First Morning Voids Are More Reliable Than Spot Urine Samples to Assess Microalbuminuria
Elsbeth C. Witte*,
Hiddo J. Lambers Heerspink,
Dick de Zeeuw,
Stephan J.L. Bakker*,
Paul E. de Jong* and
Ronald Gansevoort
* Division of Nephrology and Department of Clinical Pharmacology, University Medical Center Groningen, University of Groningen, Groningen, Netherlands
Correspondence: Dr. Hiddo J. Lambers Heerspink, Department of Clinical Pharmacology, University Medical Center Groningen, University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, Netherlands. Phone: +31-50-363-2810; Fax: +31-50-363-2812; E-mail: h.j.lambers.heerspink{at}med.umcg.nl
Received for publication March 14, 2008.
Accepted for publication October 1, 2008.
Measurement of urinary albumin excretion (UAE) in a 24-h collectionis the gold standard method to determine the presence of microalbuminuria.We sought to compare more practical alternatives—measurementof urinary albumin concentration (UAC) or albumin:creatinineratio (ACR)—in a first morning void or in a spot urinesample with this gold standard. We asked 241 participants ofa prospective cohort study to make three 24-h urine collections,a first morning void, and a spot urine sample. Regression analysisshowed that the ACR in a first morning void best agreed with24-h UAE. The prevalence of microalbuminuria determined by datafrom a first morning void (7.5%, whether by UAC or ACR) nearlyequaled the prevalence of microalbuminuria determined by 24-hUAE (10.0%), whereas the prevalence was higher when determinedby spot urine samples (25.4% for UAC and 22.4% for ACR; bothP < 0.001 versus 24-h UAE). The intraindividual coefficientsof variation of the ACR in a first morning void and 24-h UAEwere similar (19%). Intraindividual coefficients of variationsof all other measurements of albuminuria were significantlygreater. In conclusion, measurement of albuminuria in a firstmorning void, preferably as the ACR, is more reliable than aspot urine sample to diagnose and monitor microalbuminuria.
Microalbuminuria has been established as a valuable risk markerfor renal and cardiovascular complications. Consequently, treatmentguidelines from various medical societies have recommended assessmentof urinary albumin in patients with hypertension or diabetesand even in the general population to identify individuals atincreased risk for renal and cardiovascular disease.1–4
Various methods for urine collection are used in clinical practiceto determine presence of microalbuminuria. Because urinary albuminexcretion (UAE) follows a circadian rhythm, the amount of albuminexcreted in urine during a 24-h period has been considered the"gold standard"; however, 24-h urine collection is a cumbersomeprocedure. More practical and easier alternatives are collectionof a first morning void or a spot (random) urine sample. Ithas been suggested that a first morning void (collection ofthe first urine void after the individual awakes from sleep)is to be preferred over a spot urine sample (daytime randomsample), because the former is less influenced by factors suchas hydration status and physical activity, reducing the variabilitythat is caused by these factors.5 From a practical point ofview, however, spot urine samples are preferred because theycan be collected during consultation at the doctor's officeand therefore pose the least inconvenience for individuals.
As yet, only one study has compared the validity of using afirst morning void or a spot urine sample as a substitute fora 24-h urine collection to diagnose microalbuminuria and tomonitor albuminuria over time6; however, this study includedonly 11 patients, limiting the validity of the results. Theaim of this study, therefore, was to investigate whether albuminuriameasures derived from a first morning void or a spot urine samplecould be used as an alternative to a 24-h UAE to diagnose microalbuminuriaand to monitor albuminuria over time.
Study Population
A total of 241 individuals were included in the study. Table 1describes the characteristics of the overall study populationand stratified by gender. In the overall population, the medianurinary albumin concentration (UAC) derived from a spot urinesample was almost twice as high as UAC in a 24-h collection(11.5 versus 6.5 mg/L, respectively; P < 0.001), whereasUAC in a first morning void was numerically nearly similar tothe value in 24-h urine collections, although this latter differencealso reached statistical significance (6.1 versus 6.5 mg/L;P = 0.013). The median albumin:creatinine ratio (ACR) in a spoturine sample and in a first morning void were 10.5 and 5.7 mg/g,respectively, and were different from the median ACR in a 24-hurine collection (8.3 mg/g; both P < 0.001).
Table 1. Characteristics for the overall study population and men and women separatelya
Correlation between Albuminuria Measures
Regression analysis was used to evaluate which method of urinecollection and which albuminuria measure shows the best correlationwith 24-h UAE (Figure 1). Over the whole range of 24-h UAE,the first morning void showed a lower value and the spot urinesample a higher value of UAC. The same was observed for theACR. Agreement with 24-h UAE, assessed as the r2 value of theregression analysis, was better for the first morning void thanthe spot urine sample, although the difference did not reachstatistical significance (Table 2). The proportion of measurementswithin 30% of the value for 24-h UAE, as calculated with theregression equation, was statistically significantly higherwhen albuminuria measures were derived from first morning voidscompared with spot urine samples (Table 2). Finally, the Bland-Altmananalysis indicated that the mean difference (bias) with 24-hurine collections was lower when first morning void sampleswere collected. The lower SD of the mean difference of firstmorning void collections furthermore indicated that, for anindividual, the first morning void sample was more likely toagree with 24-h collection than a spot urine sample. The ACRscored better than UAC except for the bias in the Bland-Altmanplot, which was lower for the UAC derived from a first morningvoid. Essentially similar results were obtained in gender-specificsubgroups (Table 2).
Figure 1. Scatterplots showing the relationship between 24-h UAE and other albuminuria measures. (Top) Twenty-four-hour UAE versus first morning void and spot urine sample UAC, respectively. (Bottom) Twenty-four-hour UAE versus first morning void and spot urine sample ACR, respectively. •, Male; , female.
Table 2. Agreement between 24-h UAE (reference) and other albuminuria measures in the overall population and gender-specific subgroupsa
We used the Passing and Bablok regression equation to calculatevalues for UAC and the ACR that correspond with a UAE of 30mg (Table 3). These data indicate that the values obtained infirst morning voids were closer to the lower boundary indicatingmicroalbuminuria than values obtained in spot urine samples.
Table 3. Values of the various albuminuria measures corresponding to 30-mg/24 h UAE calculated with the Passing and Bablok regression equation and according literaturea
We calculated the prevalence of microalbuminuria using the cutoffvalues indicating microalbuminuria that are presently advocatedin literature.7 The prevalence of microalbuminuria based on24-h UAE, the reference value, was 10.0% (Figure 2). The prevalenceof microalbuminuria using data from first morning voids nearlyequaled the prevalence of microalbuminuria on the basis of 24-hurine collections (7.5% based on UAC and 7.5% based on ACR;P = 0.18 and P = 0.07, respectively). The prevalence of microalbuminuriawas considerably higher when data from spot urine samples wereused (25.4% based on UAC and 22.4% based on ACR; both P <0.001). When the gender-independent Kidney Disease OutcomesQuality Initiative (KDOQI) cutoff values for the ACR indicatingmicroalbuminuria were used (30 mg/g), 14.9 and 4.7% of all patientsreceived the diagnosis of microalbuminuria on the basis, respectively,of a spot urine sample (P = 0.24 versus 24-h UAE) and firstmorning void (P = 0.01 versus 24-h UAE).
Figure 2. Percentage of individuals with microalbuminuria. Cutoff values presently advocated in the literature indicating microalbuminuria are used: 24-h UAE 30 mg/24 h, UAC 20 mg/L, and the ACR gender-specific cutoff value (17 mg/g in men and 25 mg/g in women). FMV, first morning void; SUS, spot urine sample. *P 0.05 versus 24-h urine collection; #P 0.05 versus FMV.
Intraindividual Coefficient of Variation of Various Albuminuria Measures
To investigate which albuminuria measure can best be used tomonitor UAE over time, we calculated intraindividual coefficientsof variation (CVs). Because UAE in a 24-h urine collection isconsidered the "gold standard," we used intraindividual CV ofthe 24-h UAE, which was 19.0%, as the reference value for statisticalanalyses (Table 4). The intraindividual CV of albuminuria measuresderived from first morning voids were lower than that of spoturine samples. The intraindividual CV of the ACR in both a firstmorning void and a spot urine sample was lower than that ofUAC. Of note, the intraindividual CV of the ACR derived froma first morning void was the only albuminuria measure that didnot differ significantly from 24-h UAE (19.1 and 19.0%, respectively;P = 0.64). When we subdivided the study population into a groupwith low-normal (0 to 15 mg/24 h), high-normal (15 to 30 mg/24h), and microalbuminuria (>30 mg/24 h), we obtained similarresults, the only difference being that in patients with microalbuminuria,the intraindividual CV for UAC in a first morning void (24.2%)did not differ significantly from the reference value, being24-h UAE (22.5%; P = 0.74). Assessment of the intraindividualCV in gender-specific subgroups did not make any material differencesto the findings (Table 4).
Table 4. Median (interquartile range) intrapatient CV (%) for the various albuminuria measures in the overall population and in gender-specific subgroups
Agreement between 24-H UAE and ACR in a First Morning Void and Spot Urine Sample
The data indicate that the ACR in a first morning void showsthe best agreement with 24-h UAE. We subsequently investigatedwhether individuals identified by 24-h UAE as having low-normal(0 to 15 mg/24 h), high-normal (15 to 30 mg/24 h), or microalbuminuria(>30 mg/24 h) are the same as those identified by measuringthe ACR in a first morning void using gender-specific cutoffvalues indicating microalbuminuria (Table 5). These data indicatethat 81.8% of all individuals were identified in the same categoryfor UAE when the ACR derived from a first morning void was used.In contrast, when the ACR from spot urine samples was used,72.1% (P = 0.011 versus first morning void) of all individualswere correctly identified (data not shown).
Table 5. Agreement with respect to clinical class (normoalbuminuria, microalbuminuria, and macroalbuminuria) when using cutoff values presently advocated in the literature for 24-h UAE and the ACR in an FMV
This study was conducted to investigate whether albuminuriameasures derived from a first morning void and spot urine samplescan replace a 24-h UAE measurement for diagnosing microalbuminuriaand for monitoring albuminuria over time. The results indicatethat the agreement with 24-h UAE was better for albuminuriameasures derived from first morning voids than spot urine samples.Furthermore, when we used for microalbuminuria cutoff valuesthat are advocated in literature, the prevalence of microalbuminuriaon the basis of albuminuria measures derived from a first morningvoid were close to the prevalence of microalbuminuria on thebasis of 24-h UAE. Finally, the intraindividual variabilityof albuminuria measures derived from first morning voids waslower than that of spot urine samples, with the intraindividualvariability of the ACR in a first morning void being equal to24-h UAE.
A number of studies have addressed the issue of which urinecollection method (first morning void or spot urine sample)and which albuminuria measure (UAC or the ACR) can be used asalternative to measurement of 24-h UAE.8–13 These studieswere based on measurement of the UAC and ACR in either a spoturine sample or a first morning void but did not compare both.Another disadvantage is that most of these studies assessedalbuminuria measures at a single occasion but did not assessalbuminuria measures at consecutive visits. For determinationof which of the albuminuria measures can be used to replace24-h UAE, it is of importance to determine, first, which ofthe albuminuria measure shows the best agreement with 24-h UAEand, second, which of the albuminuria measures shows the leastintraindividual variability over time. To our knowledge, onlyone study determined the intraindividual variability of UACand ACR derived from a first morning void as well as from aspot urine sample and compared these values with the intraindividualvariability of 24-h UAE.6 It was reported that the intraindividualCV of the UAC in a first morning void was the lowest; however,that study included only 11 patients and stored samples at –20°Cbefore analysis. This may have introduced measurement error,because it has been reported that frozen storage of urine samplesinduces considerable variability in albumin concentration.14Given the limited number of data, the KDOQI recently recommendedthat additional research on urine collection methods and urinaryalbumin measurement is warranted.15 This study was designedto provide such data.
Albuminuria measures derived from a first morning void correspondedbest with 24-h UAE and showed a lower intraindividual and interindividualvariability than albuminuria measures derived from spot urinesamples. These results indicate that first morning voids areto be preferred over spot urine samples as an alternative to24-h urine collections. This conclusion is in contrast withrecommendations in present diabetic and hypertensive treatmentguidelines. According to these guidelines, the preferred methodto assess albuminuria is measurement of the ACR in a spot urinesample.2,4 Our data indicate that spot urine samples shouldnot be used because the cutoff value of the UAC and ACR in aspot urine sample indicating microalbuminuria show only modestagreement with the cutoff values advocated in the literature,resulting in a considerably higher prevalence of individualsbeing classified as having microalbuminuria. Furthermore, UACand ACR in a spot urine sample show a high intraindividual variability,making it less reliable to monitor albuminuria in a specificpatient. The explanation for why albuminuria measures in a firstmorning void correspond better with 24-h UAE than albuminuriameasures in a spot urine sample may be that the former is lessinfluenced by factors such as physical exercise and diet. Giventhe aforementioned data, we advocate collection of first morningvoid urine samples when 24-h urine collection is not feasible.
The ACR showed overall better agreement with 24-h UAE and alower intraindividual variability than UAC. This may be explainedby the fact that measuring only UAC is influenced by intraindividualvariations in urinary volume. Creatinine is excreted in urinewith relative constancy over time.16 When UAC is divided bycreatinine concentration, it will result in a "correction" forintraindividual variation in urinary volume. As a result ofparallel changes in urinary creatinine concentration, the ACRis more helpful in diagnosing microalbuminuria and monitoringalbuminuria over time. On the basis of this consideration, werecommend measurement of the ACR in a first morning void whendetermination of 24-h UAE is not feasible.
We observed a relatively high intraindividual variability ofalbuminuria measures in healthy individuals in this study, evenin 24-h urine collections. This finding is consistent with theliterature.17,18 Factors such as dietary nutrients intake, bodyposition, and exercise may influence intraindividual variability.19The relatively high intraindividual variability of albuminuriameasures hampers reliable classification of individuals intonormoalbuminuric or microalbuminuric range. This finding underlinesthe recommendation in treatment guidelines that urinary albuminmeasurements be repeated several times to evaluate reliablythe risk status of a specific individual.3,4
This study indicates that a lower cutoff value for the ACR indicatingmicroalbuminuria may be required. Passing and Bablok regressionanalysis showed that the value of the ACR in a first morningvoid corresponding to a UAE of 30 mg/24 h is 13.3 mg/g in menand 18.9 mg/g in women. These values are lower than the gender-specificcutoff values for microalbuminuria presently advocated in theliterature, being 17 and 25 mg/g, respectively.7 In addition,the prevalence of microalbuminuria on the basis of 24-h UAEwas 10.0%, whereas it was 7.5% on the basis of the ACR in afirst morning void. Although the difference in prevalence wasnot statistically significant, it indicates that 25% of allindividuals with microalbuminuric on the basis of 24-h UAE arenot classified as having microalbuminuria when the ACR derivedfrom a first morning void is used.
Some issues need to be addressed when interpreting our findings.Creatinine is excreted with relative constancy over time.16The low intrapatient variability of the 24-h creatinine excretion,being 9.1%, indicates that, in general, individuals did nothave problems with 24-h urine collections. Individuals who agreedto participate in this study probably found collecting a 24-hurine sample less aggravating than did individuals who refusedto participate and thereby are probably less likely to makecollection errors. This may have introduced bias. The consequencecould be that, if a random selection of the general populationwere included, then the results would probably have pointedmore in the direction of a first morning void or a spot urinesample because the individuals likely would have made more collectionerrors in the 24-h urine collection procedure. Furthermore,one should realize that our study was conducted in a predominantlywhite cohort without diabetes or hypertension. Further researchin other populations should corroborate our findings. Finally,the definitive answer to which urine collection and albuminuriameasure should be used in clinical practice should come fromprospective studies evaluating which method predicts renal andcardiovascular outcomes best. Our data do not allow performanceof such analyses because of the short follow-up time. The strengthof this study is that both 24-h urines, first morning voids,and spot urine samples were collected at three consecutive occasions.Most studies that compared the value of various albuminuriameasures did so by looking only at the correlation between 24-hUAE and either a first morning void or a spot urine sample,using a single measurement per individual.
In conclusion, albuminuria measures derived from first morningvoids are a more reliable alternative to 24-h UAE than spoturine samples to diagnose microalbuminuria and to monitor albuminuriaover time. If it is decided to collect first morning voids,then measurement of the ACR is to be preferred over UAC.
Study Population
This study was conducted of individuals who participated inthe Prevention of Renal and Vascular End-stage disease (PREVEND)study. The PREVEND study was designed to investigate prospectivelythe natural course of UAE and its relation to renal and cardiovasculardisease. Participants regularly visit an outpatient departmentonce every 3 yr for measurement of health status. Details ofthe study protocol have been published elsewhere.20 The PREVENDstudy was approved by the local medical ethics committee andis performed in accordance with the guidelines of the Declarationof Helsinki.
Study Design
The PREVEND study participants were informed about this studyduring their visit to the outpatient department. To participatein this study, individuals who were using antihypertensive medicationhad to be on a stable dosage of such medication. When individualsagreed to participate, three additional appointments were madeto visit our research unit. The time interval between visitswas 3 wk. Before the first visit, written and verbal instructionson how to collect urine samples were given. Individuals wereasked to collect a 24-h urine sample from 10:00 p.m. to 10:00p.m. The next morning, after finishing the 24-h urine collection,participants were asked to collect a midstream first morningvoid. Participants were advised to store their urine collectionsat 4°C. After delivering the 24-h urine and first morningvoid at the research unit that same day, participants were askedto collect a midstream spot urine sample at our research clinic,which mostly took place between 8:00 and 11:00 a.m. At eachof the three visits, participants thus delivered a 24-h urinecollection, a first morning void, and a spot urine sample.
Analytical Methods
Urine samples were stored in plastic containers at 4°C.UAC and urinary creatinine concentration were determined within48 h after collection. UAC was measured with a Behring BN IIanalyzer (Dade Behring, Marburg, Germany) in a central laboratory.The intra-assay and interassay CVs for urinary albumin evaluatedin our laboratory were 2.2 and 2.6%, respectively. The lowerlimit of detection was 2.40 mg/L. Urinary creatinine was determinedby an enzymatic method (Modular Analytics SWA, Roche, Tokyo,Japan) with intra-assay and interassay CVs evaluated in ourlaboratory of 1.9 and 2.1%, respectively.
Statistical Analysis
We drew scatterplots to investigate the association between24-h UAE and the various albuminuria measures. Each data pointin these plots represents the geometric mean of the three valuesthat were obtained at the three visits to our research unit.Agreement between 24-h UAE and the albuminuria measures wasassessed, first, by calculating the r2 value of the regressionanalysis between 24-h UAE and the albuminuria measure underinvestigation and, second, by calculating the amount of scatter.The amount of scatter was defined as the proportion of measurementswithin 30% of the value of 24-h UAE, determined by the regressionequation. McNemar test was used to test for differences betweenthe amount of scatter in first morning voids versus that ofspot urine samples. Because the r2 value of the regression analysisis a measure of the strength of the linear associations ratherthan a measure of agreement, we also calculated the agreementof the first morning void and spot urine sample with a 24-hcollection according to the method of Bland and Altman.21 Weused Passing and Bablok regression analysis to calculate thevalue of the UAC and ACR that corresponds with a 24-h UAE of30 mg/24 h. This was done for both first morning voids and spoturine samples. Because the creatinine component in the ACR dependson muscle mass, the ACR differs between genders because musclemass is lower in women than in men; therefore, we used gender-specificregression equations for the ACR.
We calculated the prevalence of microalbuminuria on the basisof the geometric mean value of all albuminuria measures. Forthis purpose, we used the cutoff values indicating microalbuminuriathat are presently advocated in literature (Table 6) and theKDOQI guideline.3 We used gender-specific cutoff values forthe ACR indicating microalbuminuria.7 We used McNemar test totest for differences between the prevalence of microalbuminuriaon the basis of different urine collection techniques and albuminuriameasures.
Table 6. Cutoff values presently advocated in literature indicating normoalbuminuria, microalbuminuria, and macroalbuminuria
We assessed the intraindividual CV for each albuminuria measureto determine which albuminuria measure shows the least variationover time in an individual and consequently is the best measureto monitor albuminuria over time. We calculated the intraindividualCV per individual as the SD of three measurements divided bytheir geometric mean value. Intraindividual CVs were not calculatedwhen participants did not deliver three urine collections orwhen the albumin concentration was below the detection limit.We tested differences between intraindividual CVs for statisticalsignificance by the Wilcoxon signed rank test.
Finally, we investigated whether individuals who were identifiedby 24-h UAE as having low-normal (0 to 15 mg/24 h), high-normal(15 to 30 mg/24 h), or microalbuminuria (>30 mg/24 h) werethe same as those who were identified by measurement of thegeometric mean value of the ACR in a first morning void andspot urine sample. We tested differences between the percentageof correctly identified individuals on the basis of first morningvoid and spot urine sample for significance with McNemar test.
Data are means ± SD or, in the case of non-normal distribution,medians with interquartile range. P 0.05 (two-sided) was adoptedto indicate statistical significance. Statistical analysis wascarried out using SPSS 14 (SPSS, Inc., Chicago, IL).
We thank Dade Behring (Marburg, Germany) for supplying equipment(Behring Nephelometer II) and reagents for nephelometric measurementof urinary albumin.
Footnotes
Published online ahead of print. Publication date availableat www.jasn.org.
E.C.W. and H.J.L.H. contributed equally to this work.
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Abstract
Introduction
0.05 (two-sided) was adopted to indicate statistical significance. Statistical analysis was carried out using SPSS 14 (SPSS, Inc., Chicago, IL). 
, female.