly but arbitrarily define duration of 43 months (490 days) as delineating ‘‘chronic’’ kidney disease. The rationale for defining chronicity is to differentiate CKD from acute kidney diseases (such as acute GN), including AKI, which may require different interventions, and have different etiologies and outcomes. 7 We did not define acute kidney disease (AKD) because there does not appear be an evidence base for a precise definition. The duration of kidney disease may be documented or inferred based on the clinical context. For example, a patient with decreased kidney function or kidney damage in the midst of an acute illness, without prior documentation of kidney disease, may be inferred to have AKI. Resolution over days to weeks would confirm the diagnosis of AKI. A patient with similar findings in the absence of an acute illness may be inferred to have CKD, and if followed over time would be confirmed to have CKD. In both cases, repeat ascertainment of kidney function and kidney damage is recommended for accurate diagnosis. The timing of the evaluation depends on clinical judgment, with earlier evaluation for the patients suspected of having AKI and later evaluation for the patient suspected of having CKD. For further details on the Evaluation of CKD, see Chapter 1.4. Reversibility. Most kidney diseases do not have symptoms or findings until later in their course and are detected only when they are chronic. Most causes of CKD are irreversible with a life-long course, and treatment aimed at slowing progression to kidney failure. However, chronicity is not synonymous with irreversibility. In some cases, CKD is entirely reversible, either spontaneously or with treatment, and in other cases, treatment can cause partial regression of kidney damage and improvement in function (e.g., immuno- suppressive therapies for GN). Even kidney failure may be reversed with transplantation. Because of the long course of most cases of CKD, patients often have one or more episodes of AKI, superimposed upon CKD. Decreased GFR The kidney has many functions, including excretory, endocrine and metabolic functions. The GFR is one compo- nent of excretory function, but is widely accepted as the best overall index of kidney function because it is generally reduced after widespread structural damage and most other kidney functions decline in parallel with GFR in CKD. We chose a threshold of GFR o60 ml/min/1.73 m 2 (GFR categories G3a-G5) for 43 months to indicate CKD. A GFR o60 ml/min/1.73 m2 is less than half of the normal value in young adult men and women of approximately 125 ml/min/ 1.73 m2 . Figure 2 shows a compilation of GFR measurements in apparently healthy men and women in the US and Europe by age from more than 40 years ago. 20 The age-associated GFR decline is observed in longitudinal as well as cross http://www.kidney-international.org c h a p t e r 1 & 2013 KDIGO Kidney International Supplements (2013) 3, 19–62 19 Table 2 | Criteria for CKD (either of the following present for 43 months) Markers of kidney damage (one or more) Albuminuria (AERZ30 mg/24 hours; ACRZ30 mg/g [Z3 mg/mmol]) Urine sediment abnormalities Electrolyte and other abnormalities due to tubular disorders Abnormalities detected by histology Structural abnormalities detected by imaging History of kidney transplantation Decreased GFR GFRo60 ml/min/1.73 m2 (GFR categories G3a-G5) Abbreviations: CKD, chronic kidney disease; GFR, glomerular filtration rate. Table 3 | Criteria for definition of CKD 19 Criteria Comment Duration 43 months, based on documentation or inference Duration is necessary to distinguish chronic from acute kidney diseases K Clinical evaluation will often enable documentation or inference of duration K Documentation of duration is usually not declared in epidemiologic studies GFR o60 ml/min/1.73 m 2 (GFR categories G3a-G5) GFR is the best overall index of kidney function in health and disease K The normal GFR in young adults is approximately 125 ml/min/1.73 m 2 . GFR o15 ml/min/1.73 m2 (GFR category G5) is defined as kidney failure K Decreased GFR can be detected by current estimating equations for GFR based on SCr or cystatin C but not by SCr or cystatin C alone K Decreased eGFR can be confirmed by measured GFR, if required Kidney damage as defined by structural abnormalities or functional abnormalities other than decreased GFR Albuminuria as a marker of kidney damage [increased glomerular permeability], urine AER Z30 mg/24 hours, approximately equivalent to urine ACRZ30 mg/g (Z3 mg/mmol)* K The normal urine ACR in young adults is o10 mg/g (o1 mg/mmol) K Urine ACR 30-300 mg/g (3–30 mg/mmol; category A2) generally corresponds to ‘‘microalbuminuria,’’ now referred to as ‘‘moderately increased’’ K Urine ACR 4300 mg/g (430 mg/mmol; category A3) generally corresponds to ‘‘macroalbuminuria,’’ now termed ‘‘severely increased’’ K Urine ACR42200 mg/g (220 mg/mmol) may be accompanied by signs and symptoms of nephrotic syndrome (e.g., low serum albumin, edema, and high serum cholesterol) K Threshold value corresponds approximately to urine reagent strip values of trace or +, depending on urine concentration. K High urine ACR can be confirmed by urine albumin excretion in a timed urine collection expressed as AER Urinary sediment abnormalities as markers of kidney damage K Isolated non-visible (microscopic) hematuria with abnormal RBC morphology (anisocytosis) in GBM disorders K RBC casts in proliferative glomerulonephritis K WBC casts in pyelonephritis or interstitial nephritis K Oval fat bodies or fatty casts in diseases with proteinuria K Granular casts and renal tubular epithelial cells in many parenchymal diseases (non-specific) Renal tubular disorders K Renal tubular acidosis K Nephrogenic diabetes insipidus K Renal potassium wasting K Renal magnesium wasting K Fanconi syndrome K Non-albumin proteinuria K Cystinuria Pathologic abnormalities detected by histology or inferred (examples of causes) K Glomerular diseases (diabetes, autoimmune diseases, systemic infections, drugs, neoplasia) K Vascular diseases (atherosclerosis, hypertension, ischemia, vasculitis, thrombotic microangiopathy) K Tubulointerstitial diseases (urinary tract infections, stones, obstruction, drug toxicity) K Cystic and congenital diseases 20 Kidney International Supplements (2013) 3, 19–62 c h a p t e r 1 sectional studies, but varies substantially among individuals within the population. 21 More recent data in kidney donors confirm these general trends.22,23 Limited data are available for non-whites in the US and Europe or in other countries, although data suggest that the normal range for measured GFR and the age-associated decline is similar. 24–26 A GFR o60 ml/min/1.73 m 2 can be detected by routine laboratory testing. Current estimating equations for GFR (eGFR) based on serum creatinine (SCr), but not SCr alone, are sensitive for detecting measured GFRo60 ml/min/ 1.73 m 2 . 27 A decreased eGFR using SCr can be confirmed by GFR estimation using an alternative fi