AJKD KDOQI Commentary KDOGQI US Commentary on the 2012 KDIGO Clinical Practice Guideline for the Evaluation and Management of CKD Lesley A. Inker, MD,_' Brad C. Astor, PhD,” Chester H. Fox, MD;° Tamara Isakova, MD,“ James P. Lash, MD,° Carmen A. Peralta, MD,° Manjula Kurella Tamura, MD,” and Harold |. Feldman, MD, MSCE* ‘The Natonal Kidney Foundstion-Kidney Disease Outcomes Qualiylritative (NKF-KDOQ)) guideline for ‘valuation, classicaion, and statiication of chron: Kidney disoaso (CKD) was published in 2002. Tho KDOGI guideine was wel accepted by the medical and pubicheath comenuntes, but conoems and ciésms arose a5 new evidence became avalible since the publican of the orignal guidelines. KDIGO (Kidnoy Disoase: Improving Global Outcomes) recently published an updatod guidoin to carly tho detintion and Ceassiiaton of CKD and to update recommendations for the evaluation and management of ndunis wih CCKD based on new evidence published since 2002. The primary recommendations were to retain the current efniton of CKD based on decreased glomerular firation rte or matkers of kidney damage for 3 mnths or ‘moro and to includo the cause of kidnoy disoaso and lovol of albuminuria, as woll as lovl of glomerular fitraion rato, for CKD dlasifeation. NKF-KDOOI corvoned a work group to write a commentary on tho KDIGO guideline in order to assist US practtioners in interpreting the KDIGO guieline and etemninng Rs Aappcabity within tee own practices. Overal, the commentary work group agreed with mast of the recom ‘mendations contained inthe KDIGO guidelines, paniculaty the recommendations regarding the definition and Classification of CKD. However, there were some concems aboit incorporating the cause of disease into CKD ‘assiiaton, Haddon to certain recommendations for evaluation and management ‘Am J Kidney Dis. 648)"713-735. Published by Elsover In. on Bohl ofthe National Kidney Foundation, Inc. INDEX WORDS: Estimated glomerular fitraton rate (@GFF); chronic Kidney diseases (CKO) staging) albuminuria; key disease progression; Kidney Disease: Improving Global Outcomes (KDIGO); clinical practice guidetne; Kidney Disease Quality Outcomes QualtyIntiative (KDOQ), FOREWORD It has been 12 years since the publication of the National Kidney Foundation-Kidney Disease Out ‘comes Quality Initiative (NKF-KDOQD guideline for evaluation, classification, and stratification of chronic kidney disease (CKD).! While not a new medication, a new device, or a landmark clinical tal, this guideline publication perhaps had a greater impact on the diag- nosis and management of people with CKD than any- ‘thing else that has happened in nephrology in the first decade of the 21st century. But like much in medicine, new “discoveries"—medications, devices, or clinical practice guidelines—need a test of time to understand ‘their risks, benefits, and overall place in the care of pa- tients. Asthe KDOQI CKD guideline made its way into clinical practice, much changed; creatinine assays were standardized, laboratory reports changed, new Intemna- tional Classification of Diseases (ICD-9) costes were generated, new equations for the estimation of glomer- Ular filtration rate (GFR) were developed, nephlogists and others began to speak a common language wit it ‘came to studying and taking care of those with CKD, and an explosion in CKD-related research occured, How- ‘ever, there was also concer that patients who did not have clinically meaningful kidney dysfunction were being identified as having a “discase,” patients worried (stage 3 cancer is often life-threatening. ..stage 3 CKD ‘Am J Kidney Dis. 2014:63(6):719-735, cannot be much different), the inherent imprecision of formulas used to calculate estimated GFR (@GFR) for CKD classification was often underappreciated, and stage 5 CKD came tobe interpreted by some as “time for dialysis” New information also became available, notably that albuminuria, not part of the 2002 NKF- KDOQI guideline CKD classification schema, was itself an independent predictor of important clinical ‘outcomes and that a more precise degree of risk pre- diction became available as the result of innovative in- {ternational rescarch collaborations. ‘Thus, it became clear that a revision of the 2002 ‘guideline was in order. The organization Kidney Disease: Improving Global Outcomes (KDIGO) From "Tuts Medical Center, Boston, MA: *Univrsty of Wis: ont, Madison, WE "University at Buffalo, Bufalo, NY, “Northwestern Universit: “Universiey of Minois at Chicago, Chicago, IL: “University of California, San Francisco, San Francisco, CA; “Sanford University School of Medicine, Sian Jord, CA; anal "University of Pennsylvania, Philadelphia, PA ‘Originally published online March 18, 2014 Address correspondence to Lesley A. Inker, MD, Wiliam B. Schwarre Division of Nephrology, Tats Medicat Center, Box 391, {300 Washington St, Boston MA O21. E-mail! kero laftenedicalcenter.org Published by Elvevier Inc. on behalf of the National Kidney Foundation, tne 0272-6386/836.00 gus dokorg10.1053% jh 2014.01.416 nsAJKD lnker et al ‘convened a controversies conference in 2009 and subsequently organized an international work group to review and update the NKF-KDOQI_ CKD guideline, After the international KDIGO guideline was published in 2013,” NKF-KDOQI organized its own work group to provide a US-focused com- mentary on the KDIGO guideline. The yeoman efforts of this work group, led expertly by Drs Harold Feldman and Lesley Inker, are now pre- sented in this commentary. The work group included experts in clinical nephrology, clinical epidemiology, and primary care medicine, and their many countless hours of volunteer work are much appreciated ‘As has been stated many times, guidelines are ‘guides to practice; they are not rules, they do not replace clinical judgment, they cannot anticipate pa- tient preferences, and they are not able to speak to every conceivable clinical circumstance. ‘They are also static, while medicine is not. Nonetheless, we believe that this NKF-KDOQI commentary will prove useful to physicians, nurses, and others involved in the care of patients with CKD. Michael V. Rocco, MD, MSCE_ KDOQI Chair Jeffrey S. Berns, MD Vice Chair, Guidelines and Commentary INTRODUCTION The NKF-KDOQI guideline for evaluation, classi- fication, and stratification of CKD from 2002 defined CKD as an abnormality of kidney structure or func- tion regardless of cause or specific clinical presenta- tion and proposed a staging system based on the level of GFR.’ The guideline also suggested a conceptual ‘model for the natural history of CKD that often begins with initial kidncy damage and progresses through the stages of CKD toward the outcome of kidney failure. During this progression, individuals are at an elevated risk of cardiovascular discase (CVD) and death. This ‘conceptual model highlights the clinical value of carly identification and management of paticnts with CKD and has promoted broad-based reporting of GFR by clinical laboratories to maximize the detection of secult CKD. The KDOQI guideline was well accepted by the medical and public health commu- and led to much change in clinical practice within the primary care, nephrology, and other spe- cially communities.’ However, the KDOQI guideline also stimulated some controversies and questions. In particular, there have been concems that use of its definition of CKD has caused excessive false identi- tion of CKD and that its staging system was not sufficiently informative about prognosis 1n2003, KDIGO wasestablished with the mission “to improve the care and outcomes of kidney disease par tients worldwide through the development and imple- ‘mentation of global clinical practice guidelines.” Prior to embarking on a new guideline, KDIGO often holds ‘conferences to review outstanding. questions and avail- able evidence for the purpose of assessing whether a new practice guideline is warranted. KDIGO convened such a conference in 2009, with the goal of addressing the shortfalls of the KDOQI staging system.” Analyses performed for the purpose of this conference demon- strated that GFR and albuminuria are independent and complementary predictors of important clinical na ‘outcomes, including CKD progression, end-stage renal disease (ESRD), acute kidney injury (AKD, cardiovas- ccular mortality, and all-cause mortality"? On the basis of these and other data that have been reported since the publication of the original 2002 KDOQI guideline, KDIGO formed a work group to develop an updated CKD guideline forthe international community. ‘The specific goals of the KDIGO CKD ‘guideline update were to clarify the definition and classification system of CKD and to develop appro- priate guidance forthe management of individuals with CKD.” The primary recommendations were to retain KDOQI's use of GFR as the principal basis for staging CKD, but to augment the staging scheme by incorpo- rating cause of kidney disease and level of albuminuria in addition to level of GER. The KDIGO guideline update contains a discussion of CKD progression, recommendations regarding referral to nephrologists, and management of the complications of CKD. REVIEW AND APPROVAL PROCESS FOR THIS COMMENTARY ‘Toassist US practitioners in interpreting the KDIGO guideline, the NKF-KDOQI convened a work group to write a commentary. The commentary addresses the full scope of the KDIGO guideline, focusing in particular on their relevance to and implementation in the United States. ‘The NKF-KDOQI Steering Com- mittee first selected Co-Chairs and then individual members based on their clinical andor research expertise and interest in the guideline process. Indi- vidual sections focusing on each of the topic areas of the KDIGO guideline were drafted by groups of co- authors based on detailed review of each of the KDIGO chapters supplemented by additional literature review. All KDOQI commentary work group members conferred regularly by teleconference, and consensus ‘among coauthors was achieved through discussion. A detailed discussion of the cost implications of the ‘Am J Kidney Dis. 2014168(5):719-735,DOI Commentary on KDIGO Guideline for the Evaluation and Management of CKD Box 1. Summary and Key Points ‘+ The commentary on Chapter 1 addresses the definiion| and classification of CKD, agroes with the adn of the abburinura stages, but raises concoms about th incor- poration of cause of dsoaso into staging and also high lights issues rogaréing use of GFR ostimation and albuminuria in ciical practice + The commentary on Chapter 2 addresses the defintion and identification of progression and highlights the lime tation of the proposed definitions of CKD ter assessing progression at ketney disease + The commentary on Chapter 3 addresses the manage: iment of progression and complications of CKD, and highights recommendations 10 lowor blood prossuro {goals inthe sting of proteinuria and he Fite evidence Ssupporing the impact of various components of iestyle ‘madiicaton + The commentary on Chapter 4 addresses cardiovascular disease rsk and highlights the need for individualized {decsion making n some circumstances, and emphasizes that care of patents with progressive CKD shoud include multiple caregivers + The commentary on Gnaptor 5, addressing the referral to specialists and models of care, highlights the need for Individualized docision making in somo circumstances, and that care of pationts with progressive CKD shoud include multiple caregivers. ‘Abbreviations: CKD, chronic kidney disease; GFA, glomerular ‘itraton rate recommendations is not included in this commentary, ‘This document was reviewed and approved by all co- authors and the KDOQH leadership. ‘The structure of this commentary aligns with the structure of the KDIGO guideline. Numbered text within horizontal rules is quoted directly from the KDIGO document, using the same numbering scheme as in the original (all material is reproduced with permission of KDIGO). The text that follows, written by the commentary work group, comments on key guide- line recommendations and discusses their implementa- tion in the United States (see Box | for an overview), DEFINITION AND CLASSIFICATION OF CKD Definition of CKD 11: CKD is defined as abnowmalies of Kidney sucture or function, present for ~3 months, with impleations for bait (Not Gradod [S00 table titled“Crria or CKD {either ofthe folowing present for >8 months)" AJKD Commentary ‘A formalized definition of CKD has provided great benefit to public health education efforts, research, and funding policies. The definition of CKD remains largely unchanged from previous guidelines, but has been clarified by the addition of “with implications for health,” recognizing that not all abnormalities are similarly related to outcomes. The commentary work ‘group concluded that not all structural or functional changes of the kidney have implications for health and that it is often not possible to accurately predict which patients will be negatively impacted. The classic example is the otherwise healthy kidney donor who has a GFR of $5 mL/min/1.73m*. There are imal implications for this person’s health, but some medications may need dose adjustment and there may be side effects from long-term nonsteroidal ant-inflammatory drug (NSAID) usage. Finally, we concur with the criterion of kidney abnormalities being present for at least 3 months as a means of discriminating between chronic and acute disease, both in clinical practice and research studies. ‘The duration of abnormalitcs has commonly beca ignored in research studies. Staging of CKD 12:1: We recommend that CKD i clasifid based on cause, GFA category, and albuminura category (CGA). (36) 1.22: Assign cause of CKD based on presence or absence ‘ol eystemic disease and tho location within the kidney ‘of observed or presumed pathologic anatomic find ings. (Not Graded) 1.23: Assign GFR categories as follows (Not Graded [See table led “GFR categories in CKD] 11.24: Assign albuminuria” categorie as folows (Not Graded) [S00 table tad “Abumnuria catogories in xo] “pole that where albuminuria measurement isnot avaiable, wine reagent strip results can be substituted, Commentary Numerous studies in recent years have provided convincing evidence that both lower GFR and greater levels of albuminuria are independently related to mortality, cardiovascular events, and the rate of ESRD. As reviewed in the guideline, greater levels of Cite for CKO (ether ofthe fllowing present for >3 months) atlas of Winey damage one or mor ‘Albuminuria BER = 30mg/24 hours ACR SF0mae TSFmarmMOTT Urine sediment abnormies Elecvoite and other abnormalities due to tubular disorders Abnormalities detected by histology Structural abnormalities detected by imaging History of kidney transplantation Decreased GFR GER_<60mlmivi73 m? (GFR categories 632-65) ‘Abbrovitions: CKD, chronic kidney disease; GFR, glomerular itration rat. ‘Am J Kidney Dis. 2014:63(6):719-735, 78AJKD Inker et al GFR categories in CKD GER category (GFR (in. 73 me) Terms a 90 Norma or Fgh a 6.99 Willy decreased” Ga 35.59 Nilay to moderately deceased ab 30-48 Moderately to severely decreosed ca 1529 Severely deceased Ss <15 Kidney faire ‘Abbroviations: CKD, chronic kidney disease; GFR, glomerular filtration rat. “Relative to young adult vel. Inthe absence of evidence of kidney damage, nether GFR category G1 nor G2 fui the cf albuminuria are strongly predictive of outcomes at al levels of GER at the individual and population Jevels.°"" Integrating both GFR and albuminuria into CKD staging paradigms will hopefully provide more precise classification and more accurate prog- nostic information. The commentary work group supports the addition of albuminuria into the classi fication scheme of CKD and characterization of the level of albuminuria by its severity (see last col umn in the table titled “Albuminuria categories in CKD"), rather than the terms microalbuminuria or rmacroalbuminuria We endorse the new distinetion between CKD stage 3a (GFR of 45-59 mL/min/1.73 m°) and 3b (GFR of 30-44 mL/min/1.73 m*) in the updated guideline. AS reviewed in the guideline, the risks of mortality and other outcomes vary. greatly. bet- ween these groups. The high prevalence of CKD stage 3 suggests that this distinction will have broad applications. In contrast, the commentary work group views it premature to add cause of CKD to the classification scheme, although some specific causes have been related (0 faster rates of CKD progression and other health outcomes. Notably, there are currently no ac- ‘curate methods to quantify risk based on cause of disease. The commentary work group considers that incorporating this information into the classification scheme could limit the ease of understanding and applicability of the classification scheme for referring physicians. (See chapter 5 of the KDIGO guideline for CKO. for discussion of the inclusion as specific causes or unknown causes as reason for referral.) ‘The KDIGO guideline does not address screening for CKD among specific populations. However, we thought it would be worthwhile to comment on this topic given that the recent US Preventive Services ‘Task Force recommendation highlighted the current lack of sufficient evidence to support CKD screening ‘of asymptomatic adults." A subsequent statement by the American College of Physicians (ACP) qualified these recommendations, saying that asymptomatic adults who are not at high risk for CKD should not be screened. The ACP went on to recommend not sereening for proteinuria those individuals who are currently taking an angiotensin-conyerting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB). Separate guideline recommendations for pa- tients with specific conditions placing them at higher risk of CKD (je, diabetes or hypertension) suggest routine screening may be useful, but testing strategies and. specific recommendations vary.'"'* The 2002 KDOQI guideline recommended assessment of the risk for developing CKD for all individuals, with measurement of blood pressure, albuminuria, and ‘serum creatinine to estimate the GFR among those at higher risk. The commentary work group endorses the recommendations from the original guideline for screening among individuals at high risk for CKD despite the absence of this specific recommendation in the KDIGO guideline (Box 2), and as such is in agreement with the recommendation of the ACP to Albuminuria catogorios in CKD AER Category (or9728 hours) [rmgimmo a <30 <3 a 30300 330 a 300 230 ACR [approximate e Terms <30 ‘Nowa vo mally increased 30300 Moderately nereased* 300 Severely increased” ‘Abbreviations: AER, albumin excretion rate; ACR, abumin-to-oreatinine ratio; CKD, chronic kidney disease. “Relate to young adit level “Incuding hophrcte syndrome (atbumin excretion usually >2200 mg/24 hours [ACR > 2220 mpg; >220 mmm, 76 ‘Am J Kidney Dis. 2014168(5):719-735,DOI Commentary on KDIGO Guideline for the Evaluation and Management of CKD Box 2. Potential Risk Factors for Susceptilty to and Indition of CKD Clinical Factors + Diabetes + Hypertension ‘Autoimmune diseases Systomic infections Urinary tract infections Urinary stones Lower urinary tract obstruction Neoplasia Famty history of chronic kidney diseases Recovery trom acute kidney falure Reduction in kidney mass Exposure lo cotan drugs Low bith weight Sociodemographic Factors + Older age 1 US ethnic minosty status: Aean American, American Indian, Hispanic, Asian or Pacific Islander + Exposure to contain chomical and environmental conaitons + Low incometeducation ‘Abbreviation: CKD, chronic Key disease. ‘Adapted with pormission of tho National Kidney Foundation from." sereen asymptomatic adults only if they are at high tisk for CKD, However, the commentary work group thought that information is gained from knowledge of the level of proteinuria beyond decisions to treat with an ACE inhibitor/ARB, such as prognosis and therefore disagrees with the ACP's recommendation to not sereen individuals treated with ACE-inhibitor/ ARB agents. Prognosis of CKD by GFR ‘and Albuminuria Categories: KDIGO 2012 AJKD Prognosis and Evaluation of CKD (Recommendations 1.3-1.43.8) 1.3. PREDICTING PROGNOSIS OF CKD 13:4: In prodictng risk for outcome of CKO, identity tho following variables: 1) causo of CKD, 2) GFA cato- ‘907;3) albuminuria catagory; 4) ther risk factors and ‘comorbid conditions. (Not Graded) 13.2: in people with CKD, use estimated risk of concurent ‘complcalione and iture outcomes to quide decisions for testing and treatment for CKD complications. (Not Gradoa) 113.3: in populations wth CKD, group GFR and albuminuria ccalegaries with smilar relative risk for CKD outcomes into risk categories. (Not Grade) [See Figure tiled “Prognosis of CKD by GFR and Albuminuria Categories: KDIGO 20121 14 EVALUATION OF CKD 1.41: Evaluation of ehrenioty {14.1.1 In people with GFR < 60 rUiin/.73 mf (GFR cate (govies G3e-G5) or markers of kidney damage, ‘oviow past history and previous measurements to detomine duration of kidney disease. (Not Gradec) + IF duration i= 3 montis, CKD is confimed, Follow recommendations for CKD. + If duration is not >3 months oF unclear, CKD is ‘ot confirmed. Ptionts may have CKD or Acuto Kidney diseases (incuding AKI) or both and tests shouid be repeated accoringly. 142: Evaluation of cause 14.2.1: Evaluate the efical context, neuding personal and family hisiory, soca and environmental factors, ‘medications, physical examination, laboratory ‘measures, imaging. and pathologe diagnosis, ta detemnne the causes of Kchey disease. (Not Gracoa) erin oburiaraclegores ‘Description and ong | sovetey acctosea ? Glee zg Eg [ice | syncs zs Hf [ow [eam 58 & 5 ae en eon ace ot Groen: ow risk (# no othor markers of Kidney disease, no CKD); Yellow: moderately Increased ri; Orange: high risk; Red, very high rsk ‘Am J Kidney Dis. 2014:63(6):719-735, nrAJKD lnker et al 1.43: Evaluation of GFR 1.43.1: We recommend using serum creatinine and a GFR ‘estimating equation or intial assessment. (7A) 1.43.2: Wo suggest using addtional lost (euch as cystatin or a clearance measurement) for confirnatory testing in specie ccumstances winen GFR ‘based on serum eating is ese accurate. (26) 4.43.8: We recommend that clincians (1) + use a GFRestmating equationto derive GFR from serum creatinine (@GF Rea) rather than relying on the serum creatinine concentration alone. + undorstand clinical sotings in which ©GFPa i loss accurate. 1.4.3.4: We recommend that nical laboratories should (1) + measure serum creatinine using a pectic assay wah calbration traceable to te intomalonal Standard reference marie and mininat bias compared to isotope-ctuton mass epec- trometry (IDM) retorance methodology. + feport CGFA jean addon to the serum ‘reatnine conceniration im aduls and spect the ‘equation usod whonoverroporting eGR + port GFR qa in adults using tho 2009 CKD-EPI creatinine equation. An alternative creatnine-based GFR estmating equation 15 accoplable if has boon shown to improve ‘accuracy of GFR ectimates compared 10 te 2008 CKD-EP! creatinine equation, When reporting serum creatinine: + We recommend that serum creatinine concen: tration be reported and rounded to the nearest vole number when expressed as standard Intemational units (mol) and rounded to the nearest 100th of a whole aumber when expressed as conventional unts (ng) When reporting eGFR ax: + Wo recommend that ©GFReye should bo ro- Porte and ounded to the nearest whole number and relative to a body surface area of 1.73 m* in adults using the writs mimin/3.73 + We recommend GFR levels las than 60 rl rmin/1.73 mr should be reported as “decreased” 1.48.8: We suggest measuring cysiatin C in aduts with (OGFRona 45-59 mlmiv173 mi who do not nave ‘markers of Kelney damage if confirmation of CKD ‘is required. (20) + HSGFR EGFR ua i6 60 <60 Umit 731", the cagrosis of CKD is confirmed + WOGFRy/eGFReao i =60 mimivt.73 ma, the agnosis of CKD & not confirmed. 1.43.6: Meystatn C is measured, wo sugges that heath professionals (20) + use a GFR estimating equation to derive GFR from serum cystatin C rather than ying on the sorum cystatin C concentration alone. + understand clinical setings in which eGFRyg and €GF Rosato afe less accurate 1.4.7; We recommend that clincal laboratories that mea- ‘sure eystalin C should (18) + measure serum cystatin C using an assay with calaton traceable tothe intematinal standard reerence materia + report eGFR from serum cystatin Cin adton to the serum cystatinC concentration in adults and spocity tho equation used whenover reporting GFR, and €GFRovatey ne + report ©GFRgg and @GFRuea in aduts using the 2012 CKB-EPIcystain © and2012 CKD-EPL croainine-eystan C equations, rspoctvely, oF alomative oystatin C-based GFR estimating ‘equations it thoy have been shown to improve accuracy of GFR estmates compared to the 2012 CKD-EPI cystatinC and 2012 CKD-EPL creatinine-eystatn C equatons. When porting serum oystatin C: + We recommend reporting sarum aystan © concentration rounded 0 the nearest 100" of ' whole number whan expressed as conventional uits (ng. When porting OGFA.y. and &GFRemtn: + We recommend tat eGFRoy aid eGFResaoye be ropord and rounded to the nearost whale number and relative to a body surface area of 1.78 mi adults using the units mnin/t.73 + We recommend eGFRaq and eGFResacy levels loss than 69 fmin/1.73 m? should be reported as “decreased” 143.8: We suggest measuring GFA using an exogenous fitraion marker under circumstances where ‘more accurate ascertainment of GFR wil impact ‘on treatment decisions. (28), Commentary This section focuses primarily on the aspects of valuation of GFR and albuminuria that are relevant for clinicians. Although the guideline also discusses evaluation for chronicity and cause, the commentary ‘work group agrees with these statements and does not have any additional comments. Estimation of GFR from serum creatinine remains the clinical standard worldwide. Consistent with the original KDOQI CKD guideline, the KDIGO guide- line emphasizes the importance of estimation of GFR rather than use of serum creatinine concentration alone.'”’ The guideline also recognizes the limitations ‘of creatinine and recommends additional confirmatory tests, such as measurement of cystalin C oF clearance in situations when estimates of GFR from serum creatinine are less accurate “The commentary work group agrees with the recommendation to use GFR estimating equations rather than creatinine alone for evaluation of kidney function. The commentary work group supports ‘ongoing efforts to promote the use of specific ercat- nine assays calibrated to international standard refer- cence materials with minimal bias compared to isotope-dilution mass spectrometry (IDMS) refer- cence materials." In addition, the commentary work group encourages the use of the CKD-EPL (CKD Epidemiology Collaboration) ereatinine 2009 equa tion or other similarly accurate equations.” “The KDIGO guideline also describes uses of eys- {atin C, alone oF in combination with creatinine, to estimate GFR. The guideline does not state explicitly whether GER should be estimated from eystatin © ‘Am J Kidney Dis. 2014168(5):719-735,DOI Commentary on KDIGO Guideline for the Evaluation and Management of CKD alone or in combination with creatinine, For the purposes of estimation of measured GER, the com- bination of both markers provides a more precise estimate." For determination of prognosis and risk stratification, the evidence is less certain.”” We agree with reporting both eGER,,, and €GFR.,60 mL/min/1.73 m°, the risk for CKD complications is very low. These per- sons could be considered not to have CKD. In addi- tion, the guideline work group states that prediction of risk for future adverse events is improved with the use of eystatin C-based GER estimates, asis supported by several studies, including a large meta-analysis pub- lished after the guideline; however, no specific recommendation was made by KDIGO.”” We agree that GER estimation using cystatin C alone or in combination with creatinine is useful as a confirmatory test of eGFR from creatinine, and that it improves risk stratification. However, many questions remain regarding how to incorporate cystatin C-based GER estimates into practice. The KDIGO guideline ‘mentions only one specific circumstance, but eGER used in multiple clinical settings on a routine basis and the guideline does not address most of these. For ‘example, whether creatinine- or cystatin C-based es- timates should be used to follow up patients longitu- dinally afier the initial diagnosis is made remains unaddressed. In the commentary work group's opinion, assuming a patient remains clinically stable, it seems reasonable to use cystatin C-bascd eGR esti- ‘mates at subsequent time points although there are no data to support this statement at this time. Implementation 1. Practical issues related to cystatin © measure- ment need to be considered prior to its introduction into the community at large. Notably, the price of testing is steadily decreasing, measurement is now automated, and it can be performed on existing plat- forms without the need for specialized equipment. More importantly, only cystatin C measurements obtained using assays traceable to higher level refer- ‘ence materials should be used to estimate the GER, ‘Am J Kidney Dis. 2014:63(6):719-735, AJKD 2. The availability of measured GFR as a eontir- matory test for eGER from creatinine is limited by the lack of Current Procedural Terminology (CPT) codes for nonradioactive exogenous filtration markers, which precludes its financial viability. In addition, reference materials for nonradioactive iothalamate or iohexol are not available, further limiting their wide- spread use. Evaluation of Albuminuria 144.1: We suggest using the folowing measurements for Fria teating of proteinuria (in descending order (of proference, in al casos an early moming urine sample is preferred) (28); 1) sine albumin-o-creatinine rao (ACR) 2) urine protein-o-ceatnine rato (PCR, 8) reagent stip uinalysis for total protein with automated reading, 4) reagent strip urinalysis for total protein win ‘manual reading, 1.442: We recommend that clinical laboratories report ACR and PCR in untied urine samples in acaliion to abumin concentration or proteinuria concentra tions rather man concentrations alone. (36) 1,444.21: The tem meroaloumaura should no longer be used by laboratoes, (Not Graded) 144.3: Ciiniéans noed to understand sotinge that may affct interpretation of measurements of albumin Ua and order confirmatory test as indicated (Wot Grade} '+ Contin reagent stip postive albuminuria land proteinuia by quanitaive laboratory ‘measurement and express as a ratio to creat ine whorovor possible. + Confirm ACR = 80 mg/g (=3 mmo) on ‘8 random unémed urine with a subsequent ‘arly morning urine sample. + fa more accurate estimate of abumnuria oF total proteinura is required, measure abu ‘min excretion rate or total protein excretion fate ina tined urine sample 14.4.4 tf sgniicant nor-albumin proteinuria fs suspected, use assays for specif urine proteins ( ‘aeicroglobuln, menacional heavy or ight chains, [known in some counties as "Bence Jones” Proteins). (Not Grado) Commentary ‘The guideline recommends urinary _albumin- creatinine ratio (ACR) in spot urine samples as the preferred measure rather than urine protcin or albu- ‘min. The rationale for this recommendation is that ACR is a more sensitive and specific measure of Kidney damage. Another motivation for this recom- mendation is that there are ongoing standardizatc efforts for urine albumin, whereas urine protein is more difficult to standardize. | The commentary work ‘gToup agrees with this recommendation ‘There are many factors that can affect urine protein for albumin temporarily. Some factors are related to specimen collection technique (eg, menstrual blood 79AJKD lnker et al Table 1. Factors Alfacting Urinary ACR Factor Examples of fect Prosnalytcal factors ‘Transit elevation in ‘abuminusa ‘Menstrual blood contamination Symptomatic UTI Exorcso” Upright posture (onhostate ‘potanuray (Other conditions increasing vascular permeabilly (23, sopticomia) Ininsicbiotogical variably” Genotc vaviabilty”* Intraindvidual variability Proanalyeal storage Dogradation of abumin before cond tors analysis Non renal causes of ‘Ago (lowor in chidron and odor variability n creatinine people) fexcration Face (ower in Caucasian than ‘black people) Muscie mass (e.g. lower in ‘people with amputations, paraplegia, muscular ‘ystrophy) Gene (ower in women) CChangesin creatinine _Non-steady state for creatinine excretion ax) ‘Analytical factors [rtigen excess (prozene’) Samples with very high albumin cect ‘concontations may bo falsly ropotod as low or normal using some assays’ ‘Abreviabons: ACR, albuminto-erathine rato; AKI, acute kidney intury; UT, urinary tract infection. Samples for urinary albumin (or total protein) measurement may be analyzed fesh, stored at °C fr upto 1 week, or stores at 70°C for longer periods. Freezing at 20°C appears to Fesult in oss of measurable albumin and Is not recommended. ‘When analyzing stored samples, they should be allowed to each room temperature and be thoroughly med pror to analysis.” Reproduced with permission of KDIGO trom.* contamination) and others are related to numerous physiologic factors unrelated to renal function or injury (eg, exercise, urinary tract infection; shown in Table 1). Education of clinicians for these causes of variability in measured ACR levels other than ‘changes in the level of kidney damage is necessary to promote appropriate interpretation of proteinuria data. Because untimed urinary collections are difficult to standardize, concentrations of albumin or protein from such collections can be misleading. Measure- ‘ment in the first morning urine is preferred because its protein concentration correlates. well with 24-hour protein excretion and has relatively low intra- individual variability. Reporting of the albumin or total protein as a ratio indexed to the urine creatinine helps account for the variability in urinary albumin or 79 total protein concentration measured in spot samples ‘due to changes in urinary concentration, Assuming a creatinine excretion of I g/d, an ACR of 1,000 mg/g would translate to an albumin excretion rate (AER) of 1,000 mg/d. However, this assumption is not correct. Development of validated estimating equations for creatinine excretion that account for variation in uri- nary creatinine among people may be helpful to provide ACR or protein-creatinine ratio (PCR) values that are accurate estimates of total albumin or protein excretion. Last, we endorse the elimination of “microalbuminuria” and “macroalbuminuria” from the diagnostic testing lexicon {Implementation Clinicians may be resistant to switching from urine protein to urine albumin since little evidence exists in the current medical literature for a difference in the value of these measures in predicting, clinical out- comes. Educational efforts on the value of using urine albumin, in particular related to assay methodological sues, may be required DEFINITION, IDENTIFICATION, AND PREDICTION (OF CKD PROGRESSION Definition and Identification of CKD Progression 24.4: Assess GFR and albuminuria at least annual in ‘people with CKD. Assess GFR and albuminuria more Often lor individuals at higher risk of progression, and ‘or where measurement will mpacttherapoutl decisions. (Not Gradoo) 2.1.2 Recognizo that smal fuctuations in GFR are common, ‘and ae not necessary indicative of progression. (Not Grade) 2.1.8 Define CKD progression based on ane of more ofthe following (Not Graf} + Decine in GFR catagory (=90 [G1], 60-89 {G2}, 45-88 [G3a), 30-44 [63h], 15-29 (G4), <15 [65] ‘mimi’. 73m). A certain drop in GFR is defined ‘asa drop in GFR category accompanied by a 25% or groalr dop in oGFR trom basalne. Rapid progression is defined as a sustained decine Jn oGFR of more than S mimin/.73 my. + Thecontidenceinassessingprogressionsincreased ith nereasing number of serum creatine ‘measurements and duration of followup. 2.1.4 In pooplo with CKD progression, as doined in Recommendation 2.13, review current management, ‘examine for roveribe’ causes of progression, and Consider refer to a specatst. (Not Graded) Commentary None of the recommendations in this chapter are graded. Despite having no evidence base, these rec- ‘ommendations have some face validity and address an important area, categorization of rates of kidney dis- ease progression. We agree with the guideline state- ment that the frequency of estimating GFR and measuring albuminuria should increase with severity of ‘Am J Kidney Dis. 2014168(5):719-735,DOI Commentary on KDIGO Guideline for the Evaluation and Management of CKD AJKD ‘Table 2 Dactine in Kidney Function in CKD Populations GFR dectne, Mean Sascine GFR Mean Foowap (SD) ar (os) swe ‘Suey population imine ears mum. 73 myer Mean (SD) MORO Stuty Study A: GER 2500mImin.7ame 2897.1 (87) 12 3706) Grup” Staly GFR 7524mimivi.7am? 63 150(45) 4307 abr $ ota" Study 1: GFR 25:55 mnie. 79 n? Moan (SO) 22 years = Ustal prot, usual MAP 145 3786 (80) 450759) = Usual prin. ow MAP 40 82,65) a3@541) = Low poten, usual MAP 140 53.9 (68) 3305-42) = Low pote ow MAP a1 97103) 2315-90) ‘Study 2 GER 43-45 malin 73m? Low proton, usual MAP 2 187(31) 4908-59) = Low pot, low MAP 87 188(33) 39247, = Very ow proto, usual MAP. 61 183687) 362844) = very ow poten, ow MAP 6 184,35) as e645) \WrghtJ ota. Aleican Ameicans wih hypertension Moan (SD) 4 years Moan (SE) nd GFR 2068 mlmin. 73m Low MAP 380 480 (80 129) 221 0.17) = Ustal MAP 374 45.3 (80 182) 4950.17) Erksen 8° GFR categories Gaa-G3b 3047 Median (OR) Mean Mean (GFR 30.89 mimi. 735) 55.1 (908-579) 37years—103m/min TSE Jones G ta" Nephrology reteral win GFF 726 Madan (QR) Medan (OR) Moan “atogores G3e-G5 (GFA < 60 my 29(1838) 28 years (19-41) 035mm 73h" min 73 me) Levin Reta Nephrology elena wih GFR 4231 Median Median (10) Mean Cates 6.05 (GFR = com SSmlnin’i.73m? 26 years (1.636) 2.65 nilmiv'.73 "year mi 73 0) ‘Avbreviaions: Cl, confidence interval. CKD, chronic Kidney daease; GFR, glomeriarfiraton rate; IQR, interquartile range: KDIGO, Kidney Disease: Improving Global Outcomes; MAP, mean areal prossuro; MDA, Modtestion of Dit Renal Disease; SD, standard deviation; SE, standard eror. Feproduced with permission of KDIGO frm.” disease. The commentary work group also agrees that it is important to recognize the inherent variability of ‘reatinine when interpreting change in GFR. However, the commentary work group is concerned! about the proposed magnitude of change in eGFR that signals discase progression for the following reasons. First, a definition based on percentage reduction of ‘GFR will differ across starting levels of GFR and the duration of time over which the changes occur. For ‘example, a 25% reduction in ¢GER when beginning with levels such as 60 mL/min/1.73 m? would imply a loss of 15 mL/min/1.73 m*,asubstantial loss of kidney function ifit occurred over a relatively shor time (eg, 2 years). Second, this amount of change is greater than the mean annual decline in eGFR found in any of the studies among individuals with CKD reported Cable 2) and is greater than the third criterion listed by the KDIGO guideline as indicating rapid progression (©5 mLAmin/1.73 m? per year). Indeed, the evidence described in the KDIGO guideline from the Alberta Kidney Disease Network suggests that a decline of <25% is also associated with increased risk of all ‘cause mortality and ESRD (lable 3). °* ‘Third, changes in eGR may be secondary to progression of ‘Am J Kidney Dis. 2014:63(6):719-735, CKD or superimposed AKI, and these often cannot be differentiated by considering a single value. Use of this stringent cutoff point for clinical decision making, such as referral as deseribed in chapter 5 of the KDIGO guideline, may lead referring physicians to avoid Table 3. CKD Progression and Rsk of Al-Cause Mortality and ESAD Using Baseline (ist) GFR ‘cause mortality ESRD Detintton of progression Ht" (65% G) HR (5 CH) Certain se 151(146-1.55) 0.33 (026-0.42) Uncertain rise 112(108-4.15) 0394(0.30-051) ‘Stable (reference) Ret Ret Uncertain drop 0.98 (095-1.01) 2:19(1.84-2.47) Contain drop 1.89(1.89-1.95) 6.11 (456-6.71) “Abbreviations: I, confines interval, CKD, chronic Kidney dscase; GFR, siomeruiar ration rate; ESRD, end-stage renal ‘disease: HR, hazard rato. “ESRD defined as requring renal replacement therapy ‘Adjusted for age, gender, hypertension, dabetes, protein lua, Charlson comorbiciies and baseline (irs!) «GFR, Data from Turin et al." Reproduced with permission of KDIGO from.? ratAJKD lnker et al earlier and appropriate investigations of kidney disease. Albuminuria is central throughout the KDIGO guidetine for the definition and staging of disease, and ‘elsewhere inthis chapter it is stated that assessment of | albuminuria “should be undertaken to evaluate pro- ©) Nevertheless, the severity of albu- ‘minuria or changes in albuminuria over time is not included in the proposed definition of progression. ‘The KDIGO guideline justifies this by saying that there are no data to support specific cut points for change in albuminuria that are associated with kidney disease progression. The commentary work group agrees that changes in albuminuria should not be included in the definition of progression. However, if increases in alburninuria are not considered progres- sion of CKD, the rationale for their measurement with a frequency similar to eGR is not clear. The points made in chapter 1 of the KDIGO guideline about ‘causes of variation in albuminuria are relevant here ‘oo when determining changes in albuminuria, Regression of mild/moderate albuminuria is not ‘uncommon, and discussion of how to evaluate remis- sion of CKD with respect to both improvements in GFR and albuminuria is not included in the guideline. Predictors of Progression 2.2.1 ently factors associated wth GKD progression nim progrosss. These incude cause of CKD, lvel of GFR, lovel of abuminuria, ago, sox, racolthnicty, oovatod BP, hypergyccmia, dysipidemia, smaking,obesly, history of cardiovascular disease, ongoing exposure to ophrotoxc agents, and others. (Nat Gradog) Commentary The commentary work group agrees with the KDIGO guideline about the key factors that inform prognosis. We also agree that prediction models may be a valuable tool, but they should be validated in a wide variety of clinical settings to ensure their generalizability prior to widespread use. Implementation 1. Itis important to differentiate between progres- sion of chronic disease and acute injury. The defini- tions of cach are different. As the definition of CKD progression is currently writen, small changes in GER could be consistent with AKI, whereas only large changes in GFR would indicate progressive CKD. However, small changes may be consistent with progressive CKD rather than AKI. Clinicians will need to attend to other clinical indicators to be able to accurately identify the cause of changes in GER. Education of non-nephrologists. as to how 0 differentiate these clinical entities will be challenging. 2. Change in GFR may be due to true change in GER or due to changes in the non-GFR determinants 72 of creatinine concentrations, including assay fluctua- tions. Differentiating between these requires serial assessments and consideration of potential changes in the non-GER determinants of creatinine. Education of non-nephrologists as to how to differentiate these clinical entities will be challenging, 3. Use of validated prediction models for progres- sion of kidney disease may be able to incorporate numerous clinical factors and provide a single prog- nostic metric, which can gide decisions. Incorporation of such models into laboratory systems may facilitate their use, MANAGEMENT OF PROGRESSION AND ‘COMPLICATIONS OF CKD Prevention of CKD Progression (Recommendations 3.1.1-3.1.11) (BP and FAAS inerrption 8.1.1: Individuals BP targets and agents according to age, coenistent cardiovascular dsease and ather comor bidites, risk of progression of CKD, presence ‘oF absence of retinopathy (in CKD patients with di botos), and tolerance of reatmeant as described Inthe KDIGO 2012 Biood Pressure Guideine, (Not Graded) 3.1.2: Inquire about postural izzinoss and check for postural Inypotension rogulary when toating CKD pationts with BP-iowering drugs. (Not Graded) 9.1.8: Talor BP treatment regimens in eidety patents with CKD by carefuly considering age, comorbidities and ther therapies, with gradual escalation of treatment land close attention to adverse events related to BBP treamont, including olectolto disordors, acute 90 mm Hg dastole bo treated with BP towering drugs to mainiain a BP that is consistent =140 mm Hg systole and 90 mm Hg diastolic. (16) 3.1.5: We suggest that in both dabetic and non-abetic adults with CKD and with uno albumin excretion ‘of =30 mg/24 hours (or equivalent) whose office BP 's consitenty >130 mm Hg systole or >80 mm Hg lastalic be treated wih BP lowering druge to ‘maintain a BP thats consistenty =130 men Hg systolic and =80 mm Hg dias. (20) 3.1.6: We suggest tna an ARB or ACE bo usod in abot. adute wih CKD and urine albumin excretion 30-800 mg/24 hours (or equivalent). (20) 9.1.7: We recommend that an ARE or ACE-Ibe used in both dabotc ad non diabotc aduls with CKD and Urine albumin excretion = 300 mgi24 hours {or equivalent). (18) 9.1.4 There & Insuicent evidencs to recommend comining an ACE-| with ARBS to prevent progression ef CKD. (Not Graded) 9.1.8 We recommend that in chien with CKD, BPowering lueatment is started whon BP is consistenity above the 90" percent for age, sex, and height. (1) ‘Am J Kidney Dis. 2014168(5):719-735,DOI Commentary on KDIGO Guideline for the Evaluation and Management of CKD 3.1.10: We suggest that in chidron with CKD (partalary those wit proteinuria), BP is lowered to consistently achieve systolic and diastolic readings less than ‘or equal to the 60" percentile for age, ex, and hoight, unlegs achieving these targts le ited by signs or symptoms of hypotension. (20) '8.1.11: We suggest that an ARB oF ACE: be used in cnt dren with CKD in whom treatment wih EP-owering ‘drugs is indicat, irespoctive of tho lovel of Commentary Section 3.1 of the KDIGO guideline reviews the evidence in support of the recommendations aimed at delaying CKD_ progression. Recommendations for management of blood pressure were derived from the 2012 KDIGO clinical practice guideline for manage- ment of blood pressure in CKD.” These recommen- dations are based! on moderately strong evidence, with most of them falling between level 1B and 2D. The guidetine encourages individualized targets based on age and tolerability of the chosen regimen and also provides specific blood pressure targets based on level of albuminuria and comorbid conditions. For example, the recommended target blood pressure for patients with CKD without albuminuria is =140/90 mm Hg, whereas it is =130/80mm Hg for patients with albumin excretion > 30 mg/24 h. This represents. a departure from the target recommended by the 2004 KDOQI Clinical Practice Guidelines on Hyper- tension and Antihypertensive Agents in CKD, which recommended =130/80 mm Hg for all patients with CKD.”* Overall, we agree with these recommenda- tions, but also note that the blood pressure goal of = 130/80 mm Hg forindividuals with albuminuria i based on relatively low-quality evidence (2D). The pane! members appointed to the Eighth Joint National Committees GNC 8) recently released the 2014 ‘evidence-based guideline for the management of high blood pressure in adults.”’ In patients with CKD, they recommend initiation of treatment for blood pressur- ¢s> 140/90 mm Hg for patients of all ages without differentiation of targets by level of proteinuria. Higher ‘quality evidence regarding the safety and efficacy of intensive blood pressure control will be forthcoming from the ongoing National Institutes of Health-spon- sored Systolic Blood Pressure Intervention Trial (SPRINT), which includes a CKD subgroup." ‘The KDIGO guideline recommends an ACE in- hibitor or ARB for patients with diabetes. whose uri- nary albumin excretion is 30-300 mg/24 h and for all patients, with and without diabetes, whose urinary albumin excretion is >300 mg/24h. We agree with the guideline-specific recommendations to use an ACE inhibitor or ARB and not the combination given the accumulating evidence of harm with combination therapy.” ‘Am J Kidney Dis. 2014:63(6):719-735, AJKD Prevention of CKD Progression (Recommendations 3.1.12:3.1.18) (CKD and risk of AKI 3.1.12: We racommand that al poople wah CKD are con- ‘sidered to be at increased nak of AKI. (74) 8.1.12: Inpeope wth CKD, the recommendations detaled in the KDIGO AKI Guideline should be folowed for managomont of those at risk of AKI during intorcurent ness, or when undergoing Investigation and procedures that are Hkely to nerease the risk of AKI. (Not Grado) Protein ntake 8.1.13: We suggest Iowering protein intake to 0.8 gko/day in adults with diabetes (20) or without diabetes (28) and GFR < 30 mimin’. 73 mF (GFR categories 6465), with appropriate esucaton 3.1.14: We suggest avoiding high protein intake (1.3 gay day) in adults with CKD at risk of progression, (20) Giycemic control 8.1.18: We recommend a target hemogiobin A (HAs) of ~7.0% (63 mova) to prevent or delay’ pro- ‘gression of the microvascular complications of ca botes, including diabete kidney disease. (1A) 8.1.18: We recommend not treating to an HDA. target of 7.0% (<53 mmolimal) in patents at risk of hyponiycemia. (16) 3.1.17: We suggest thal arget HbA, be extended Above 70% (53 modo) ind viduals with ccmorbdtios or iit fe expectancy and risk of hypoglycemia. (20) 3.1.18: ln people wih CKD and dabates, lyeeme contrat should be pat ofa muitfactorat intervention strategy adtressing blood pressure contol and cardiovascular risk, promoting heuse ofangoiensin- convoting enzyme inhibition or angiotensin receplor blockade, stain, and antplaolt therapy where ctncal indicated, (Not Graded) Commentary “The single level 1A. guideline is derived from the KDOQI Clinical Practice Guideline for Diabetes and CKD: 2012 Update” that recommended a target he- moglobin ‘Ay. (HbA) in diabetes. Motivated by recent evidence of harm with intensive glycemic control," "* the guideline recommends a. target HbA,, of ~7%, with the higher target for those with a limited life expectancy, comorbid conditions, or an tlevated risk of hypoglycemi, Prevention of CKD Progression (Recommendations 3.1.19-3.1.22) ‘Sat intake 3.1.19: We rocommond ioworng salt intake to <90 mano (2 9) por day of sodium (cortesponding to 5 g ‘of sodium chloride) in adults, unless cortraincécated (CKD). (1) 9.1.19:1: We recommend restriction of soctum intake for chilean with CKD who have hypertension (eystole andior castalic blood pressure 95" percentile) or pretypertension (systolic andor ‘diastolic blood pressure >80" percentile andAJKD lnker et al <5" percentle), following the age-bases Recommended Daiy Intake. (10) 1.19.2: We rocommend supplemental ttoe wator and sodium supplements for children with CKD and polyura to avoid chronic intravascular depletion And to promote optimal growth. (10) Pyperuricemia: 9.1.20: There insufficient evidence to support or refute fhe uso of agonts to lowar serum uric acid concenta- tions in people wih CKD and ether symptomatic oF asymptomatic hyperuricemia in order to delay progression of CKD. (Not Graded) Leste ‘8.1.21: We recommend that people with CKD be encour ‘aged to undertake physical activity compatible With cardiovascular health and tolerance {aiming for atleast 20 minutes 5 times per week), achieve a healthy weight (BMI 20 to 25, accorcing to county specie domographies), and stop smoking, (1D) Adktional dctary advice 21.22: We recommend that individuals with CKD receive ‘export dotary advco and information in tho context ‘of an education program, talored to severity ff CKD and the need to intervene on salt, phos: palo, potassium, and protein intake whore Indicated, (16) Commentary The guideline addresses dietary modifications and lifestyle changes in CKD. ‘The commentary work group concurs with most of these recommendations with the following caveat. The recommendation to maintain a body mass index (BMI) of 20-25 kg/m? may be inappropriate for certain patients with CKD. Observational data suggest that the relationship be- tween BMI and risk of adverse outcomes in CKD may be different from that in the general popula- tion. Moreover, given the propensity for fluid retention in CKD, we thought that BMI may not accurately reflect body fat in this setting."” In addi- tion, overly restrictive dietary prescriptions. may diminish total caloric intake, markedly reduce protein intake, and result in malnutrition. We agree with the ungraded statement that there is insufficient evidence to make recommentations for use of uric acid-lowering agents for the prevention of CKD progression, Complications of CKD ‘22 COMPLICATIONS ASSOCIATED WITH LOSS OF KIDNEY FUNCTION Denton and identification of anemia in CKD ‘3.2.1: Diagnose anemia in adults and childron >15 years with CKD when the Hb conoenteaton is <13.0 94 (190 9/9 in males and 12.0.9 (120 gi} in females. (Not Graded) '322: Diagnose anomia in cildon with CKD it Hb con centration is <11.0. 91 (<110 gf) in chien 08-5 years, <11.5 gid (11599 In chidren 5-12 years ‘and <12.0 9 (120 gf) i children 12-15 years. (Not Gradea) Evaluation of anemia in people with CKD 3.2.8 To dently anemia in people with CKD measure HD concentration (Not Graded} + "when elicaly indicated in people with (GFF 60 mimin/1. 73." (GFF categories Gisy;, atleast annually n people with GFR 20-59 mlimind 41.78 nF (GFR categories G3a-G3b); + atleast twice per year in people with GFR < 30 mi smin/1-731m? (GFR catogorios 64-65). 3.3 CKD METABOLIC BONE DISEASE INCLUDING LABORATORY ABNORMALITIES 8.8.1: We recommend measurng serum leves of caiium, phosphate, PTH, and alkaline phosphatase activity atleast once in adits with GFR = 45 mlmavt. 73? (GFR categories G3b-G5) in order to determine ‘baseline values and inform prediction equations used. (10) 9.8.2: We suggest not to perform bone mineral density testing routinely in those with eGFA < 45 mimi 41.73? (GFR categories G3b-G5), 2 information ‘may be misleadig or unhelpful. (25) 3.33% In pooplo with GFR < 45 mlimin/.73 m# (GFR cato- ‘gores G-G5), we suggest maintaning serum ‘Phosphate concentrations ithe noma range ‘according to local laboratory reference values. (20) 3.8.4 In pooplo with GFR = 45 mlimin’.73 m? (GFR calo- ‘gories G3b-Gs) the optimal PTH level is not ‘known. We suggest that people wth levels of intact PTH above te upper normal limit ofthe assay ‘are ist evaliated for hyperphosphatemia, hypoca' ‘cemia, and vitamin D deficiency. (20) ‘Vitamin D supplementation and bisphosphonates in pecple wen CKD 3.3.5: We suggest not to routnaly prscrbo vitamin D sup- jplomonts or vitamin D analogs, in the absence ‘ol suspected or documented daicioncy, to suppress ‘elevated PTH concentrations in people with CKD fot on alysis. (26) 3.3.6: We suggest natn prsorbe Bieptasphonate treatment In people with GFR < 90 n¥mini.73 (GFR ‘clegures G4-G5)wthauta song cal rationale (265 34 acioosis: {3.4.1: We suggest that in people with CKD and serum Br ccaronate conceniations <22 mmoll weatment wih ‘ora bicarbonate supplementation be given to main- tain serum bicarbonate within the nomal ange, unless contraindicated. (26) Commentary Previously published guideline statements on ane mia” and CKD-mineral and bone disorder (CKD- MBD)"” areincluded in the KDIGO CKD guideline and are mostly unchanged from these original publications. However, the recommendations for the use of vitamin D supplementation. is more CKD-MBD guideline, ” with a suggestion to prescribe vitamin D supplementation only if there is evidence of documented deficiency. Use of bone mineral density ‘Am J Kidney Dis. 2014168(5):719-735,DOI Commentary on KDIGO Guideline for the Evaluation and Management of CKD testing is discouraged in patients with GER < 45 mL min/1.73 m?, and there is a suggestion not to prescribe bisphosphonates in patients with GFR < 30 mLfnin/ 1.73 m, Use of bicarbonate supplements issuggested in patients with serum bicarbonate levels < 23 mmol. “Tables 4and 5 outline the use of phosphate binders and bisphosphonates, respectively."” ‘Although the recommendations in this section were not based on strong evidence, the commentary work group agreed with most of the guideline statements We thought that there are insufficient data to endorse the recommendation to use markers of mineral metabolism in risk prediction models, Implementation I. There are multiple recommendations made for ‘the management of CKD and it may be challenging AJKD to implement all of them for any one patient. Approaching the recommendations in this chapter with some flexibility may allow clinicians to iden- tify aspects of the guideline that may be more applicable to individual patients with CKD and to modify treatment strategies over the course of care In addition, evidence is strongest for recommenda- tions related to management of diabetes and hy- pertension, which often complicate CKD. Thus, it ‘would be justifiable to first devote effort to setting blood pressure and glycemic goals, tailor antihy- pertensive and hypoglycemic therapies to individual patients, and monitor for side effects of the medications. 2. Because reduction in dietary sodium may facilitate achievement of blood pressure goals and the widespread use of sodium in the US food supply, “Table 4. Phosphate-Binding Agents in Routine Clinical Practice and Their Ranked Cost Agent Dosey ‘Aumiium hycroxide 1425-285 9 Calcium citrate 1589 Magnesium carbonate 07-14 9 (pls calcium ‘carbonate 0.39-0.68 g) Callum acetate 435mg ‘pls Magnesium carbonate £235 mg, 3-10 tablets daly 369 Calum acotate and Magnesium ‘carbonate combination CCaiclum carbonate Calcium acetate Lanthanum carbonate 3a Savelamer HCI 49069 Sovelamer carbonate 48969 Cinleal experience and evidence base Ranked cost” Extensive nical experience in CKD and 1 ESRD, no RCT comparison vorsus placebo. Aluminium accumulates in bone ‘and neural sae wih longterm use, ‘voids calcium Limited trial evidence in ESRD. Reduction in 2 ‘hosphalo and clovation in cacium dose- dependent SShort-tom ACT evidence in ESRD, fs 3 Frypercalcemia SShort-tom ACT evidence in ESRD, fs 3 ypercalcomia Exensive dinical experience in CKD and 4 ESRD, lmtod RCT evidonco vorsus placebo. Reduction in phosphate and flvation in caicium both dose-dependent Extonsve dnical exporionco in ESRD; ROT 4 ‘evidence comparing to her bindors. ‘Reduction in phosphate and eevation in calcium dose-dependent but lss than with calcium carbonate Exionsive prospective cohort evidonco, RCT 5 ‘evidence compared to other hosphato binders. Potental for accumulation in bone and ather seuss, avoids calcium Extonsve prospective cohort evidence in 6 'ESAD; RCT evidence compared to other [Phosphate binders; surogate and patent- contered autcomes, avoids calcium CT evidence compared to other phosphate 6 binders; equivalaney studies compared sevelamer HO}, avoids calcium "Note: Data as of January 2073, ‘Abbreviations: CKD, chronic kidney disease; ESRD, end-stage renal dsease; RCT, randomized controled ta. ‘The average annual cost of aluminium hydroxide in the UK, for example, is L51/year, equivalent to US$B4Yyear. The cost of lanthanum and sevelamer nthe UK is 38-42 times higher and the cost of calcium and magnesiu-based binders 5-7 times higher than aluminium hieoxide (ll drug costs derived from 2011 Briish National Formulary lit prices) Reproduced with pemission of KDIGO from.” ‘Am J Kidney Dis. 2014:63(6):719-735,AJKD lnker et al ‘Table 5. Summary Data for Bisphosphonates and CKD ose, trequency and route ‘Spactal considerations for CKD Agent Inateations of aaministation| and cinlal tra notes ‘Alendronale Postmenopausal osteoporosis 10mg daily, oral GER = 35 miinin/4-73:m*: not recommended Conicosterol use 701mg wookly, oral No eported adverse events speciicto CKD Clodronate Malgnancy-elated bone dssase 1.6-32 g dally, ora GFR < 10 mlininvt.731:contrandiated GFR 10-20 mimit. 72m? reduce dose by 50% Etironate Postmenopausal osteoporosis 400.mg dally for 14 days, oral___-ld onal impaiment: reduce doso Conicosterol use 5-10 mglkg daly for upto 6 months Moderate or severe renal mpairmant. avold Paget disease No data in CKD lbandronate Malgnancyrelated bone dlesase 160mg month, oral GFA < 30 milimivt.73m*: not recommended Postmenopausal osteoporosis mg every Zbmonths intravenous No reported adverse events spectic to CKD Pamidronaie Matgnancy-olated bone disoase 15.6079 single dose, inravonous GFF < 30 miimin1.73.m® avoid Pagets disease ‘90 mg weekly for 6 weeks, AKI reported Fisedronate Postmenopausal osteoporosis Sm daly, oral GFR < 90 mitnin/1.73 m*: contradicted Conicosterold use 36 mg wookly, oral No eported adverse events spect to CKD Pagots disease Tiludonato Paget's disease 400 mg dally for 3 morths (CrCl < 80 mini: containcatod ‘No cata i CKD Zoledronate Malgnancyeated bone dsease 4-5mg single dose, intravenous GFF < 30 miimin/.73.m® avoid Postmenopausal osteoporosis, Pagat’s disease GFA = 6omilnin/t.73m®: graded dose reducton 'No data in CKD, AK roportd in non-CKD "Note: Data as of January 2073, ‘Abbreviations: AKI, aculo ken inury: CKD, chronic Kidney diseaso; CrCl, creatinine clearance; GFR, glomerular fitration rato Reproduced with permission of KDIGO from,” it seems reasonable to incorporate counseling on dictary sodium reduction into routine management of hypertension. However, achieving this goal is extremely difficult, in part because measurement of the sodium intake’ is not easy to implement, often requiring a 24-hour urine collection. In addition, access to expert dietary counseling may be a chal- lenge for most US predialysis CKD care settings with the current billing and payment structure for allied health care professions, including dietitians. Population-level interventions, including modifica tions of sodium content in processed foods, will be required to effect substantive reductions in sodium intake." OTHER COMPLICATIONS OF CKD CKD and CVD “41.1 We recommend that all popie with CKD be consi cred at increased ik or cardiovascular disease. (1A) 441.2: We recommend that the lvel of care for ichemic heart disease offered to people with CKD should ‘not bo prejudiced by thoi CKD. (74) 4.19 We suggest that adults with CKD at risk for athero sceroie events be offered trestment with antiplatelet ‘agents unless there is an increased bleeding tsk that neods to bo balanced against the possible car sdovascular bones (26) 4.1.4: We suggest thal the lovl of care fr heat titre ‘forod to poopio with CKD should bo the samo as is ‘offered to those without CKD. (24) 4.1.5: In pooplo wth GKD and heart falure, any escalation in therapy andlor cinical detororation should promt ‘monitoring of GFR and serum potassium concentration. (Not Graded) Commentary ‘The increased risk of cardiovascular illness in the CKD population was highlighted in the 2002 KDOQI CKD guideline.' Since then, additional strong evi- dence has emerged in support ofthis relationship and several nontraditional CKD-specific risk factors for CVD have been identified."""* Despite these find- ings, patients with CKD remain under-represcnted in interventional studies and as a consequence, the evi- dence basis for the recommendations related to car- diovascular risk reduction in CKD remains limited, Nonetheless, given the large burden of CVD in pa- tients with CKD who have a high prevalence of traditional cardiovascular risk factors, we agree with the recommendation. that risk-factor modification strategies recommended for the general population are wicated for patients with CKD. Additionally, the ‘commentary work group believes that guideline 4.1.3 recommending antiplatelet therapy could have placed ‘Am J Kidney Dis. 2014168(5):719-735,DOI Commentary on KDIGO Guideline for the Evaluation and Management of CKD more emphasis on aspirin (acetylsalicylic acid) as initial therapy, the agent for which there is the strongest evidence of effectiveness in patients. with cKoes The evidence in support of CKD-specific thera- peutic strategies for management of heart failure is similarly lacking. Indeed, most of the data reviewed by the guidelines for management of coronary heart disease in patients with CKD were derived from post hoe analyses of clinical trials outside of the setting of CKD.” Given that these analyses demonstrate effectiveness of these therapies in the CKD popu- lation, the guideline recommends delivery of stan- dard heart failure treatments for patients with CKD. We support these recommendations and also agree with the recommendation that any alterations in therapy should be accompanied by close monitoring of patients? GFR and potassium levels. Finally, we believe that the guideline should have placed greater ‘emphasis on the risk for hyperkalemia and AKI associated with dual blockade of the renin- angiotensin-aldosterone system (RAAS)"”*°" and recommend increased vigilance in monitoring of serum potassium and kidney function in these circumstances. Caveats When interpreting Tests for CVD in People ‘With CKD [BNP N-terminal proBNP (NT-proBNP) 4.2.1; In poople with GFR 60 mmit.73 m* (GFR calogorios G3a-G5), we recommend that serum Concentratons of BNPINT-proBNP be interpreted ‘wih caution and in celaton to GFR with respect to agnosis of hear failure and assessment of volume status. (18), Troponins 4.2.2: In poople with GFR < 60 mlimin/4.73 m# (GFR calogorios G3a-G8), wo recommend that serum con- Centrations of roponin be interpreted with caution with respectto dagnwosis of acute coronary syndrome. (15) Noninvasive testing 42:3: We recommend that peope with CKD presenting with chest pain shouldbe investigated for underying cardiac disease and other disorders according to the ‘same local practice for peope without CKD (and subsequent treatment should be intated similar). (28) 4.2.4 We suggest that cincians are familar wih the limitations of noninvasive cardiac tts (2g. exercise octrocardography [ECG], nuclear imaging, echo- cartography, et) in adults wth CKD and Interpret the sults accoreingly. (26) Commentary ‘The KDIGO guideline highlights the fact that cardiac biomarkers (B-type natriuretic peptide [BNP N-terminal pro-BNP [NT-pro-BNP] and troponin) ‘Am J Kidney Dis. 2014:63(6):719-735, AJKD may be less refiable at lower levels of kidney function. ‘These markers are inversely associated with level of GER, suggesting that they may be filtered by the kidney and that higher levels would be derived from decreased filtration, at least in part, rather than exclusively from true cardiac damage. However, in CKD populations, BNP levels have been strongly associated with left ventricular hypertrophy and left ventricular dysfune- tion, even outside the setting of acute myocardial ischemia.” In addition, elevated concentrations of, troponin T and troponin I by ultrasensitive assays have ‘been associated with increased mortality." ‘The commentary work group acknowledges that the preponderance of literature examining cardiac testing in the setting of kidney disease focuses only on in- dividuals with ESRD. Nevertheless, we agree with the KDIGO's emphasis on using the same diagnostic investigation for patients with CKD presenting with possible acute coronary syndrome as used for in- dividuals without CKD. We agree that in the clinical context of chest pain, elevations of troponins must not automatically be attributed to reduced kidney function. Since these biomarkers may be elevated in the setting of CKD in the absence of acute ischemia due to chronic left ventricular wall stress, it is important to apply clinical judgment and evaluate trends in bi CKD and Peripheral Arterial Disease 4.3.1: We recommend that aduls with CKD be regularly ‘oxaminod for signs of poriphoral arora isoaso and 'be considered for usual approaches to therapy. (18) 4.8.2: We suggest that aduts wth CKD and diabetes are Commentary We agree with the KDIGO guideline that periph- eral arterial disease is a serious and common problem in patients with CKD. However, we do not believe there is sufficient evidence to support a strategy of routine sereening of this population with ankle- brachial index. As acknowledged in the guideline, ankle-brachial index test results may have more limited value in CKD because of the high prevalence of calcified vasculature, Additionally, systematic screening has the potential to lead to adverse out- comes and increased costs as a consequence of additional testing (eg, angiography) and interventions. ‘A more prudent approach might be to limit sereening and testing (0 individuals with symptoms or signs of Timb ischemia. Medication Management and Patient Safety in CKD “4.1; We recommendthat prescribers shoutl take GFRinto| account whion drug dosing. (14) rerAJKD lnker et al 4.4.2: Where precision is require for dosing (ae to narrow therapeutic or toxic range) andor estimates may bo unrolable (0.9, duo to low muscle mass), wo ‘recommend methods based upon cystatin C or direct ‘measurement of GFR. (10) 44.3: We recommend temporary discontinuation of pot tialy nephrotoxic and renal excreted drugs in people wih a GFR ~<60mlmavt.73m? (GFR calegores 632-68) who have sorous infereurent loss. that increases the risk of AKI. These agents include, but are not lined to: RAAS blockers (ncuding ACE-s, ARBs, aldosterone inhibitor, direct rein in- hibtow), duroics, NSAIDs, metformin, thu, and dgoxn. (10) 4.44: We recommend that adults with CKD seek medical or Phamaciet advice before using over-the-counter ‘medicines or nuttional pre supplements 16) 44.5: We recommend not using herbal remecies in people wih CKD. (32) 4.4.8: We recommend that ellormin be continuedin people wih GFR = 45 mlmi.73m* (GFR categories ‘G1-G3q); ts use shouldbe reviewed in those with GFR 30-44 mimin/.73 (GFR catogory G30}; and it shouldbe dscontnued in people wih GFR < 20 mi/ rmin/1.73 mi (GFR categories G4-G5).(10) 44.7; We recommend that all peopie taking potently ephrotex agents such as lithium and cakeinaurin Inmibtors should nave thee GFR, electrolytes and drug levels regulary montored. (14) 4.4.8: People with CKD should not be denied therapies for cathor conditons such as cancor bu there should be appropriate dose adjustment of cytotoxic drugs ‘according to knowiedge of GFR. (No Gradeq) Commentary Many commonly prescribed drugs or their metab- olites are exereted by the kidneys and require dose adjustment to avoid potentially life-threatening. com- plications. Furthermore, several commonly used drugs are nephrotoxic and may hasten progression of CKD or lead to AKI. Therefore, the guideline rec- commends drug dosing based on the level of GFR. Further, it recommends. that monitoring of thei mugs excreted by the kidneys or that are potentially nephrotoxic during periods of illness that predispose to AKI. We agree with the emphasis placed on drug dosing since this is often an under-recognized issue in the setting of CKD and has important implications for patient safety (Table 6). However, we were concerned about the recommendation to use cystatin C-based GER estimates for drug dosing given uncertainty regarding direct effects of drugs on cystatin C generation, The commentary work group agrees with the guideline’s moderate approach to metformin dosing, which is consistent with recommendations recently published in the updated KDOQI guideline fordiabetes and CKD.” The US Food and Drug Administration 78 (FDA) had mandated a black-box warning for metfor- ‘min that indicates it i contraindicated in patients with serum creatinine = 1.5 mg/dL in men and =1.4 mg/dL. jn women based on the risk for lactic acidosis, How- ever, some have questioned this warning and argued that it has prevented many individuals from benefitting from this drug.” It is now recognized thatthe risk for lactic acidosis in patients on metformin is extremely low, and the KDIGO guidelines reflects this new evidence.” Imaging Studies “45.1: Balance th risk of acute impaimment in kidney func- ‘ion due to contrast agent use against the diagnostic value and therapoutic implications ofthe Investigation. (Not Grado) Radiocontrast 452: We recommend that all people with GFR < 60 limi 173m (GFA catogories G3a-G5) undorgoing loctve investigation invotvng the intravascular ‘ininitration ot odnaled radio contast media ‘should be managod according tothe KDIGO Gtnical Practice Guidane fr AKI nctuding + Avoidance of high osmolar agents (16); + Use of lowest possible radio contrast dose (Not Grade); + Witheawa! of potentay nephrotoxic agents bore and after the procedure (1) + Adoquate hydration wth saline betore, during, and ator tho procedure (14) + Measurement of GFR 48-96 hours after tho procedure (10), Gadolisum-based contrast media 4.53: We recommend net using gadoliium-contaning contrast media in people wih GFR-<15 mlminy 173m? (GFA category G8) uness there is no alter ‘native appropriates. (16) 4.54: We suggest that people with a GFA < 20min 1173n¥ (GFR categories G4-G5) who require ‘gadolinum containng contrast media are preferentially offered a macrocyclic chelate ‘reparation. (26) ‘Bowel preparation 45.5: We recommend nol to use oral phosphato-containing ‘bowl proparations in poop with a GFR = 60 mlimitd 4.731? (GFR categories G3a-G6) or in those. now to be at sk of phoephato nophropathy. (14) Commentary We agree with these recommendations on the use of contrast agents in imaging studies. In particular, we also agree with the guideline recommendation to avoid gadolinium for people with GFR < 15 mL/min! 1.73 m? versus <30 mL/min/1.73 m° as is stated in the FDA’s black box waming.”' Notably, we also agree with the omission of a recommendation to not use Neacetyleysicine and/or sodium bicarbonate to prevent AKI caused by radio contrast media duc to inconsistencies in the available evidence. ‘Am J Kidney Dis. 2014168(5):719-735,001 mnt on KOCO Gi re Eton nd Migr of AJKD “Table 6. Cautonary Notes fr Prescibing in People With CKD Agente Cautionary notes 1. Antihypertensivesicardiac medications RAAS antagonists (ACE-Is, ARBs, Avoid in people with suspected funcional renal artery stenosis ‘adosterone antagonists, dract + Start at lower dose In people wth GFR -< 45 mlmin.73 n° rean inbitors) + Assess GFR and measure serum potassium within 1 week of stating or following any dose escalation + Temporarty suspend dung intercurrent fness, planned IV radocontrast administration, bow preparation prior to colonoscopy, or pir to major surgory + Do. not routinely slscontinue in people with GFR = SOmimint.73m* as they remain nephroprotectve Beta-blockers + Reduce dose by 50% mn people with GFR < 20 mini. 73 mr Digoxin + Reduce dose based on plasma concentrations 2. Analgesics Nsalos + Avoid in people with GFR < 30 mvmin't 78m {Prolonged therapy isnot recommended in people with GFR < 60 mlimin'.73.m® + Should not be used in poopl taking ithium + Avoid in peopl taking RAAS blocking agoats Opioids + Reduce dose when GFR = 60 mlimint.73 m? + Use wit caution in people with GFR < 18 miliinv1.73.m? 43, Antimicrobials Penieiia + Risk of exystaluria when GFR < 15 mlimin.73.m€ with high doses. {Neurotoxicity with benzylpenicin when GFR = 15 mlmin/.73m® with high doses (maximum, 6 gttay) ‘Aminogycosides + duce dose andor increase dosage interval when GFR < 60 milinit.73 mi + Monitor sorum loves (tough and oak) + Avoid concomitant ototoxic agents such as furosemide Macrlides + Reduce dose by 50% when GFR < 30 mimin't.73.m® Fluoroquinolones + Reduce dose by 50% when GFR < 16 mimin't.73.m* Totracyetnes + Reduce dose when GFR = 45 mllmivt.73 m®; can exacerbate uremia Atitungals + Avoid amphotericin unioss no altrnatve when GFR = 60 miimin/.73 a + Reduce maintenance dose of fluconazole by 80% when GER = 48 mimin/1.73 {+ lduce dose of tucytosine when GFF < 60 mlimevt.73m° 4. Hypoglycemics Suifonyiureas + Avoid agonts that aro mainly renal excrated (0.9. glyburide’ glbenctamido) {Other agonts that are main metabolized in tho IWer may noad reduced dose when GFA < 90 mlmin/.79 m?(@.. aieazide, gguidone) Ina + Party ronaly excreted and may noed reduced dose whon GFR < 30 miiin/t.73 Metin ‘Suggest avoid whon GFR < 30 mimin/t73 mi, but consider risk-beneft if GFR is stablo Review use when GFR = 45 mimin/.73.m" Probably safe when GFR = 45 mimin/1.73 m= ‘Suspend in people who become acataly unwell 5. Lipi- towering Stating + No increase in toxisty fr simvastatn dosed at 20 mg per day or simvastatin 20 mg fezetimide 10mg combinations per day in people win GFR = 30 mlimint.73 mor on daysis +Other tials of stains in people wih GFR < 15 mlimin/.73 mor on dalysis also showed no ‘excess toxicity Fenofrate + lncreases SC by approximately 0.19 mgil (12 uma) 6. Chemotherapeutic Cisplatin + Reduce dose when GFR < 60 mllmint.73 m? {Avoid when GFR <0 mimmin/t.73 m2 Metpnatan + Reduce dase when GFR < 60 mimi 3.73 m? Methotrexate + Reduce dase when GFR < 60 mimi. 7am? {Avoid f possible when GFR < 15 miinivt.73.m 7. Anticoagulants + Halve the dose when GFR < 90 muimivt.73 mF {Consider switch to conventional heparin oF atematively moniter plasma ant-actor Xa in those at high Fisk for bleecing (Continued) ‘Am J Kidney Dis. 2014:63(6):719-735, 79AJKD lnker et al “Table 6 (Cont). Cautionay Notes for Proveribing in Pooplo With CKD Agente Cautionary notes Warfarin + lncreased risk of blaeding when GFR < 30 mifin/1.73 m= {Uso lower doses and monitr dose whon GFR < 30 muminit.73:m® | Miscellaneous tutu + Nophrotexic and may cause renal tubular dystunction wit prolonged use even at therapeutic levels + Moritor GFR, eloctroytes, and ithium levels 6 monthly or more frequent ifthe dove changes forthe pation is acutely unwol + Avoid using concomitant NSAIDS {Maintain hycration during intercurent ess + Risicbenefitof drug in spect situation must be weighed "Note: Data as of January 2073 Abbreviations: ACE-I, angiotensin-converting enzyme inhibitor, ARB, angiotensin-receptor blocker, CKD, chronic kidney disease; GFR, glomerua fitraton rte; IV, firavenous; KDIGO, Kidney Disease: Improving Global Outcomes; NSAIDs, non-steroidal ant- inlammatory drugs; RAS, renn-angiotansin aldosterone syetom: SC, serum creainin. Reproduced wih permission of KDIGO from, CKD and Risks for Infections, AKI, Hospitalizations, ‘and Mortality CKD and sk of infections 4.6.1: We recommend that all aduts with CKD are offered annual vaccination wih influenza vaccine, unioss ontraindicated. (16) 4.6.2: Werecemmendthatallacuts with eGFR < 30 mimi’ 1.78m® (GFA categories G4-G5) and those at igh risk of pneumococcal infection (e.g, nephratic syndrome, diabetes, or those receiving mmunosup- pression receive vaccination with polyatont [pneumococcal vaccine uniess contraindicated. (16) 4.6.3: We recommend that all adults with CKD who have received pneumococcal vaccination are offered tevaccinaion within 5 years. (76) 4.6.4: We recommend that all adults who are at high risk of progression of CKD and have GFR = 30mmliny 1:78m® (GFR categories G4-Gs) be immunized ‘against hepatts B and the response contimed by appropriate serological testing. (15) 4.6.5: Consideration of five vaccine should inlude an apo- ‘ecaton of the patients immune satus and should bo in re wih recommendations trom offal or {governmental Bose. (Not Gradec) 4.6.6: Pediatric mmunizaton schedules should be folowed ‘according to official international and regional ‘recommendations for children with CKD. (ot Grado) (CKD and rik of AKI 4.6.7. Wo rocommond that all poopie with CKD are con- sidord tobe at ineroasod risk of AKI. (7A) 48.7.1: In people with CKD, the recommendations detaled inthe KDIGO AKI Guidaine shouldbe followed for managoment of thoso at rsk of AKI during Intercurrnt tlnoss, or when undergoing investiga- tion and procedures that are ikely to Increase the fak of AKL. (Not Gradec) CKD and risk of hospitalization and morality 4.6.8: CKD disease management programs should be ‘eveloped in order to optimize the community man- ‘agement of people with CKD and reduce the risk of hospital admission. (Not Graded} 4.6. Interventions to reduce hospitalization and mortality for poople wih CKD should pay close altonton to the management of assocatod comorbid conditions and cardiovascular disease i particular (Not Graded) Commentary We agree with the guideline that the benefits of ‘immunization are far greater than the associated risks. If there are no contruindications, patients with CKD should receive the influenza vaeeine annually and the pneumococcal. vaccine with a booster vaccination ‘every 5 years.” Newer vaccines recommended for the general population should also be administered 10 patients with CKD. As emphasized in the guideline, ‘hile the recommendations for hepatitis B vaccine are Timited to patients with CKD who may undergo renal replacement therapy (RRT), all patients with CKD may benefit from vaccination if they have not been previously immunized or developed natural immunity from prior hepatitis B infection Compared to the original KDOQI CKD guideline, these KDIGO recommendations devote greater atten- tion tothe risk of AKL in patients with CKD and refer to the KDIGO AKI guideline for more specific recom- mendations,” This strong. emphasis is a byproduct of the emergence ofthe large body of literature on AKI in CKD. since the publication of the KDOQL CKD guidelines. The commentary work group agrees with this position, Given insufficient data on spocitie causal mecha- nisms forthe observed associations between CKD and risks of hospitalization and mortality, the guideline docs not identify targeted interventions. Instead, a ccomprchensive approach to care for multiple comorbid conditions especially CVD, is appropriately promoted as best clinical practice. The commentary work group agrees with this approach. ‘Am J Kidney Dis. 2014168(5):719-735,DOI Commentary on KDIGO Guideline for the Evaluation and Management of CKD Implementation L. The risks of complications of CKD, such as CVD, infections, AKI, and others discussed in th chapter, may be less well known (0 non- nephrologist providers. For example, in the case of CVD, educational efforts should be focused on primary care providers, emergency medicine phy- sicians, nephrologists, and cardiologists. Education on immunizations in patients with CKD should 2. Management of the increased cardiovascular risk will require coordination of care among. providers. ‘This issue is more fully explored in chapter 5S of the KDIGO guideline. For example, the need for addi- tional peripheral arterial disease evaluation and in- terventions will require involvement of radiologists ‘and. vascular surgeons. Primary care providers. will likely take on primary responsibility for managing CVD risk in patients with CKD, whereas nephrologists will often maintain a narrower focus on management of specific CKD-related issues (eg, resistant hyper- tension, mineral and bone disorders, and anemia). 3. Implementation will require the further devel- ‘opment of electronic medical record systems to pro- vide reabtime alerts and guidance in drug dosing for patients with CKD. Reporting of eGFR in units of mL/min will also facilitate appropriate drug dosage adjustment by all providers and health care professionals 4. Pharmacovigilance systems may also faci prevention of unsafe exposure to contrast agents and {0 oral phosphate-containing bowel preparations in als with GFR < 60 mL/min/1.73 m’. REFERRAL TO SPECIALISTS AND ‘MODELS OF CARE Referral to Specialist Services 6.1.1: We recommend retoral to speciatstKeney care servers for people with CKD in the folowing er cumstances (16) ‘+ AKI or abrupt sustained tall in GFR + GER = 90 mlmin/1.73# (GFR categories G45)"; + 8coniston finding of signiicantabuminuria (ACR= 200 mgj [= 90 mpfmmaljor AER'= 900 mg 24 hours, approximately equivalent to POR. 590mg9g[=50mginmo] or PER = 600my2+ hous) + progression of CKD (s00 Flcommendation 2.1.3 or detinton) + Urinary red cel casts, RBG >20 per high power fild sustained and not readily explained + CKD and hypertension relractary to treatment with 4 0 more antinypertonsive agents persistent abnormalities of serum potassium: Fecurtont o extensive nephvolihasis: 1 hereditary kidney disease. ‘Am J Kidney Dis. 2014:63(6):719-735, AJKD 5.1.2: We recommend timely refer for planning renal replacement therapy (ART) in people with progressive ‘CKO in whom tho risk of kidnoy failure wihin 1 year 's 10-20% or higher, as determined by validated ok prediction took. (76) ‘it the is a stable colated nding, fomal reforal (La formal consutaion and ongoing care management) may not De necessary and advice from specialist services may be al that is oquired to facltate best cae forthe patents. Tis wil be health-care system dependent. ‘The aim sto avoid at retetal, defined here as referral to specalist services less than 1 year below start of ART. Commentary Both of these recommendations were level | grade recommendations. These are common sense, clear, and actionable recommendations that should be straightforward for the primary care physician to implement. We agree that consideration of both GER and albuminuria will guide appropriate referrals, thereby reducing problems of under-teferral and late referral to nephrologists. We also agree that referral of all patients with CKD stage 4 or worse will promote interventions to delay progression and reduce CKD complications, as well as the ability to prepare for RRT. In contrast, the commentary work group ques- tioned the appropriateness of referring all patients with ACR > 300 mg/g. Rather, the commentary work group thought that the decision to refer should be tailored to the specific needs of the patient and the provider’s capacity to deliver specialty care. In the ‘pinion of the commentary work group. 2 groups of patients who should be referred are those with side effects or contraindications to ACE-inhibito/ARB therapy. but albuminuria > 300 mg/g or nephrotic- range albuminuria or proteinuria, We suggest modi- fying the list above to add: + Questions about the etiology of albuminuria + Difficulty with decreasing level of albuminuria despite institution of ACE-inhibitor or ARB therapy. We believe the recommendations to use validated prediction models for the development of kidney failure to guide timely referral for RRT is appropriate. ‘The commentary work group notes that the current available prediction models are based on observa- tional studies of patients in nephrology clinics. who progressed to ESRD in non-US populations. Prior to their widespread use, these or other models should be validated in other cohorts that are generalizable to the US population with CKD. Among certain subgroups ‘of patients, the risk of death is higher than the risk of ESRD." If planning for RRT is not properly tar- ‘geted 0 patients with a high enough risk of ESRD, then the costs and/or harms of this care might outstrip the benefits 731AJKD lnker et al Care of the Patient With Progressive CKD ‘5.2.1: We suggest that people with progressive CKD should bbo managod in a mulidsciplinary care soting. (28) ‘Tho mutelscolinary team shoul include or havo access to detary counseling, education and Counseling about dtorant RAT modalities, transplant ‘options, vascular access surgery, and ethical, psy- choiogcal, and social care. (Not Graded) 5.22: Commentary KDIGO recommendations regarding the care of patients with progressive CKD are not based on strong evidence, but we believe that they are sensible and rooted in existing models of care for individuals with other chronic diseases. Timing the Initiation of RRT ‘58.4: We suggest that clalysis be intiated when one or ‘mare othe following are present symptoms or signs atibutable to Kidney failure (serosits, acid base oF slectroyio abnormalities, purus); Inability t0 contol volume status or blond pressure; a progres- sive deterioration in nutitonal status eactory tod ‘tary intervention; or cognitve impaiment, Tis often but not invariably occurs in the GFF range between § and 10 milmin/.73 m2. (2 Living donor preemptive renal transplantation in ‘adults should be considered when te GFR is 20 mi mmin/.73 mi, and thor is evdonce of progressive and ineversible CKD over the precoding 6-12 months. (Not Grado) 532 Commentary ‘The commentary work group agrees with KDIGO that dialysis initiation, for both peritoneal dialysis and hemodialysis, should not be based on estimates of kidney function alone, but should take into account symptoms and other complications of advancing Kidney disease. We further recommend that the terpretation of symptoms be individualized with ‘consideration of the expected benefit each patient may derive from starting dialysis Structure and Process of Comprehensive Conservative Management ‘84.1; Conservative management should be an option in [Peopie who choose notto pursue RAT and tis should bbe supported by a comprenensive management program. (Not Graded) [AILCKD programs and care providers should be able to daliver advance care planning for poop with a recognized neod fr end--ife car, including these people undergoing conservative Kidney care. (Not Graded) Coordinated end ote care should be avaiable to poopie and families though ether primary care or Specialist care as local circumstances dictate. (Not Grado) ‘The comprehenswve conservative management pro- {gram should include protocols for symptom and, a2: 543: 544 ‘pain management, psychological care, spiritual care, land cuturaly senstive care for the dying patient and thoi famiy(whothor at home, ina hospice or a hospital setting), followed bythe provision of cuituraly appropriate bereavement suppor. (Nat Graded) Commentary ‘The KDIGO guideline presents 4 ungraded rec- ‘ommendations regarding the details of comprehen- sive conservative management. We agree with the goals of these recommendations, noting theit con- sistency with practice guidelines on shared decision making from the Renal Physician’s Association and the American Board of Internal Medicine/ American Society of Nephrology “Choosing Wisely” campaign." However, these recommendations ‘may be difficult to implement in the United States duc to uneven access to palliative care across health care systems, a shortage of palliative-care physi- cians, limited training of US nephrologists in these areas, and poor reimbursement for these and other cognitive services. Implementation 1, Agreement for the coordination of referral to nephrologists and joint clinical management by primary care physicians, nephrologists, and other specialists should follow the principles of the patient- centered medical home, which is a paradigm whereby the relationships and communication among. pro- vviders are specified and mechanisms exist for regular review of the agreement’s effectiveness. Payment systems should promote this coordination of eare by, for example, reimbursing for electronic or telephone ‘communication among providers. 2. The elements of multidisciplinary care teams fare present in many, but not all US health care systems and some payers may not reimburse for the services provided by nonphysician team members For eligible patients with an eGFR of 15-29 mL/ min/1.73 m?, CKD education services are reim- bbursable through the Kidney Disease Education Benefit of the Medicare Improvements for Patients and Providers Act of 2008, However, this is. not accessible 0 all patients due to copays and incon- sistent implementation of education services across US nephrology practices. 3. With respect tothe timing of dialysis initiation, a strategy of “watchful waiting” until the appearance of ‘uremic symptoms represents a significant shift in US practice and has potential to result in significant cost savings for the health care system. Parity in the payment structure for dialysis management and advanced CKD management could facilitate rede- ployment of resources to safely manage patients in advanced CKD clinics. ‘Am J Kidney Dis. 2014168(5):719-735,DOI Commentary on KDIGO Guideline for the Evaluation and Management of CKD 4, Many US nephrology practices and health care systems are not equipped to incorporate recommen- dations concerning conservative management of advanced CKD into clinical practice. To facilitate the implementation of these recommendations, profes- sional societies and accreditation organizations should emphasize training in palliative care for all nephrology providers. Payment reforms for palliative care services and adoption of quality metrics for palliative CKD care should also provide incentives to ‘manage patients with advanced CKD who elect not to receive RT." CONCLUSION ‘The KDIGO guideline recommendations on eval- uation and management of CKD serve as an excellent summary of the state our knowledge and available evidence on CKD. Importantly, they provide an important and necded update to the staging system based on newly available data. They also highlight gaps in knowledge to guide future investigative efforts ACKNOWLEDGEMENTS Gaidatine recommendations included inthis aril originally ‘were published in Kidney duemational Supplements and were reprodoced with permission from KDIGO, ‘We thank Des Jeffrey Bers, Michael Choi, Holly Kramer, Michadl Rocco, and Joseph Vassalot for eatfilreview of dis manuscript: and Kerry Willis, Emily Howell, and James Pupan- kolaw from the NKF for ep in eoortinating the work of the soup and prcparng the mansscript. Sippore: No financial support was require er the development ‘of this commentary. Financial Disclosure: De Unker has swesived research grant support frm the NKF forthe alysis of clinical rials for GFR. dectine as a sirmgate marker and from Gilead Science, Ine for ‘GFR measerement and estimation in IV-infcted patients anc from Pharmalink forthe analyses of clnial wiak for potcinusa asa sumogate marker in IgA nephropathy, Dr Kurela Tra has served as a speaker for Satelite Healthcare: and Drs Astor, Fold rman, Fox, sakova, Lash, and Peralta have no finaeial relation ‘hips with any commercial entity producing health care-related presets andor services. REFERENCES 1. National Kidney Foundation, K/DOQI clinical practice uideines for chron kidney disease: evaluation, casfcaion, tn stratification, Am J Kidney Dis, 2002;39(ayppl2):S1-8266, 2. Kidney Disease: Improving Global Ouomes (KDIGO) ‘CKD Work Group. KDIGO 2012 clinical practice guidline for ‘he evaluation and management of chronic kidney disease. Kidney na Supp. 2013:31-180. 13. 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