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28. Zeisberg M, Shah AA, Kalluri R. Bone morphogenic protein-7induces mesenchymal-to-epithelial transition in adult renalbroblasts and facilitates regeneration of injured kidney. J Biol Chem 2005; 280: 80348100

29. Wang S, Chen Q, Simon TC et al . Bone morphogenic protein-7(BMP-7), a novel therapy for diabetic nephropathy. Kidney Int2003; 63: 20372049

Received for publication: 9.11.05Accepted in revised form: 28.11.05

Nephrol Dial Transplant (2006) 21: 573576doi:10.1093/ndt/gfk014Advance Access publication 29 December 2005

Measurement of microalbuminuria what the nephrologistshould know

Josep Redon

Hypertension Clinic, Department of Internal Medicine, Hospital Cl nico, University of Valencia, Valencia, Spain

Keywords: microalbuminuria; urinary albumin excretion;hypertension; diabetes; cardiovascular risk

Introduction

During the last few years, a subtle increase in urinaryalbumin excretion (UAE) not detectable by routinemethods, so called microalbuminuria, has been identi-ed as a prognostic marker for renal and/or cardio-vascular risk in diabetic and non-diabetic subjects [1].Consequently, assessment of microalbuminuria is nowrecommended as a risk stratication strategy not onlyin diabetic subjects, but also in the management of hypertensive patients [25]. In order to make the bestclinical use of UAE, the physician who measures UAEshould know several facts:

a. what kind of albumin molecules are present in theurine, and which methods are most suitable forassessing each of them;

b. what method of urine sampling is recommended andhow should one interpret the UAE values;

c. how can one reduce the variability of the UAEestimate and

d. how should one evaluate the results and manage thepatient based on the results of UAE determination.

Albumin is an electronegative serum protein witha molecular mass of 66349Da. After glomerularltration, part of the albumin is reabsorbed by tubularepithelial cells. Proteases split the albumin moleculeinto fragments, some of which back-leak into thetubular uid [6]. In addition, albumin can reach theurine from an inammatory lesion at any site fromthe renal pelvis to the urethra. In the absence of inammation in the urinary tract, intact albumin of glomerular origin is the major source of albumin inthe urine and only a small amount of small albuminfragments are present.

Methods to measure urinary albumin

Albumin can be detected by several methods basedon precipitation (boiling, sulphosalicylic acid), dye-binding (biuret, tetrabromphenol, albumin blue 580) orimmunologic detection (radioimmunoassay, nephelo-metry, test-strip) (Table 1). While the immunoreactivemethods estimate only complete albumin moleculesrecognized by antibodies, peptide fragments of albumincan be assessed by dye tests and specic spectro-photometry [7,8]. The immunologic methods are mostfrequently used for clinical purposes, not only becausethey are easy to use at relatively low cost, but alsobecause they are able to detect small amounts of albumin in the range dened as microalbuminuria,i.e.


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Recently it has been emphasized that the amountof complete molecules of albumin in the urine that isnot recognized by the immunologic methods is notnegligible. These molecules are detected, however, byhigh performance liquid chromatography (HPLC) [7].Although its clinical signicance is not fully under-stood, the proportion of non-immunoreactive overthe immunoreactive albumin depends on the totalamount of albumin in the urine: the lower the amount,the higher the proportion of non-immunoreactivealbumin [9]. Whether or not the albumin which isnot immunnoreactive represents an early stage in thenatural history and indicates a high risk of progressionto the stage of microalbuminuria must be assessed infuture prospective studies [10]. Whatever the case,even when non-immunoreactive albumin can uncoversubjects at risk of increasing UAE over time, consid-ering cost and accessibility of the HPLC technique,its widespread application in large populations willbe difcult unless more readily available methodsare developed.

Methods to report UAE

The concentration of urinary albumin depends onthe amount of albumin excreted and on the urineconcentration. A precise assessment is only possible if these two factors are considered. Methods based ontimed urine collection or on simultaneous assessmentof urine creatinine concentration have been used toavoid these confounders of the urinary albuminconcentration. Collecting and measuring albumin inurine samples during 24 h (mg/24 h) or timed-overnight(mg/min) is frequently used in specialized settings.In contrast, for primary care and epidemiologicalstudies, a correction is performed by simultaneouslyassessing creatinine excretion (mg/g Cr or mg/mmol Cr)

in spot samples, collected from the rst voided urine orat the time of the clinic visit. The correspondencebetween different UAE values at the level of the classical threshold to dene microalbuminuria,i.e. >30 mg/24 h, and at the lowest UAE that pointsto an increased cardiovascular risk, i.e. 5 mg/min atnight, is shown in Table 2.

Variability of UAE

The variability of UAE is one of the most importantlimitations of assessment for clinical purposes. This

variability is affected by a large number of factorswhich must be kept in mind when interpreting theresults. Fever, vigorous exercise, heart failure, haema-

turia and urinary tract infection produce a transitoryincrease in UAE which is more or less persistentdepending on the cause, the intensity and the durationof the respective condition [11].

Urinary albumin excretion follows a circadianpattern. In normal volunteers, UAE decreases at night-time in recumbent position to approximately 70% of the values during the period of activity [12] (Figure 1).A similar circadian variability is also observed inhypertensive subjects, although their UAE is signi-cantly higher than in healthy normotensive individuals.In patients with type 1 diabetes, however, the differ-ences in UAE between periods of activity and sleep arequite large when compared to non-diabetic subjects(Figure 2). This may reect a greater damage to andpermeability of the glomerular basal membrane indiabetic subjects, coupled with higher variabilityin glomerular ltration as a consequence of transitoryhyperglycaemic periods.

Besides transitory factors and circadian variability,the reproducibility of UAE is limited and severalstudies have reported coefcients varying from of 10to 25% [12]. This variability depends not only on thecollection time of the urine sample, but also on thetype of disease and the absolute amount of urinaryalbumin excreted. From the above, it is clear that

Table 1. Methods to assess albumin in urine

PrecipitationBoiling, sulphosaticylic acid

Dye-bindingBiuret, tetrabromphenol, albumin blue 580

Antibody-bindingTest strips, nephelometry, radioimmunoassay

Molecular size/shapeHPLC, spectrophotometry

Table 2. UAE threshold to dene risk for nephropathy and forcardiovascular risk according urine samples and units

Units Urine sample

Spot Night 24 h

mg/24 h 30 (15)mg/min 20 (5)mg/mmol Cr 3 (2)mg/g Cr 30 (20)

1

10

100

1000

1 10 100

N i g h t U A E ( m g

/ m i n )

Day UAE ( mg/min)

1000

Fig. 1. Circadian variation of UAE in subjects with essentialhypertension. UAE is lower in resting conditions at night thanduring daytime activity.

574 Nephrol Dial Transplant (2006) 21: Editorial Comments


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the reproducibility is lower in collections obtainedduring awake periods than for samples obtainedduring night time or for the rst voided urine.Likewise, the reproducibility is poorer in type 1 diabeticas compared to hypertensive patients, even whenthe UAE is in the same range. Finally, the reproduc-ibility is better in the low range than in the highrange of UAE. UAE is largely skewed towards highvalues.

From a practical point of view, assessing taking allthese factors into consideration, we suggest UAE bydetermination of albumin in at least two urine samplesobtained in the same fashion within a period of

several days. The best samples are those collectedfrom night time or rst morning urine. Although it isadvisable to test the urine shortly after its collection, if necessary, urine can be kept at 4 C and withoutexposure to light for a week before the measurementis made [13].

Evaluation of UAE

Conventionally, UAE values have been categorizedaccording to the presence or the absence of micro-albuminuria. The presence of microalbuminuria pointsto a high cardiovascular and/or renal risk whichrequires intensication of treatment:

further reduction of blood pressure by more intensi-ed antihypertensive treatment,

improvement of glucose control andblockade of the reninangiotensin system according to

current guidelines.

Microalbuminuria has classically been dened asUAE from 30300 mg/24 h or equivalent amounts whentimed overnight or spot urine samples are used(see Table 2). The denition is based on the resultsof studies in diabetic patients which established

microalbuminuria as a marker of the risk to developnephropathy [14]. Several pieces of evidence indicatethat one misses valuable information when one usesthis categorization of UAE. Treating UAE values asa continuous variable provides advantages when usedat baseline to assess the risk and during the follow-upto assess the effect of treatment.

Although the natural history of microalbuminuria

is not well dened, subjects with UAE below theoutlined threshold, but with values in the highest rangeof normality, are at risk of advancing toward the stageof microalbuminuria. In type 1 diabetes, a progressiveincrement of UAE in a relatively short period of time isobserved in subjects who are prone to develop diabeticnephropathy, while subjects not prone maintain lowstable UAE for years [1517]. No data are availablefor hypertensive patients or for the general population,but it is logical to assume that a progressive increaseof albuminuria will occur over time in these individualsas well [18,19]. The rate of change in this case is slower,however, than that observed in patients with type 1diabetes. If the subject develops type 2 diabetes, the rateof progression is accelerated [20]. In one study of ourgroup, hypertensive subjects with an initial UAE levelin the high normal range, from 1529 mg/24 h, hadan increased risk of progressing towards microalbu-minuria despite antihypertensive treatment [18].Consequently, the importance of UAE values in thehighest range of normality is not negligible with respectto the risk of progression of UAE when assessed atbaseline.

Even more important is the prognostic valueof subtle increments in UAE. In studies on the poten-tial prognostic value of microalbuminuria for car-diovascular events, the threshold value indicating

an increased risk was well below the UAE valuesdening microalbuminuria regardless of the populationincluded [21]. The progressive increase of risk at valuesbelow the threshold of microalbuminuria was alsoconrmed by Klausen who noted that the risk of cardiovascular events was increased in hypertensivepatients across a wide range of UAE values [22].In hypertensive patients with a timed overnightUAE above 5 mg/min, total mortality and coronaryevents were increased independent of blood pressurevalues and other potential confounders. The risk of coronary heart disease and death increased signicantlyby 70 and 50%, respectively, in patients with UAEvalues between 5 and 10 mg/min, and even by 100%for both outcomes in patients with UAE values higherthan 10 mg/min. These ndings illustrate that evensuch relatively low values of UAE have prognosticvalue [22].

Furthermore, reduction of UAE is a well-establishedtreatment target in diabetic subjects. It protects notonly against progression towards renal damage, butalso reduces the risk of cardiovascular disease in thishigh risk group.

In non-diabetic subjects the potential of micro-albuminuria as an intermediate endpoint during anti-hypertensive treatment is still unclear, but recent

1

10

100

1000

1 10 100 1000

Second day 24h ( mg/min)

F i r s

t d a y

2 4 h ( m g

/ m i n )

Fig. 2. Relationship between UAE assessed on two different days1 week apart in patients with type 1 diabetes (open circles) andessential hypertension (closed circles).

Nephrol Dial Transplant (2006) 21: Editorial Comments 575


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information shows that the in-treatment levels of urinary albumin are closely related to the risk of asubsequent cardiovascular event [19]: the greater thereduction of UAE, the lower the cardiovascular risk.Monitoring UAE can therefore be clinically useful toassess the success of interventions.

Conclusions

The assessment of subtle increases in UAE is a powerfulway to identify individuals at high cardiovascular riskin need of multiple cardiovascular risk factor interven-tion. Changes in UAE seem to run in parallel tochanges in cardiovascular risk. Prompt intervention toavoid a progressive increase of UAE may provide betterprotection. Assessment of albuminuria during treat-ment is an easy way to monitor the success of thetherapy. Values of UAE lower than considered in thepast are associated with increased cardiovascular riskand a higher risk of progression towards higher values

of UAE. These considerations illustrate the necessity toavoid categorization of UAE according to whether thethreshold of microalbuminuria is transgressed or not.We therefore encourage to treat UAE as a continuousvariable and to base evaluation on the absolute valuesof UAE [21].

Conict of interest statement . This is to conrm that no conict of interest exist concerning to the above manuscript entitledMeasurement of microalbuminuria what the nephrologistshould know.

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Received for publication: 18.10.05Accepted in revised form: 29.11.05

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