Review
Supplemental content at
IMPORTANCE Because early-stage kidney disease is asymptomatic and is associated with both jama.com
morbidity and mortality, laboratory measurements are required for its detection. CME Quiz at
jamanetworkcme.com and
OBJECTIVE To summarize evidence supporting the use of laboratory tests for glomerular CME Questions page 851
filtration rate (GFR) and albuminuria to detect and stage acute kidney injury, acute kidney
diseases and disorders, and chronic kidney disease in adults.
EVIDENCE REVIEW We reviewed recent guidelines from various professional groups identified
via the National Guideline Clearing House and author knowledge, and systematically searched
MEDLINE for other sources of evidence for selected topics.
FINDINGS The KDIGO (Kidney Disease Improving Global Outcomes) guidelines define and
stage acute and chronic kidney diseases by GFR and albuminuria. For initial assessment of
GFR, measuring serum creatinine and reporting estimated GFR based on serum creatinine
(eGFRcr) using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) 2009
equation is recommended. If confirmation of GFR is required because of conditions that
affect serum creatinine independent of GFR (eg, extremes of muscle mass or diet), or
interference with the assay, cystatin C should be measured and estimated GFR should be
calculated and reported using cystatin C (eGFRcys) and serum creatinine (eGFRcr-cys) or GFR
should be measured directly using a clearance procedure. Initial assessment of albuminuria
includes measuring urine albumin and creatinine in an untimed spot urine collection and
reporting albumin-to-creatinine ratio. If confirmation of albuminuria is required because of
Author Affiliations: Division of
diurnal variation or conditions affecting creatinine excretion, such as extremes of muscle
Nephrology, Tufts Medical Center,
mass or diet, the albumin excretion rate should be measured from a timed urine collection. Boston, Massachusetts.
Corresponding Author: Andrew S.
CONCLUSIONS AND RELEVANCE Detection and staging of acute and chronic kidney diseases Levey, MD, Division of Nephrology,
can be relatively simple. Because of the morbidity and mortality associated with kidney Tufts Medical Center,
800 Washington St,
disease, early diagnosis is important and should be pursued in at-risk populations.
Box 391, Boston, MA 02111
(alevey@tuftsmedicalcenter.org).
JAMA. 2015;313(8):837-846. doi:10.1001/jama.2015.0602 Section Editor: Mary McGrae
McDermott, MD, Senior Editor.
A
cute and chronic kidney diseases are common in adults and tection. Measurement of serum creatinine and urine protein is of-
are associated with increased risk for kidney failure, com- ten performed in the general medical evaluation of adults with acute
plications, and mortality (Table 1).1-3 Acute kidney injury and chronic illness. Serum creatinine is routinely measured in the ba-
affects 10% to 20% of hospitalized adults and chronic kidney dis- sic metabolic panel and proteinuria is ascertained along with rou-
ease is found in more than 10% of nonhospitalized adults. Kidney tine urinalysis. However, until recently, uncertainty and contro-
failure is the end stage of acute and chronic kidney disease and may versy existed regarding the definitions for acute and chronic kidney
require treatment by dialysis or transplantation. Earlier stages of kid- diseases, which tests should be obtained to diagnose them, and how
ney disease are 10 to 1000 times more common in the population the tests should be reported and interpreted (Box 1).
than kidney failure, depending on age and the clinical setting, and The international organization KDIGO (Kidney Disease Improv-
are associated with electrolyte and acid-base disorders, fluid over- ing Global Outcomes) attempted to resolve these controversies by up-
load, metabolic and endocrine complications, toxicity of drugs ex- dating prior evidence-based consensus definitions, staging systems,
creted by the kidneys, and cardiovascular disease. and the proper laboratory evaluation for acute and chronic kidney
Early detection facilitates the appropriate diagnosis and treat- diseases.2,3 These guidelines use glomerular filtration rate (GFR), gen-
ment of acute and chronic kidney diseases, but early-stage kidney erally accepted as the best index of kidney function in health and dis-
disease is usually asymptomatic and requires laboratory tests for de- ease, and albuminuria, a marker of kidney damage, as the principal kid-
jama.com (Reprinted) JAMA February 24, 2015 Volume 313, Number 8 837
Acute Kidney Injury Acute Kidney Diseases and Disorders Chronic Kidney Disease
Duration Within 2-7 days ≤3 Months >3 Months
Functional criterion Increase in serum creatinine by 50% Glomerular filtration rate <60 mL/min Glomerular filtration rate <60 mL/min/1.73 m2
within 7 days or /1.73 m2 or
Increase in serum creatinine by 0.3 mg/dL Decline in glomerular filtration rate by
(26.5 μmol/L) within 2 days or >35% times baseline or
Urine output <0.5 mL/kg/h for 6 hours Increase in serum creatinine by >50%
times baseline
Structural criterion None required Marker of kidney damage (albuminuria, Marker of kidney damage (albuminuria is most
hematuria, or pyuria are most common) common)
Examplesa Decreased kidney perfusion (prerenal Acute and rapidly progressive Diabetic kidney disease
disorders) glomerulonephritis Hypertensive nephrosclerosis
Urinary tract obstruction (postrenal Acute presentations of nephrotic Chronic glomerulonephritis
disorders) syndrome Chronic interstitial nephritis
Intrinsic kidney diseases (acute tubular Acute pyelonephritis Chronic pyelonephritis
necrosis, acute interstitial nephritis) Partial obstruction of the urinary tract Polycystic kidney disease
Chronic heart failure
Chronic liver disease
Staging Serum creatinine and urine output Not defined Albuminuria categories (albumin to creatinine
categories: ratio, mg/g approximately equivalent to albumin
Stage 1: serum creatinine increase by ≥0.3 excretion rate, mg/d) and related terms:
mg/dL from baseline or serum creatinine A1: ≤30, normal to mildly increased
increase by 1.5 to 1.9 times baseline or A2: >30-300, moderately increased (formerly
urine output <0.5 mL/kg/h for 6 to 12 microalbuminuria)
hours A3: >300, severely increased (includes nephrotic
Stage 2: serum creatinine increase by 2.0 syndrome, > ≈ 2000)
to 2.9 times baseline or urine output <0.5 GFR categories (mL/min/1.73 m2) and related
mL/kg/h for ≥12 hours terms:
Stage 3: serum creatinine increase by ≥3.0 G1: >90, normal or high
times baseline or G2: 60-89, mildly decreased
serum creatinine ≥4 mg/dL or renal G3a: 45-59, mildly to moderately decreased
replacement therapy G3b: 30-44, moderately to severely decreased
G4: 15-29, severely decreased
G5: <15 or treated by dialysis, kidney failure
Burden Incidence 10% to 20% among adults Unknown Prevalence ≈ 10% in nonhospitalized adults
requiring hospitalization (0.3% requiring (higher in elderly patients)
dialysis) Lifetime risk ≈ 50%
Prevalence of kidney failure treated by dialysis or
transplantation ≈ 0.3% (higher in elderly patients)
Lifetime risk of kidney failure 2% to 8% (higher in
black patients)
a
Conversion factors: To convert serum creatinine from mg/dL to μmol/L, Additional diagnostic testing is required to determine the cause of disease and
multiply by 88.4. The approximate conversion of albumin-to-creatinine ratio treatment.
from mg/g to mg/mol, divide by 10 (data for Table 1 were adapted).1
ney measures to define and stage acute and chronic kidney diseases. tionsthatmayhavebeenreportedafterthe2012KDIGOguideline.The
KDIGOguidelinesalsoproviderecommendationsfortheinitialandcon- reviewwasrestrictedtoequationsdevelopedandevaluatedusingstan-
firmatory tests for these diseases (Figure). The evaluation of GFR and dardized assays for creatinine and cystatin C. GFR measurement meth-
albuminuria is reviewed here in the context of the KDIGO guidelines, ods were reviewed5 in 2009 and MEDLINE was searched for system-
the guidelines are compared with other recent guidelines and more re- atic reviews that may have appeared after that publication.
cently published literature, and areas of uncertainty are addressed. Testing for chronic kidney disease in high-risk populations was
reviewed by Deo et al in 2010.6 The National Guideline Clearance
House was searched for guidelines appearing after this publication
regarding this topic. MEDLINE was searched for systematic re-
Sources of Evidence
views or meta-analyses on methods for albuminuria testing in high-
The most recent KDIGO guidelines were reviewed.2,3 These were de- risk populations that may have appeared subsequent to publica-
veloped by an independent and global group of volunteers with exper- tion of the KDIGO chronic kidney disease guideline.3
tiseinkidneydiseasesupportedbyaprofessionalevidence-reviewteam. All MEDLINE searches were limited to English-language stud-
Guidelines and evidence reviews were submitted for open review by ies of human subjects. Additional information regarding the search
clinician and researcher experts, stakeholders, and the public. The strategies, search terms, and number of articles reviewed is re-
KDIGO guidelines on acute kidney injury and chronic kidney disease ported in the eTable and eAppendix 1 (in the Supplement).
werepublishedin2012and2013,respectively.2,3 Additionally,searches
of the literature (through December 2014) focused on the evaluation
of kidney disease.
Spectrum of Acute and Chronic Kidney Disease
The National Guideline Clearance House was searched for kid-
ney disease testing guidelines. The creatinine-based GFR estimating Acute and chronic kidney diseases encompass a spectrum of disor-
equations were reviewed4 in 2011 and MEDLINE was also searched for ders that are defined by measures of kidney structure, function, or dis-
any newer literature on this topic, as well as for cystatin C–based equa- ease duration, irrespective of the causes for kidney disease (Table 1).1-3
838 JAMA February 24, 2015 Volume 313, Number 8 (Reprinted) jama.com
Methods for Albuminuria Testing in High-Risk Populations validated risk-prediction instruments to estimate the risk of pro-
A recent meta-analysis showed that automated reagent strips had gression to kidney failure to assist clinical decision making.55
lower sensitivity than ACR for detecting albuminuria in patients with
diabetes and hypertension.59 Another meta-analysis showed that
albumin concentration and ACR had similar performance charac-
Conclusions
teristics in detecting albuminuria in patients with diabetes.60 It is
likely that ACR would be more accurate for distinguishing among cat- Acute and chronic kidney diseases are common and can be detected
egories of albuminuria as defined by KDIGO3 and monitoring changes bysimplelaboratorytests.RecentKDIGOguidelinesresolveuncertainty
overtime. and controversy regarding the definitions for acute and chronic kidney
disease,determinationofwhichtestsshouldbeusedtodiagnosethese
Evaluating and Predicting Chronic Kidney Disease Progression conditions, and how the tests should be reported and interpreted. Kid-
There is no accepted definition for chronic kidney disease progres- ney diseaases are defined and staged based primarily on GFR as a mea-
sion. For clinical trials of drugs intended to slow the progression of sure of kidney function and albuminuria as a marker of kidney damage.
of chronic kidney disease, the US Food and Drug Administration Initial tests include serum creatinine to estimate GFR and urine ACR in
uses a doubling of baseline serum creatinine, equivalent to a 57% an untimed spot urine specimen to estimate albuminuria. Based on
decline in eGFR, as a surrogate end point for kidney failure. Unfor- these tests, clinicians can make an initial assessment of the presence or
tunately, doubling of serum creatinine is a late event in chronic kid- absence of kidney disease and its severity. Confirmatory tests should
ney disease. Data from recent meta-analyses suggest that smaller be undertaken for decision making if there is uncertainty about the ac-
changes in eGFR (30% or 40% decline) or a doubling of urine curacyofinitialtests.ConfirmatorytestsincludeeGFRcysoraclearance
albumin are associated with a higher risk of subsequent kidney procedure to measure GFR and urine AER in a timed urine specimen.
failure and mortality.61-63 It seems reasonable to use these mea- Additionaldiagnostictestingisrequiredtodeterminethecauseofacute
sures in clinical practice. In addition, we suggest that clinicians use and chronic kidney diseases and to guide their treatment.
ARTICLE INFORMATION the study but hade no role in the collection, 8. Levey AS, Coresh J. Chronic kidney disease.
Author Contributions: Drs Levey and Inker had full management, analysis, and interpretation of the Lancet. 2012;379(9811):165-180.
access to all of the data in the study and take data; preparation, review, or approval of the 9. Bellomo R, Kellum JA, Ronco C. Acute kidney
responsibility for the integrity of the data and the manuscript; and decision to submit the manuscript injury. Lancet. 2012;380(9843):756-766.
accuracy of the data analysis. for publication.
10. Bellomo R, Ronco C, Kellum JA, et al. Acute
Study concept and design: Levey, Inker. renal failure—definition, outcome measures, animal
Acquisition, analysis, or interpretation of data: REFERENCES
models, fluid therapy and information technology
Levey, Becker, Inker. 1. Eckardt KU, Coresh J, Devuyst O, et al. Evolving needs. Crit Care. 2004;8(4):R204-R212.
Drafting of the manuscript: Levey, Becker, Inker. importance of kidney disease. Lancet. 2013;382
Critical revision of the manuscript for important (9887):158-169. 11. Mehta RL, Kellum JA, Shah SV, et al. Acute
intellectual content: Levey, Inker. Kidney Injury Network: report of an initiative to
2. Kidney Disease; Improving Global Outcomes improve outcomes in acute kidney injury. Crit Care.
Administrative, technical, or material support: (KDIGO) Acute Kidney Injury Work Group. KDIGO
Levey, Becker, Inker. 2007;11(2):R31.
clinical practice guideline for acute kidney injury.
Study supervision: Levey. http://www.kdigo.org/clinical_practice_guidelines 12. National Kidney Foundation. K/DOQI clinical
Conflict of Interest Disclosures: All authors have /pdf/KDIGO%20AKI%20Guideline.pdf. Accessed practice guidelines for chronic kidney disease. Am J
completed and submitted the ICMJE Form for February 5, 2015. Kidney Dis. 2002;39(2 suppl 1):S1-266.
Disclosure of Potential Conflicts of Interest. Dr 3. Kidney Disease: Improving Global Outcomes 13. Palevsky PM, Liu KD, Brophy PD, et al KDOQI
Levey reports that he was chair of the workgroup (KDIGO). KDIGO clinical practice guideline for the US commentary on the 2012 KDIGO clinical practice
for the 2002 KDOQI (Kidney Disease Outcomes evaluation and management of chronic kidney guideline for acute kidney injury. Am J Kidney
Quality Initiative) chronic kidney disease guideline disease. http://www.kdigo.org/home/guidelines Dis.2013;61(5):649-672.
and member of the workgroup for the 2012 KDIGO /ckd-evaluation-management/. Accessed February 14. Inker LA, Astor BC, Fox CH, et al KDOQI US
(Kidney Disease Improving Global Outcomes) 5, 2015. commentary on the 2012 KDIGO clinical practice
chronic kidney disease guidelines. Dr Inker reports guideline for the evaluation and management of
that she was cochair of the workgroup for the 2013 4. Earley A, Miskulin D, Lamb EJ, Levey AS, Uhlig K.
Estimating equations for glomerular filtration rate in CKD. Am J Kidney Dis. 2014;63(5):713-735.
KDOQI commentary on the 2012 KDIGO chronic
kidney disease guideline. Dr Levey reports being the era of creatinine standardization. Ann Intern Med. 15. James M, Bouchard J, Ho J, et al Canadian
the principal investigator and Dr Inker reports being 2012;156(11):785-795. Society of Nephrology commentary on the 2012
the clinical director for the CKD-EPI (Chronic Kidney 5. Stevens LA, Levey AS. Measured GFR as a KDIGO clinical practice guideline for acute kidney
Disease Epidemiology Collaboration) research confirmatory test for estimated GFR. J Am Soc injury. Am J Kidney Dis. 2013;61(5):673-685.
group, which developed the CKD-EPI equations for Nephrol. 2009;20(11):2305-2313. 16. Akbari A, Clase CM, Acott P, et al Canadian
glomerular filtration rate (GFR) estimation. Drs 6. Deo A, Sarnak M, Uhlig K. US guidelines on the Society of Nephrology Commentary on the KDIGO
Levey and Inker have applied for a patent for management of chronic kidney disease. In: Clinical Practice Guideline for CKD Evaluation and
precise estimation of GFR using a panel of filtration Daugirdas J, ed. Handbook of Chronic Kidney Management. Am J Kidney Dis. 2015;65(2):177-205
markers. No other disclosures were reported. Disease Management. Philadelphia, PA: Lippincott 17. National Institute for Health and Care
Funding/Support: The CKD-EPI research group Williams & Wilkins; 2011:566-580. Excellence. Acute kidney injury: prevention,
reports receipt of grant support from the National 7. Levey AS, Inker LA. UpToDate: Wolters Kluwer detection and management of acute kidney injury
Institute of Diabetes and Digestive and Kidney Health website. Definition and staging of chronic up to the point of renal replacement therapy. http:
Diseases (U01 DK 053869P). kidney disease in adults. http://www.uptodate.com //guidance.nice.org.uk/cg169. Accessed January 3,
Role of the Funder/Sponsor: The National /contents/definition-and-staging-of-chronic- 2015.
Institute of Diabetes and Digestive and Kidney kidney-disease-in-adults. Accessed February 5, 2015. 18. National Institute for Health and Care
Disease participated in the design and conduct of Excellence. Chronic kidney disease (partial update):
jama.com (Reprinted) JAMA February 24, 2015 Volume 313, Number 8 845
Figure. Stepwise Evaluation for Detection of Acute and Chronic Kidney Disease
Perform confirmatory
test if necessary Measure serum cystatin C and calculate Measure albumin excretion rate
eGFRcr-cys and eGFRcys (for steady state) in timed urine collection
Clearance procedure to measure GFR
Evidence of
kidney disease eGFRcr-cys or eGFRcys or measured GFR Urine albumin excretion rate
<60 mL/min per 1.73 m2 >30 mg/day
Duration of
kidney disease Acute kidney injury Acute kidney disease Chronic kidney disease Acute kidney disease Chronic kidney disease
2-7 days ≤3 months >3 months ≤3 months >3 months
eGFRcr indicates estimated glomerular filtration rate based on serum creatinine; CKD-EPI, Chronic Kidney Disease Epidemiology Collaboration; eGFRcr-cys, eGFR
based on serum creatinine and cystatin C; eGFRcys, eGFR based on cystatin C.
ance measurements require either multiple measurements of serum higher ranges of eGFR (>60 mL/min/1.73 m2) and allows reporting
concentrations or timed urine collections and are not routinely per- eGFRcr as a numeric value throughout the entire range. Other guide-
formed. GFR is usually estimated from serum concentrations of a lines and commentaries concurred with the recommendation to use
marker of filtration using GFR estimating equations. These equa- the CKD-EPI 2009 creatinine equation.14,16,18 Our search revealed sev-
tions account for non-GFR related factors that influence marker se- eral new equations since the KDIGO guideline review, but none were
rum concentrations including the rate of the generation, renal tu- more accurate in North America, Europe, and Australia than the
bular reabsorption or secretion, and extrarenal elimination of the CKD-EPI 2009 equation (eAppendix 2 in the Supplement).
marker. The most accurate estimating equations were developed In some situations, eGFRcr may not be accurate (Table 3). These
using standardized assays for creatinine and cystatin C measured in include clinical conditions that influence non-GFR factors that affect
diverse populations. The estimating equations have minimal sys- serum creatinine concentration, creatinine not being in a steady state
tematic bias (average deviation from the measured GFR), but are rela- (as occurs when GFR is rapidly changing, eg, during acute kidney in-
tively imprecise, with approximately 10% to 20% of estimates de- jury), and presence of substances in the blood that interfere with
viating by more than 30% from the measured GFR. serum creatinine assays. Creatinine is a 113-Da amino acid metabo-
lite distributed throughout the total body water compartment and
Initial Tests freely filtered by the glomeruli. Non-GFR factors include deviation
Serum creatinine testing should not be used as a stand-alone source in generation of creatinine generation due to extremes of muscle
for assessing kidney function. When serum creatinine is measured, es- mass and ingestion in the diet, inhibition of secretion by the renal
timated GFR (eGFRcr) should be calculated and reported by the clini- tubule (trimethoprim and fenofibrate), and interference with ex-
cal laboratory (Box 2).3 eGFRcr is best calculated using the 2009 trarenal elimination by gut bacteria (broad spectrum antibiotics). The
Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) 2009 CKD-EPI and MDRD study equations both compute eGFR from
equation.41 This equation is preferable to the MDRD (Modification of serum creatinine plus age, sex, and race (African American vs non–
Diet in Renal Disease) study equation42 because it is more accurate in African American) as surrogates for muscle mass and report values
840 JAMA February 24, 2015 Volume 313, Number 8 (Reprinted) jama.com
Table 2. Origin of KDIGO Guidelines on the Definition and Staging of Acute and Chronic Kidney Diseases and Concurrence of Other Evidence-Based
Guidelines and Commentaries
Acute Kidney Injury Acute Kidney Diseases and Disorders Chronic Kidney Disease
KDIGO guidelines Harmonizes definitions and staging systems New definition to include conditions Retains prior NKF-KDOQI12 definition and
from prior guidelines10,11 based on increase that do not meet the criteria for modifies staging to include cause plus
in serum creatinine and oliguria2 acute kidney injury or chronic kidney levels of albuminuria and glomerular
disease2 filtration rate (CGA nomenclature)3
NKF-KDOQI commentary Concurs with KDIGO definition based on a Suggests evidence is not sufficient to Concurs with KDIGO definition and
50% increase in serum creatinine, but has implement the definition13 expresses reservations that including cause
reservations about criteria of oliguria and of disease in staging will be difficult for
0.3-mg/dL increase in serum creatinine in nonkidney specialists14
patients with decreased baseline GFR and
also concurs with KDIGO staging13
CSN commentary Concurs with KDIGO definition based on a Suggests evidence is not sufficient to Concurs with KDIGO definition and
50% increase in serum creatinine and also implement the definition15 suggests adding an albuminuria category
concurs with KDIGO staging15 for nephrotic range proteinuria16
NICE guideline Concurs with KDIGO definition and staging17 Not discussed17 Concurs with KDIGO definition and does
not include cause of disease in staging18
KHA-CARI commentary Concurs with KDIGO definition and suggests Not discussed19 Not applicable
staging based on duration rather than peak
increase in serum creatinine19
Abbreviations: CGA, (cause, level of glomerular filtration rate, level of Australasians with Renal Impairment; NICE, National Institute for Clinical
albuminuria; CSN, Canadian Society of Nephrology; KDIGO, Kidney Disease Excellence; NKF-KDOQI, National Kidney Foundation Kidney Disease Outcomes
Improving Global Outcomes; KHA-CARI, Kidney Health Australia Caring for Quality Initiative.
indexed to 1.73 m2 body surface area. Deviation from expected val- that affect the serum concentrations of cystatin C are not well under-
ues for creatinine generation by muscle mass and diet are major stood,butarethoughttoincludethyroidandglucocorticoidhormones,
causes of error in eGFRcr. Even using standardized assays, interfer- obesity,inflammation,andsmoking.Differencesbetweenthenon-GFR
ing substances such as ketones can also lead to errors in eGFRcr. factorsthataffectserumcystatinCandcreatinineprobablyaccountfor
Using the CKD-EPI 2009 creatinine equation, 50%, 100%, and thestrongerassociationbetweendiminishedeGFRcysthaneGFRcrand
200% increases in serum creatinine during steady state conditions all-cause and cardiovascular disease mortality.45 Although a standard-
reflect 39%, 57%, and 74% decreases in eGFRcr, respectively. How- izedreferencematerialisnowavailable,considerablevariationremains
ever during acute kidney injury, creatinine may be in the nonsteady among cystatin C assays.46 and it is more costly than serum creatinine
state condition, and the eGFRcr is a less accurate estimate of mea- measurements.
sured GFR (Table 3). Nonetheless, reporting eGFRcr in acute kid- The KDIGO guideline focuses on a relatively common clinical situ-
ney injury may be useful since changes in eGFR show the direction ation when eGFRcr-cys may be helpful, confirmation of chronic kid-
and magnitude of kidney function changes in terms of GFR, simpli- ney disease.3 In some patients, moderate-to-severe decrease in
fying the interpretation of changing kidney function in patients with eGFRcr (45-59 mL/min/1.73 m2) may be the only indication for the
decreased baseline GFR. diagnosis of chronic kidney disease. In these patients, eGFRcr-cys
less than 60 mL/min/1.73 m2 is associated with greater likelihood
Confirmatory Tests of measured GFR less than 60 mL/min/1.73 m2 and a worse prog-
In clinical conditions when eGFRcr is anticipated not to be accurate nosis than patients with eGFRcr-cys greater than or equal to 60 mL/
enough for clinical decision making (as described previously and in min/1.73 m.3,44,45 Confirmation of chronic kidney disease may be par-
Table 3), confirmatory tests should be pursued to better estimate ticularly helpful for deciding whether or not to avoid agents and
GFR. These include estimating GFR using serum cystatin C with or medications that are toxic to the kidneys (eg, iodinated radiocon-
without accompanying serum creatinine (eGFRcr-cys or eGFRcys) trast, nonsteroid anti-inflammatory drugs, aminoglycoside antibi-
or a clearance measurement (Box 2). otics). Other situations in which it may be helpful to have a more ac-
CystatinCisanalternativeendogenousfiltrationmarkerthatgained curate GFR estimate include adjustment of a dose of medication with
acceptance in recent years.43 eGFRcys and eGFRcr-cys should be re- systemic toxicity that is excreted by glomerular filtration (eg, metho-
ported using the CKD-EPI 2012 equations44 when serum cystatin C is trexate or carboplatinum) or in the evaluation of kidney donors.
measured (Box 2).2 Several new equations estimate eGFRcys and In patients in whom eGFRcr is likely to be inaccurate due to non-
eGFRcr-cys, but none are more accurate than the CKD-EPI 2012 equa- GFR factors affecting serum creatinine or interference with creati-
tions(eAppendix2intheSupplement).Usingasecondendogenousfil- nine assays, and in whom there are likely minimal non-GFR factors af-
trationmarkertoestimateGFRimprovestheprecisionofGFRestimates fecting cystatin C (as described previously and in Table 3), it may be
over what can be achieved using only one marker. However, clinicians preferabletorelyoneGFRcysratherthaneGFRcr-cys.Thishasnotbeen
should understand the clinical settings in which eGFRcys and eGFRcr- widely studied but a recent publication describes better perfor-
cys are less accurate (Table 3). Cystatin C is a 13 300-Da serum protein mance of eGFRcys vs eGFRcr or eGFRcr-cys in amputees.47 eGFRcys
that is freely filtered, reabsorbed, and extensively catabolized by the is less influenced by race and ethnicity than eGFRcr or eGFRcr-cys, po-
renaltubule.Itisproducedbyallnucleatedcellsanddistributedthrough- tentially allowing GFR estimation without specification of race.
out the extracellular fluid. Serum concentrations of cystatin C are less NICE concurred with the recommendation to use eGFRcr-cys for
influenced by muscle mass and diet than creatinine. Non-GFR factors confirmation of chronic kidney disease.18 KDOQI and CSN agreed that
jama.com (Reprinted) JAMA February 24, 2015 Volume 313, Number 8 841
Initial Testing Using Creatinine Report eGFRcys and eGFRcr-cys in adults using the 2012 CKD-EPI cys-
Recommendations to Clinicians tatin C and 2012 CKD-EPI creatinine-cystatin C equations, respec-
Use a GFR estimating equation to derive eGFRcr rather than relying on tively, or alternative cystatin C–based GFR estimating equations if they
the serum creatinine concentration alone (1B)b have been shown to improve accuracy of eGFRs compared with the
2012 CKD-EPI equations (1B)b
Understand clinical settings in which eGFRcr is less accurate (see Table
3) (1B)b Confirmation of Chronic Kidney Disease
Measure cystatin C in adults with eGFRcr 45 to 59 mL/min/1.73m2 who
Recommendations to Clinical Laboratories
do not have markers of kidney damage (2C)b
Measure serum creatinine using a specific assay with calibration trace-
If eGFRcys or eGFRcr-cys is also less than 60 mL/min/1.73 m2, the
able to the international standard reference materials and minimal bias
diagnosis of chronic kidney disease is confirmed
compared with isotope-dilution mass spectrometry reference meth-
odology (1B)b If eGFRcys of eGFRcr-cys is 60 mL/min/1.73 m2 or greater, the diag-
nosis of chronic kidney disease is not confirmed
Report eGFRcr in addition to the serum creatinine concentration in
adults and specify the equation used whenever reporting eGFRcr (1B)b Confirmatory Testing Using Measured GFR
Report eGFRcr in adults using the 2009 CKD-EPI (Chronic Kidney Dis- Recommendations to Clinicians
ease Epidemiology Collaboration) creatinine equation Measure GFR using an exogenous filtration marker under circum-
An alternative eGFRcr equation is acceptable if it has been shown to stances in which more accurate ascertainment of GFR will affect treat-
improve accuracy of GFR estimates compared with the 2009 ment decisions (2B)b
CKD-EPI creatinine equation (1B)b a
KDIGO (Kidney Disease Improving Global Outcomes) recommendations 1.4.3.1
to 1.4.3.8. are from the KDIGO 2012 clinical practice guideline.3
Confirmatory Testing Using Cystatin C
b
Recommendations to Clinicians Within each recommendation, the strength of recommendation is indicated
Use a GFR estimating equation to derive GFR from serum cystatin C as level 1 (“We recommend …”), level 2 (“We suggest …”), or not graded, and
(eGFRcys) rather than relying on the serum cystatin C concentration the quality of the supporting evidence is shown as A (high), B (moderate), C
alone (2C)b (low), or D (very low).
cystatin C has promise as an alternative filtration marker, but recom- glomerular capillary wall hinders passage of albumin and other large
mendedagainstwidespreadusebecauseofconcernsregardingincom- serum proteins into the Bowman space. Larger body size, upright
plete understanding of non-GFR factors affecting its serum concentra- posture, pregnancy, exercise, fever, and activation of the renin-
tion and higher costs and incomplete standardization of assays.14,16 angiotensin system are associated with a higher AER, and there is
If even more accurate GFR assessment is required, the KDIGO significant diurnal and day-to-day variation. The mean value for AER
guidelines recommend a clearance measurement using an exog- (5-10 mg/day) in young healthy adults generally increases with age.
enous filtration marker. A variety of exogenous filtration markers are An AER of more than or equal to 30 mg per day generally reflects
available for use in either urinary or plasma clearance techniques. A re- an alteration in structure of the glomerular capillary wall.
cent systematic review evaluated the accuracy of alternative meth- Accurate assessment of the AER requires collection of a timed
ods in comparison with the classic procedure of the urinary clearance urine specimen, which is inconvenient and can be inaccurate due to
of inulin.48 Of note, urinary creatinine clearance did not meet the cri- errors in timing, incomplete bladder emptying, incomplete collec-
terion for accuracy due to large systematic bias and imprecision. tions, and spills. To overcome the difficulty in collecting a timed urine
In conclusion, serum creatinine and eGFRcr should be the in- collection, albuminuria is generally assessed from measures of al-
tial test for the assessment of kidney function. If it is not suffi- buminuria in a spot urine sample (Table 3).
ciently accurate for clinical decision making, cystatin C can be mea-
sured for estimation of eGFRcr-cys and eGFRcys, or GFR can be Initial Assessment
measured using a clearance procedure. A variety of methods are available. Measuring the albumin-to-
creatinine ratio (ACR) in an untimed specimen is the preferred ap-
proach (Box 3).3 Measuring albumin is preferred vs total protein be-
cause the method for quantifying total urine protein cannot be
Evaluation of Albuminuria
standardized because of its variable composition. Recently, the in-
Principles ternational standard reference material for serum albumin mea-
Normal urine contains a variety of proteins including filtered serum surement was adopted as the standard reference material for urine
proteins and proteins derived from the kidney and urinary tract. The albumin measurement, enabling the standardization of urine albu-
842 JAMA February 24, 2015 Volume 313, Number 8 (Reprinted) jama.com
Table 3. Primary Use of Estimated GFR using Creatinine or Cystatin C and Urine Albumin-to-Creatinine Ratio and Sources of Error in Interpretationa
min testing.49 However, current methods for albumin measure- ferred because it minimizes variation due to diurnal changes in AER
ment are based on immunoassays, which are more expensive than and in urine concentration. Other guidelines and commentaries con-
methods for total urine protein measurement. curred with these recommendations.14,16
The rationale for preferring measurement of ACR and protein-
to-creatinine ratio (PCR) to albumin and total protein concentra- Confirmatory Tests
tion is to overcome variation in urine concentration and dilution. Clinicians should understand the clinical settings in which urine ACR
Many studies show high correlations between urine ACR and PCR is less accurate (Table 3). They should know when confirmation of
in untimed spot samples with AER and protein excretion rate (PER) initial testing with additional untimed urine specimens or timed urine
in timed urine specimens.12 Because average values of creatinine ex- specimens is necessary and when a more accurate assessment of
cretion exceed 1.0 g per day, urine ACR and PCR (measured as mg/g) albuminuria is required. Examples include the detection of early dia-
generally exceed AER and PER (measured as mg/d), but the rela- betic kidney disease (previously termed microalbuminuria) or evalu-
tionship between them varies by body size and other factors affect- ation of potential kidney transplant donors.
ing creatinine generation. Clinical laboratories should measure cre-
atinine when urine albumin or total protein are requested, and
express the results as ACR or PCR in addition to albumin or total pro-
Areas of Uncertainty
tein concentration. To overcome variation by creatinine genera-
tion, some investigators have proposed estimating creatinine ex- Indications for Testing for Acute and Chronic Kidney Disease
cretion rate (CER) and multiplying this quantity by ACR to estimate Current guidelines do not recommend screening for kidney dis-
AER.50 ease in the general US population.51 However, most guidelines rec-
Reagent strips (dipsticks) allow inexpensive, point-of-care, semi- ommend testing for chronic kidney disease in high-risk popula-
quantitative assessment of urine total protein concentration. They tions, including patients with hypertension, diabetes, cardiovascular
are more sensitive to albumin than other proteins, but lack speci- disease, HIV infection, or a family history of kidney failure (eAppen-
ficity. Automated readers are more accurate than manual reading dix 2 in the Supplement). Monitoring kidney function is recom-
of reagent strips. For all methods, an early morning sample is pre- mended during ongoing therapy with many medications including
jama.com (Reprinted) JAMA February 24, 2015 Volume 313, Number 8 843
844 JAMA February 24, 2015 Volume 313, Number 8 (Reprinted) jama.com
Methods for Albuminuria Testing in High-Risk Populations validated risk-prediction instruments to estimate the risk of pro-
A recent meta-analysis showed that automated reagent strips had gression to kidney failure to assist clinical decision making.55
lower sensitivity than ACR for detecting albuminuria in patients with
diabetes and hypertension.59 Another meta-analysis showed that
albumin concentration and ACR had similar performance charac-
Conclusions
teristics in detecting albuminuria in patients with diabetes.60 It is
likely that ACR would be more accurate for distinguishing among cat- Acute and chronic kidney diseases are common and can be detected
egories of albuminuria as defined by KDIGO3 and monitoring changes bysimplelaboratorytests.RecentKDIGOguidelinesresolveuncertainty
overtime. and controversy regarding the definitions for acute and chronic kidney
disease,determinationofwhichtestsshouldbeusedtodiagnosethese
Evaluating and Predicting Chronic Kidney Disease Progression conditions, and how the tests should be reported and interpreted. Kid-
There is no accepted definition for chronic kidney disease progres- ney diseaases are defined and staged based primarily on GFR as a mea-
sion. For clinical trials of drugs intended to slow the progression of sure of kidney function and albuminuria as a marker of kidney damage.
of chronic kidney disease, the US Food and Drug Administration Initial tests include serum creatinine to estimate GFR and urine ACR in
uses a doubling of baseline serum creatinine, equivalent to a 57% an untimed spot urine specimen to estimate albuminuria. Based on
decline in eGFR, as a surrogate end point for kidney failure. Unfor- these tests, clinicians can make an initial assessment of the presence or
tunately, doubling of serum creatinine is a late event in chronic kid- absence of kidney disease and its severity. Confirmatory tests should
ney disease. Data from recent meta-analyses suggest that smaller be undertaken for decision making if there is uncertainty about the ac-
changes in eGFR (30% or 40% decline) or a doubling of urine curacyofinitialtests.ConfirmatorytestsincludeeGFRcysoraclearance
albumin are associated with a higher risk of subsequent kidney procedure to measure GFR and urine AER in a timed urine specimen.
failure and mortality.61-63 It seems reasonable to use these mea- Additionaldiagnostictestingisrequiredtodeterminethecauseofacute
sures in clinical practice. In addition, we suggest that clinicians use and chronic kidney diseases and to guide their treatment.
ARTICLE INFORMATION the study but hade no role in the collection, 8. Levey AS, Coresh J. Chronic kidney disease.
Author Contributions: Drs Levey and Inker had full management, analysis, and interpretation of the Lancet. 2012;379(9811):165-180.
access to all of the data in the study and take data; preparation, review, or approval of the 9. Bellomo R, Kellum JA, Ronco C. Acute kidney
responsibility for the integrity of the data and the manuscript; and decision to submit the manuscript injury. Lancet. 2012;380(9843):756-766.
accuracy of the data analysis. for publication.
10. Bellomo R, Ronco C, Kellum JA, et al. Acute
Study concept and design: Levey, Inker. renal failure—definition, outcome measures, animal
Acquisition, analysis, or interpretation of data: REFERENCES
models, fluid therapy and information technology
Levey, Becker, Inker. 1. Eckardt KU, Coresh J, Devuyst O, et al. Evolving needs. Crit Care. 2004;8(4):R204-R212.
Drafting of the manuscript: Levey, Becker, Inker. importance of kidney disease. Lancet. 2013;382
Critical revision of the manuscript for important (9887):158-169. 11. Mehta RL, Kellum JA, Shah SV, et al. Acute
intellectual content: Levey, Inker. Kidney Injury Network: report of an initiative to
2. Kidney Disease; Improving Global Outcomes improve outcomes in acute kidney injury. Crit Care.
Administrative, technical, or material support: (KDIGO) Acute Kidney Injury Work Group. KDIGO
Levey, Becker, Inker. 2007;11(2):R31.
clinical practice guideline for acute kidney injury.
Study supervision: Levey. http://www.kdigo.org/clinical_practice_guidelines 12. National Kidney Foundation. K/DOQI clinical
Conflict of Interest Disclosures: All authors have /pdf/KDIGO%20AKI%20Guideline.pdf. Accessed practice guidelines for chronic kidney disease. Am J
completed and submitted the ICMJE Form for February 5, 2015. Kidney Dis. 2002;39(2 suppl 1):S1-266.
Disclosure of Potential Conflicts of Interest. Dr 3. Kidney Disease: Improving Global Outcomes 13. Palevsky PM, Liu KD, Brophy PD, et al KDOQI
Levey reports that he was chair of the workgroup (KDIGO). KDIGO clinical practice guideline for the US commentary on the 2012 KDIGO clinical practice
for the 2002 KDOQI (Kidney Disease Outcomes evaluation and management of chronic kidney guideline for acute kidney injury. Am J Kidney
Quality Initiative) chronic kidney disease guideline disease. http://www.kdigo.org/home/guidelines Dis.2013;61(5):649-672.
and member of the workgroup for the 2012 KDIGO /ckd-evaluation-management/. Accessed February 14. Inker LA, Astor BC, Fox CH, et al KDOQI US
(Kidney Disease Improving Global Outcomes) 5, 2015. commentary on the 2012 KDIGO clinical practice
chronic kidney disease guidelines. Dr Inker reports guideline for the evaluation and management of
that she was cochair of the workgroup for the 2013 4. Earley A, Miskulin D, Lamb EJ, Levey AS, Uhlig K.
Estimating equations for glomerular filtration rate in CKD. Am J Kidney Dis. 2014;63(5):713-735.
KDOQI commentary on the 2012 KDIGO chronic
kidney disease guideline. Dr Levey reports being the era of creatinine standardization. Ann Intern Med. 15. James M, Bouchard J, Ho J, et al Canadian
the principal investigator and Dr Inker reports being 2012;156(11):785-795. Society of Nephrology commentary on the 2012
the clinical director for the CKD-EPI (Chronic Kidney 5. Stevens LA, Levey AS. Measured GFR as a KDIGO clinical practice guideline for acute kidney
Disease Epidemiology Collaboration) research confirmatory test for estimated GFR. J Am Soc injury. Am J Kidney Dis. 2013;61(5):673-685.
group, which developed the CKD-EPI equations for Nephrol. 2009;20(11):2305-2313. 16. Akbari A, Clase CM, Acott P, et al Canadian
glomerular filtration rate (GFR) estimation. Drs 6. Deo A, Sarnak M, Uhlig K. US guidelines on the Society of Nephrology Commentary on the KDIGO
Levey and Inker have applied for a patent for management of chronic kidney disease. In: Clinical Practice Guideline for CKD Evaluation and
precise estimation of GFR using a panel of filtration Daugirdas J, ed. Handbook of Chronic Kidney Management. Am J Kidney Dis. 2015;65(2):177-205
markers. No other disclosures were reported. Disease Management. Philadelphia, PA: Lippincott 17. National Institute for Health and Care
Funding/Support: The CKD-EPI research group Williams & Wilkins; 2011:566-580. Excellence. Acute kidney injury: prevention,
reports receipt of grant support from the National 7. Levey AS, Inker LA. UpToDate: Wolters Kluwer detection and management of acute kidney injury
Institute of Diabetes and Digestive and Kidney Health website. Definition and staging of chronic up to the point of renal replacement therapy. http:
Diseases (U01 DK 053869P). kidney disease in adults. http://www.uptodate.com //guidance.nice.org.uk/cg169. Accessed January 3,
Role of the Funder/Sponsor: The National /contents/definition-and-staging-of-chronic- 2015.
Institute of Diabetes and Digestive and Kidney kidney-disease-in-adults. Accessed February 5, 2015. 18. National Institute for Health and Care
Disease participated in the design and conduct of Excellence. Chronic kidney disease (partial update):
jama.com (Reprinted) JAMA February 24, 2015 Volume 313, Number 8 845
early identification and management of chronic higher albuminuria are associated with mortality 48. Soveri I, Berg UB, Bjork J, et al Measuring GFR.
kidney disease in adults in primary and secondary and end-stage renal disease. Kidney Int. 2011;79(12): Am J Kidney Dis. 2014;64(3):411-424.
care. 2014. https://www.nice.org.uk/guidance/cg182. 1331-1340. 49. Miller WG, Bruns DE, Hortin GL, et al. Current
Accessed January 3, 2015. 34. Hallan SI, Matsushita K, Sang Y, et al. Age and issues in measurement and reporting of urinary
19. Kidney Health Australia. KHA-CARI adaptation association of kidney measures with mortality and albumin excretion. Clin Chem. 2009;55(1):24-38.
of the KDIGO Clinical Practice Guideline for Acute end-stage renal disease. JAMA. 2012;308(22): 50. Inker LA. Albuminuria: time to focus on
Kidney Injury 2014. http://cari.org.au/CKD/CKD 2349-2360. accuracy. Am J Kidney Dis. 2014;63(3):378-381.
%20aki/Section_1_Definition_of%20AKI_Final.pdf. 35. Nitsch D, Grams M, Sang Y, et al. Associations of
Accessed January 3, 2015. 51. Moyer VA, et al. Screening for chronic kidney
estimated glomerular filtration rate and albuminuria disease. Ann Intern Med. 2012;157(8):567-570.
20. Uchino S, Bellomo R, Goldsmith D, Bates S, with mortality and renal failure by sex:
Ronco C. An assessment of the RIFLE criteria for a meta-analysis. BMJ. 2013;346:f324. 52. de Boer IH. Chronic kidney disease—a challenge
acute renal failure in hospitalized patients. Crit Care for all ages. JAMA. 2012;308(22):2401-2402.
36. Wen CP, Matsushita K, Coresh J, et al. Relative
Med. 2006;34(7):1913-1917. risks of chronic kidney disease for mortality and 53. Stevens LA, Coresh J, Levey AS. CKD in the
21. Bagshaw SM, George C, Dinu I, Bellomo R. A end-stage renal disease across races are similar. elderly–old questions and new challenges. Am J
multi-centre evaluation of the RIFLE criteria for Kidney Int. 2014;86(4):819-827. Kidney Dis. 2008;51(3):353-357.
early acute kidney injury in critically ill patients. 37. Mahmoodi BK, Matsushita K, Woodward M, 54. Moynihan R, Glassock R, Doust J. Chronic
Nephrol Dial Transplant. 2008;23(4):1203-1210. et al. Associations of kidney disease measures with kidney disease controversy: how expanding
22. Kellum JA, Bellomo R, Ronco C. Classification of mortality and end-stage renal disease in individuals definitions are unnecessarily labelling many people
acute kidney injury using RIFLE: what’s the with and without hypertension. Lancet. 2012;380 as diseased. BMJ. 2013;347:f4298.
purpose? Crit Care Med. 2007;35(8):1983-1984. (9854):1649-1661. 55. Tangri N, Stevens LA, Griffith J, et al. A
23. Ricci Z, Cruz D, Ronco C. The RIFLE criteria and 38. Fox CS, Matsushita K, Woodward M, et al. predictive model for progression of chronic kidney
mortality in acute kidney injury: a systematic Associations of kidney disease measures with disease to kidney failure. JAMA. 2011;305(15):1553-
review. Kidney Int. 2008;73(5):538-546. mortality and end-stage renal disease in individuals 1559.
24. Thakar CV, Christianson A, Freyberg R, with and without diabetes. Lancet. 2012;380 56. Levey AS, Kramer H. Obesity, glomerular
Almenoff P, Render ML. Incidence and outcomes of (9854):1662-1673. hyperfiltration, and the surface area correction. Am
acute kidney injury in intensive care units. Crit Care 39. Stevens LA, Coresh J, Greene T, Levey AS. J Kidney Dis. 2010;56(2):255-258.
Med. 2009;37(9):2552-2558. Assessing kidney function—measured and 57. Stevens LA, Levey AS. Use of the MDRD study
25. Joannidis M, Metnitz B, Bauer P, et al. Acute estimated glomerular filtration rate. N Engl J Med. equation to estimate kidney function for drug
kidney injury in critically ill patients classified by 2006;354(23):2473-2483. dosing. Clin Pharmacol Ther. 2009;86(5):465-467.
AKIN versus RIFLE using the SAPS 3 database. 40. Levey AS, Inker LA, Coresh J. GFR estimation. 58. Matzke GR, Aronoff GR, Atkinson AJ Jr, et al.
Intensive Care Med. 2009;35(10):1692-1702. Am J Kidney Dis. 2014;63(5):820-834. Drug dosing consideration in patients with acute
26. Ostermann M, Chang RW. Acute kidney injury 41. Levey AS, Stevens LA, Schmid CH, et al. A new and chronic kidney disease-a clinical update from
in the intensive care unit according to RIFLE. Crit equation to estimate glomerular filtration rate. Ann Kidney Disease: Improving Global Outcomes
Care Med. 2007;35(8):1837-1843; quiz 1852. Intern Med. 2009;150(9):604-612. (KDIGO). Kidney Int. 2011;80(11):1122-1137.
27. Ali T, Khan I, Simpson W, et al. Incidence and 42. Levey AS, Coresh J, Greene T, et al. Using 59. McTaggart MP, Newall RG, Hirst JA, et al.
outcomes in acute kidney injury. J Am Soc Nephrol. standardized serum creatinine values in the Diagnostic accuracy of point-of-care tests for
2007;18(4):1292-1298. modification of diet in renal disease study equation detecting albuminuria. Ann Intern Med. 2014;160
for estimating glomerular filtration rate. Ann Intern (8):550-557.
28. Eckardt KU, Berns JS, Rocco MV, Kasiske BL.
Definition and classification of CKD. Am J Kidney Dis. Med. 2006;145(4):247-254. 60. Wu HY, Peng YS, Chiang CK, et al. Diagnostic
2009;53(6):915-920. 43. Levey AS, Fan L, Eckfeldt JH, Inker LA. Cystatin performance of random urine samples using
C for glomerular filtration rate estimation: coming albumin concentration vs ratio of albumin to
29. Levey AS, de Jong PE, Coresh J, et al. The creatinine for microalbuminuria screening in
definition, classification, and prognosis of chronic of age. Clin Chem. 2014;60(7):916-919.
patients with diabetes mellitus. JAMA Intern Med.
kidney disease. Kidney Int. 2011;80(1):17-28. 44. Inker LA, Schmid CH, Tighiouart H, et al; 2014;174(7):1108-1115.
30. Matsushita K, van der Velde M, Astor BC, et al. CKD-EPI Investigators. Estimating glomerular
filtration rate from serum creatinine and cystatin C. 61. Lambers Heerspink HJ, Kropelin TF, Hoekman J,
Association of estimated glomerular filtration rate de Zeeuw D. Drug-induced reduction in albuminuria
and albuminuria with all-cause and cardiovascular N Engl J Med. 2012;367(1):20-29.
is associated with subsequent renoprotection:
mortality in general population cohorts. Lancet. 45. Shlipak MG, Matsushita K, Ärnlöv J, et al; CKD a meta-analysis (published online November 24,
2010;375(9731):2073-2081. Prognosis Consortium. Cystatin C versus creatinine 2014). J Am Soc Nephrol. doi.org/10.1681/ASN
31. van der Velde M, Matsushita K, Coresh J, et al. in determining risk based on kidney function. .2014070688
Lower estimated glomerular filtration rate and N Engl J Med. 2013;369(10):932-943.
62. Inker LA, Levey AS, Pandya K, Stoycheff N,
higher albuminuria are associated with all-cause 46. Grubb A, Blirup-Jensen S, Lindström V, et al. Okparavero A, Greene T. Early change in proteinuria
and cardiovascular mortality. Kidney Int. 2011;79 First certified reference material for cystatin C in as a surrogate end point for kidney disease
(12):1341-1352. human serum ERM-DA471/IFCC. Clin Chem Lab Med. progression. Am J Kidney Dis. 2014;64(1):74-85.
32. Gansevoort RT, Matsushita K, van der Velde M, 2010;48(11):1619-1621.
63. Levey AS, Inker LA, Matsushita K, et al. GFR
et al. Lower estimated GFR and higher albuminuria 47. Thurlow JS, Abbott KC, Linberg A, Little D, decline as an end point for clinical trials in CKD. Am
are associated with adverse kidney outcomes. Fenderson J, Olson SW. SCr and SCysC J Kidney Dis. 2014;64(6):821-835.
Kidney Int. 2011;80(1):93-104. concentrations before and after traumatic
33. Astor BC, Matsushita K, Gansevoort RT, et al. amputation in male soldiers: a case-control study.
Lower estimated glomerular filtration rate and Am J Kidney Dis. 2014;63(1):167-170.
846 JAMA February 24, 2015 Volume 313, Number 8 (Reprinted) jama.com