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Clinical Review & Education

Review

Glomerular Filtration Rate and Albuminuria for Detection


and Staging of Acute and Chronic Kidney Disease in Adults
A Systematic Review
Andrew S. Levey, MD; Cassandra Becker, BS; Lesley A. Inker, MD, MS

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-

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Clinical Review & Education Review Use of Lab Tests in Detecting Kidney Disease

Table 1. Definitions, Stages, and Burden of Kidney Diseasea

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

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Use of Lab Tests in Detecting Kidney Disease Review Clinical Review & Education

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):

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Clinical Review & Education Review Use of Lab Tests in Detecting Kidney Disease

Figure. Stepwise Evaluation for Detection of Acute and Chronic Kidney Disease

Assessment of Glomerular Filtration Rate Assessment of Albuminuria


Initial assessment
Measure serum creatinine and Measure urine albumin and urine creatinine
calculate eGFRcr using the CKD-EPI in a spot (untimed) urine specimen and
2009 equation calculate albumin-to-creatinine ratio

Evidence of kidney disease


eGFRcr <60 mL/min per 1.73 m2 or increase Urine albumin-to-creatinine ratio
in serum creatinine by 50% within 7 days >30 mg/g
or 0.3 mg/dL within 2 days

Assess possible limitations


to interpretation Not in steady state Not in steady state
Abnormal muscle mass Abnormal muscle mass
Extremes of protein intake Extremes of protein intake
Other urinary tract infection,
heavy exercise, menstruation

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

Assess for related


complications Fluid retention Hypoalbuminemia
Acid-base and electrolyte disorders Fluid retention
Metabolic and hormonal disorders Hyperlipidemia
Drug toxicity Deep vein thrombosis
Cardiovascular disease Cardiovascular disease
Uremia (if severe) Nephrotic syndrome (if severe)
Other: infections, cognitive impairment,
frailty

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

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Use of Lab Tests in Detecting Kidney Disease Review Clinical Review & Education

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

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Clinical Review & Education Review Use of Lab Tests in Detecting Kidney Disease

Box 2. KDIGO Recommendations for Evaluation of GFR and Commentsa

General Recommendations Recommendations to Clinical Laboratories


Use serum creatinine and a glomerular filtration rate (GFR) estimating Measure serum cystatin C using an assay with calibration traceable to
equation for initial assessment (1A)b the international standard reference material (1B)b
Use additional tests (such as cystatin C or a clearance measurement) Report eGFRcys and eGFRcr-cys in addition to the serum cystatin C con-
for confirmatory testing in specific circumstances when estimated GFR centration in adults and specify the equation used whenever report-
based on serum creatinine (eGFRcr) is less accurate (2B)b ing eGFRcys and eGFRcr-cys (1B)b

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).

Understand clinical settings in which eGFRcys and eGFRcr-cys are less


accurate (see Table 3) (2C)b

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-

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Use of Lab Tests in Detecting Kidney Disease Review Clinical Review & Education

Table 3. Primary Use of Estimated GFR using Creatinine or Cystatin C and Urine Albumin-to-Creatinine Ratio and Sources of Error in Interpretationa

eGFRcr eGFRcys Urine ACR


Primary use Initial test for assessment of GFR Confirmatory test for assessment of GFR Initial test for assessment of
albuminuria
Errors in interpretation
Nonsteady state (acute Change in eGFR lags behind the change Change in eGFR lags behind the change in ACR overestimates AER when mGFR is
kidney injury) in mGFR (eGFR overestimates mGFR mGFR (eGFR overestimates mGFR when declining (creatinine excretion is
when mGFR is declining and mGFR is declining and underestimates decreased) and underestimates AER
underestimates mGFR when mGFR is mGFR when mGFR is rising) when mGFR is rising (creatinine
rising) excretion is increased)
Non-GFR factorsb Directly measured in clinical studies Hypothesized from clinical observations NA
and epidemiologic studies
Factors affecting generation Decreased by large muscle mass, high Decreased in hyperthyroidism, Decreased by large muscle mass (higher
protein diet, ingestion of cooked meat glucocorticoid excess, and possibly urinary creatinine concentration)
and creatine supplements obesity, inflammation, and smoking Increased by small muscle mass (lower
Increased by small muscle mass, limb Increased in hypothyroidism urinary creatinine excretion)
amputation, muscle-wasting diseases
Factors affecting tubular Decreased by drug-induced inhibition NA NA
reabsorption or secretion of secretion (trimethoprim, cimetidine,
fenofibrate)
Factors affecting extrarenal Decreased by inhibition of gut Increased by large losses of extracellular NA
elimination creatininase by antibiotics fluid (drainage of pleural fluid or ascites)
Increased by dialysis, large losses of
extracellular fluid (drainage of pleural
fluid or ascites)
Range Less precise at higher GFR due to Less precise at higher GFR, due to higher Less precise at lower ACR, due to higher
higher biological variability in non-GFR biological variability in non-GFR factors biologic variability in AER and larger
factors relative to GFR and larger relative to GFR and larger measurement measurement error in urine albumin
measurement error in serum creatinine error in serum cystatin C and GFR concentration
and GFR
Interference with assays Spectral interferences (bilirubin, some NA Very high urine albumin concentration
drugs) (“prozone effect”)
Chemical interferences (glucose,
ketones, bilirubin, some drugs)
Interfering conditions NA NA Contamination with albumin in
menstrual blood and lower urinary tract
inflammation
a
Abbreviations: ACR, albumin-to-creatinine ratio; AER, albumin excretion rate; Reference test for GFR is mGFR using clearance methods; reference test for
eGFRcr, estimated GFR based on serum creatinine; eGFRcys, estimated GFR albuminuria is AER in timed urine collection.
based on cystatin C; GFR, glomerular filtration rate; mGFR, measured GFR; b
Effects of factors affecting non-GFR determinants refer to effects on eGFR.
NA, not applicable.

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

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Clinical Review & Education Review Use of Lab Tests in Detecting Kidney Disease

Assessment of Duration of Kidney Disease


Box 3. KDIGO Recommendations for Evaluation of Albuminuriaa A frequent clinical problem is initial evaluation of patients in whom
decreased eGFRcr or albuminuria is discovered for the first time. Cur-
General Recommendations rent studies do not provide substantial data about the relative fre-
Use untimed urine specimens for initial assessment quency of acute or chronic kidney disease in this setting. The im-
Use repeat untimed urine specimens or timed urine specimens for portance of evaluation depends on the patient’s clinical condition.
confirmatory testing in specific circumstances when single measure- Acute kidney injury may require urgent attention to avoid life-
ments or untimed urine specimens are less accurate
threatening complications, while chronic kidney disease can gen-
Initial Testing Using Untimed Urine Specimens erally be managed as an outpatient. The first step is to review prior
Recommendations to Clinicians medical records for past evidence of decreased GFR, albuminuria (or
Use the following measurements for initial testing of proteinuria (in proteinuria), or other markers of kidney damage. In patients with
descending order of preference, in all cases an early morning urine
acute illness, monitoring urine output and serum creatinine will al-
sample is preferred) (2B)
1. urine albumin-to-creatinine ratio (ACR)
low early detection of acute kidney injury. Without other data, re-
peat testing within 1 to 2 weeks is indicated. A renal ultrasound is
2. urine protein-to-creatinine ratio (PCR)
helpful since detection of small kidneys provides unequivocal evi-
3. reagent strip urinalysis for total protein with automated reading
dence of chronic kidney disease.
4. reagent strip urinalysis for total protein with manual reading

Recommendations to Clinical Laboratories Assessment of Special Populations:


Report ACR and PCR in untimed urine samples in addition to albu- Elderly, Racial and Ethnic Minority, and Obese Patients
min concentration or proteinuria concentrations rather than the con- Decreased GFR and albuminuria are common in elderly patients, es-
centrations alone (1B) pecially in association with cardiovascular disease and its related risk
The term microalbuminuria should no longer be used by laborato- factors, but the cause of kidney disease is often not known with cer-
ries (Not Graded) tainty. There is debate about whether these abnormalities reflect
Confirmatory Testing Using Repeat Measurements of Untimed aging or disease processes,52,53 and as with other common chronic
Urine Specimens or Timed Urine Specimens conditions in elderly patients, there is debate about overdiagnosis.54
Recommendations to Clinicians Nevertheless, it is prudent to assess decreased eGFR for purposes
Understand clinical settings that may affect interpretation of mea- of drug dosing and for avoiding drugs that are toxic to the kidneys
surements of albuminuria and order confirmatory tests as indicated
(previously described). Knowing the level of eGFR and urine ACR,
(Not Graded) (see Table 3)
in combination with age and sex, is also useful in predicting the risk
Confirm reagent strip–positive albuminuria and proteinuria by quan-
of kidney failure.55 Racial and ethnic minorities in the United States
titative laboratory measurement and express as a ratio to creatinine
wherever possible are at increased risk for chronic kidney disease. Racial and ethnic
variation in creatinine generation leads to uncertainty in the diag-
Confirm ACR of 30 mg/g or greater (ⱖ3mg/mmol) on a random un-
timed urine with a subsequent early morning urine sample nostic thresholds for disease definition or staging based on eGFRcr
and ACR within these groups in the United States and worldwide.
If a more accurate estimate of albuminuria or total proteinuria is re-
quired, measure albumin excretion rate or total protein excretion rate eGFRcys may be more accurate than eGFRcr in assessing individu-
in a timed urine sample als of racial and ethnic groups other than white and African Ameri-
can. Obesity is a risk factor for chronic kidney disease. Body size in-
Confirmatory Testing for Nonalbumin Proteinuria
fluences GFR and generation of both creatinine and cystatin C,
Recommendations to Clinicians
If significant nonalbumin proteinuria is suspected, use assays for spe-
making it difficult to interpret measured and estimated GFR, whether
cific urine proteins (eg, α1-microglobulin, β2-microglobulin, mono- or not they are indexed by body surface area.56 Presently, the GFR
clonal heavy or light chains, [known in some countries as ‘‘Bence and albuminuria thresholds for the definition of kidney disease are
Jones’’ proteins]) (Not Graded) based on risk associations and do not differ by age, race and ethnic-
a
KDIGO (Kidney Disease Improving Global Outcomes) recommendations ity, or body size, but this remains an important topic for research.
1.4.4.1 to 1.4.4.4 are from the KDIGO 2012 clinical practice guideline.3 Within
each recommendation, the strength of recommendation is indicated as Dosing of Medication
Level 1 (“We recommend …”), Level 2 (“We suggest …”), or Not Graded, and
There are conflicting recommendations about methods for assess-
the quality of the supporting evidence is shown as A (high), B (moderate),
C (low), or D (very low). ment of kidney function for drug development and dosing.57 The 2011
KDIGOclinicalupdateondrugdosinginpatientswithacuteandchronic
kidney diseases recommended using GFR rather than creatinine clear-
diuretics, nonsteroidal anti-inflammatory drugs, and many newer ance to evaluate kidney function for drug dosing. They also recom-
drugs used for HIV and chemotherapy. Patients with acute medical mended use of the most accurate method for GFR evaluation for each
conditions undergo frequent laboratory testing that can reveal the patient rather than relying on estimated creatinine clearance from the
presence of acute and also chronic kidney disease. The high preva- Cockcroft-Gault equation.58 The MDRD Study equation and the CKD-
lence of kidney diseases in the general population and the low cost EPI 2009 creatinine equation are both more accurate than the Cock-
of serum creatinine assays and urinalysis support these practices. croft-Gault equation for estimating measured GFR.40 Because drug
However, like many accepted practices in clinical medicine, there dosing is based on body size, it is important to express GFR as mL/
have not been large-scale randomized trials to assess the benefits, min,withoutindexingforbodysurfacearea.ToconverteGFRfrommL/
harms, and cost effectiveness. min/1.73 m2 to mL/min, multiply by body surface area/1.73.

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Use of Lab Tests in Detecting Kidney Disease Review Clinical Review & Education

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
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