Microalbuminuria as an Early Marker for Cardiovascular Disease
Dick de Zeeuw*,
Hans-Henrik Parving and
Robert H. Henning*
* Department of Clinical Pharmacology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands; and Steno Diabetes Center, Gentofte, and Faculty of Health Science, Aarhus University, Denmark
Address correspondence to: Dr. Dick de Zeeuw, Department of Clinical Pharmacology, Ant Deusinglaan 1, 9713 AV Groningen, The Netherlands. Phone: +31-50-3632810; Fax: +31-50-3632812; E-mail: d.de.zeeuw{at}med.umcg.nl
Excretion of albumin in the urine is highly variable, rangingfrom nondetectable quantities to milligrams of albumin and evengrams of albumin. Microalbuminuria is defined as low levelsof urinary albumin excretion of 30 to 300 mg/d. Microalbuminuriais highly prevalent; in hypertensive and diabetic populations,its prevalence varies from 10 to 40%. It is interesting thatmicroalbuminuria also is found frequently in seemingly healthyindividuals (5 to 7%). The variable excretion of albumin inthe urine is related to the risk for the individual to developcardiovascular (CV) disease: Absence or very low levels of albuminuriais associated with low CV risk, whereas the CV risk increasesmarkedly with increasing amount of albumin in the urine (evenwithin the now considered normal range). The predictive powerof urinary albumin levels for CV risk is independent of otherCV risk factors and not only is present in individual with diabetesand/or hypertension but also in healthy individuals. Treatmentsthat lower albuminuria are associated with CV protection, asdemonstrated in randomized, controlled trials of patients withdiabetes as well as in patients with hypertension. There ispreliminary evidence that albuminuria lowering is CV protectivein healthy individuals with an elevated albumin excretion rate.Differences between individuals in their level of albumin excretionare already observed at a very early age (just after birth).In fact, the interindividual variability seems to be relativelyconstant in the first 5 decades of life, indicating that microalbuminuriais not necessarily a consequence of vascular damage at laterage. Higher levels of urinary albumin seem to reflect the ordinaryinterindividual variability in (renal and systemic) endothelialfunction. Experimental data show that between strains and evenwithin strains, rats at young age show a remarkable differencein individual endothelial function, and this is strongly relatedto the susceptibility of that rat to organ damage. In conclusion,albuminuria seems to be a sensitive marker very early in lifefor the susceptibility of an individual to CV disease. It thereforemay be an ideal target for early primary prevention using CV-protectivetherapy regimens.
Microalbuminuria is defined as small quantities of albumin inthe urine, ranging from 30 to 300 mg/d. The term is confusing,because it does not reflect small albumin molecules but ratherlittle more than normal quantities of the molecule. A betterterm would be hyperalbuminuria. The definition of microalbuminuriais complicated further by three factors: Different samplingtechniques (including consequent corrections for sampling errors),different albumin detection techniques, and difference in albuminquantity ranges (for references, see [1]).
First, the collection of urine is not standardized among ourprofession. Four different sampling methods are used: 24-h urinecollection, overnight-timed urine collection, spot morning urinecollection (first void), and finally random spot sampling. Thebest standard would be 24-h collection, because this overcomesthe influence of diurnal variation in albumin excretion. However,daily collections are cumbersome and subject to collection errors.The other end of the spectrum is spot random sampling, becauseit is subject to both incidental diurnal variation and the prevalentconcentration/dilution of that urine sample, giving an overestimationand underestimation, respectively, of the true albumin excretion.To overcome the latter, urinary albumin/creatinine ratio isused. However, this again is biased by the fact that creatinineexcretion varies between gender and within gender and introducesan extra measurement error.
The standard techniques of measuring urinary albumin vary. Theyall apply an antibody that forms a complex with the albuminto be detected. It is interesting that the antibody used israised against serum albumin and is applied in the detectionof both serum and urinary albumin. This assumes that the antigenicityof urinary albumin is similar to serum albumin. Use of HPLCtechniques to measure urinary albumin indeed revealed that thereare urinary albumin molecules that are not detected by the standardantibody techniques.
Finally, the term microalbuminuria is defined by a lower limitand a higher limit for the urinary albumin level. Below 30 mg/d(or 20 mg/L) is considered normal, and above 300 mg/d (or 200g/L) is considered to be macroalbuminuria (also called overtalbuminuria). Although one should recognize the necessity fora clear definition of the term microalbuminuria, one shouldinterpret the term with caution, because albuminuria is a continuousvariable. This is particularly relevant for the often-used endpoint in trials nowadays, such as the transition of an individualfrom normal to microalbuminuria or from microalbuminuria toovert albuminuria.
From this, one may conclude that the definition of microalbuminuriais far from being standardized, with all of the confusing consequences.Currently ongoing guideline discussion within the renal community(Kidney Disease: Improve Global Outcomes [KDIGO]) should reachout to guidelines committees in the diabetes, hypertension,and cardiovascular (CV) societies to address these issues andpropose one urine sampling technique, one detection method foralbuminuria, and a clear upper and lower limit definition formicroalbuminuria.
Microalbuminuria is highly prevalent in several disease states.Widely known is the high prevalence in individuals with diabetes.A recent worldwide survey (2) showed that in 40% of the patientswith diabetes and without known kidney disease, the levels ofurinary albumin were in the microalbuminuric range. Similardata (20%) were found in a large population study (AustralianDiabetes, Obesity, and Lifestyle Study [AusDiab]) (3). The transitionfrom normo- to microalbuminuria is frequent despite adequatetreatment: 2 to 2.5% per year (4,5).
The prevalence of microalbuminuria in patients with hypertensionis less consistent in large population or cohort studies, varyingfrom 8 to 23%. In 1974, Parving et al. (6) demonstrated thepresence of microalbuminuria in patients with untreated essentialhypertension. General population studies such as AusDiab andPrevention of Renal and Vascular End Stage Disease (PREVEND)show an 8 to 11.5% prevalence of microalbuminuria in individualswith hypertension (7,8). The Losartan Intervention for EndpointReduction (LIFE) trial in hypertensive patients with electrocardiographicsigns of left ventricular hypertrophy (LVH) showed a 23% prevalence(9). No large population studies have studied the incidenceof microalbuminuria in a specific hypertensive cohort of patients.
The prevalence of microalbuminuria in the general populationis in the range of 5 to 7% according to several large cohortstudies: PREVEND, Nord-Trøndelag Health Study (HUNT),AusDiab (7,8,10). Recent data from PREVEND show that the incidenceof an individual’s moving from a normoalbuminuric to amicroalbuminuric classification occurs at a rate of approximately8% in 4 yr, which is surprisingly close to that of treated diabetes.Most frequently, the individuals moved from high-normal albuminlevels to microalbuminuria (11).
Mogensen (12) wrote a seminal paper in 1984, describing theimportance of microalbuminuria not only as a renal risk factorbut also as a CV risk factor in patients with diabetes. Thishas led to many subsequent studies’ confirming the importanceof microalbuminuria in estimating risk for patients with diabetes(reviews [13,14]). Yuyun et al. (15) showed recently that theCV predictive effect was comparable for type 1 and type 2 diabetes,although at a lower risk for type 1.
Despite that the Framingham study also established in 1984 thatproteinuria is an important risk marker of (CV) mortality inthe general population (16), this has never led albuminuriato be added to the list of important CV risk factors/markersor incorporated in CV risk engines. It lasted 20 yr before thetopic got proper attention again. Several important studiesfollowed each other, the Multinational Monitoring of Trendsand Determinants in Cardiovascular Disease (MONICA) study, PREVEND,HUNT, and European Prospective Investigation into Cancer (EPIC)(10,17–19). They all showed that, like in diabetes, microalbuminuriais predictive for CV events. Hillege et al. (18) showed clearlythat urinary albumin is in this respect a continuous risk markerwith no lower limit, which was confirmed and stressed againin a recent study by Klausen et al. (20) that showed that onlyslightly raised levels of albumin well in the normoalbuminuricrange relate to increased CV risk.
In the patient with hypertension, microalbuminuria has beendiscovered as an important factor, although it has not penetratedall guidelines. The groups of Bigazzi and Campese et al. reviewedthe importance of microalbuminuria as a CV risk predictor (21).Larger cohort studies confirmed this to be independent fromother risk markers in the general hypertensive population (MONICA)(22), a hypertensive cohort with LVH (LIFE) (23), and in individualswith already increased CV risk (Heart Outcomes Prevention Evaluation[HOPE]) (24).
In the above studies, microalbuminuria was associated and clusteredwith other widely known CV risk factors (age, diabetes, hypertension,LVH, overweight, metabolic syndrome, etc.) that could explainthe increased CV risk. Careful correction for such factors andpost hoc selection of "healthy" individuals in the large generalpopulation cohorts did still reveal the marked and overwhelmingindependent predictive power of microalbuminuria. This was confirmedby the recent Framingham publication of Arnlov et al. (25) thatshowed elegantly that in normotensive individuals without diabetesand with normal renal function, microalbuminuria remains a strongpredictor for CV outcome.
Finally, microalbuminuria not only predicts CV risk but alsoseems to be a sensitive marker for detecting new onset of otherCV risk factors, such as hypertension and diabetes. Brantsmaet al. (26) showed that individuals with microalbuminuria hadan approximately four-fold increase in the risk for developingsubsequent new-onset diabetes than those with low normal urinaryalbumin levels, even after correcting for baseline glucose andinsulin levels or after excluding those with impaired fastingglucose or metabolic syndrome. Brantsma et al. (27) similarlyfound that microalbuminuria increased the risk for de novo hypertensionby two-fold as compared with normal albuminuria levels.
Albuminuria seems to be an independent and strong predictorfor CV disease. However, for albuminuria to be a target fortherapy, one needs to prove that lowering of albuminuria perse is cardioprotective. Several strategies are available tolower urinary albumin excretion in the microalbuminuric range.Widely known is the albuminuria-lowering effect of antihypertensiveagents, in particular those that intervene in the renin-angiotensin-aldosteronesystem. However, statins and glucose-aminoglycans also havebeen proved to lower albuminuria (28–30). Some of thesestrategies have been proved in randomized, controlled trialsto be cardioprotective. However, few have been directed at albuminurialowering per se to evaluate the effect on CV outcome. The Irbesartanin Patients with Type 2 Diabetes and Microalbuminuria (IRMA-2)study, evaluating the effect of the angiotensin II antagonistirbesartan, shows that albuminuria can be substantially loweredin microalbuminuric hypertensive patients with type 2 diabetes,and this is associated with renal protection and some degreeof CV protection (31). However, this study was not powered toaddress the effect on CV events. The Prevention of Renal andVascular Endstage Disease Intervention Trial (PREVEND-IT) isthe only randomized trial to study the effect of albuminurialowering in microalbuminuric "healthy" individuals (other CVrisk factors were excluded). Asselbergs et al. (32) indeed showedthat the lowering of albuminuria with the angiotensin-convertingenzyme inhibitor fosinopril tended to be cardioprotective. Arecent post hoc analysis of the LIFE trial found similar resultsin hypertensive patients: The more the angiotensin II antagonistlosartan lowered albuminuria, the more the patient was cardioprotected,irrespective of the effect on other CV risk factors (33). FutureCV trials involving drugs that target albuminuria more specificallyare needed to resolve the issue of whether specific loweringof albuminuria results in CV protection and whether this isa cost-effective health care approach. In this issue’sFrontiers in Nephrology, De Jong and Curhan (34) review thepublic health perspectives of screening and monitoring of urinealbumin excretion in relation to CV disease prevention.
Microalbuminuria: Consequence or Cause of Organ Damage
The classical view on the cause of microalbuminuria and proteinuriais that these are the consequence of renal damage. Under physiologiccircumstances, the glomerular filter forms a barrier to preventmacromolecules such as albumin from reaching the urinary space.However, large quantities of albumin may reach the primary filtrateaccording to several experimental studies. That the final urinecontains no or only small quantities of albumin is because theproximal tubule is equipped with an effective albumin reabsorptionsystem that subsequently metabolizes albumin to fragments andamino acids. Damage to the glomerular barrier and/or damageto the reabsorptive or metabolizing capacities of the proximaltubule therefore should lead to increased excretion of albuminor its fragments in the urine. The pathophysiology of renalalbumin leakage includes that this albumin leak may damage theglomerulus through increased mesangial protein trafficking.In addition, an increased tubular burden of albumin reabsorptionmay damage the proximal tubule, leading to interstitial inflammationand loss of functioning kidney tissue (35). Indeed, this processseems to be reflected in the loss of filtration power that oneobserves with increasing levels of urinary albumin, such asin patients who have diabetes and show transition from normo-to micro- and macroalbuminuria.
Assuming that excess urinary albumin loss is a consequence ofrenal damage, one wonders how, particularly in the low albuminuriaranges, microalbuminuria is such a powerful predictor of CVdisease. Could it be that even small changes in kidney functionoffset a (neuro)humoral cascade that influences the CV system?In this issue’s Frontiers in Nephrology, Amann et al.(36) describe the potential relation between changes in kidneyfunction and the potential consequences for the CV system. Theremay be an alternative explanation, however; microalbuminuriareflects impaired vascular function in general and is associatedwith a higher susceptibility to CV and renal events. Indeed,Deckert et al. (37) proposed in the Steno hypothesis that albuminleakage is a result of widespread vascular damage. This hypothesislinks impaired vascular endothelial function with vascular leakageof albumin. The kidney thus would become a window to the vasculature:Leaky renal vessels reflecting the permeability of the vasculaturein general. Several studies have shown that microalbuminuriaindeed is associated with increased permeability to macromoleculesof peripheral vascular beds (38,39). In addition, microalbuminuriais associated with changes in vasomotor tone regulation of peripheralvessels, although this remains controversial (40–42).This hypothesis indeed unifies the idea that damage to the renalvasculature could lead to glomerular barrier changes or evenproximal tubular changes that would explain leakage of albumininto the urinary space and subsequent renal risk, whereas damageto the systemic vasculature leads to increased CV risk. In thisissue’s Frontiers in Nephrology, Stehouwer and Smulders(43) review the potential relation among endothelial function,microalbuminuria, inflammation, and the consequences for theCV system.
Assuming that the Steno hypothesis is valid, the important questionsremain: What is the cause of the vascular damage? What is thecause of endothelial dysfunction? The underlying cause of theendothelial dysfunction and thus microalbuminuria still couldbe a parameter or a condition that directly causes CV and/orrenal risk. An alternative may be that there is no pathologicvascular damage but that individuals are born with varying degreesof vascular function (within a physiologic range) and thus excretevariable amount of albumin. Recent experimental data lead usto extend the Steno hypothesis. When one measures endothelialfunction in renal vessels of young, healthy rats, one findsthat there is a marked variability in the capacity of the endotheliumto regulate vasomotor tone. This is present within a strain,but there also is a difference between strains. Striking, thisnormal variation in endothelial function of healthy rats isassociated with their susceptibility to subsequent renal damagein life (Figure 1) (44,45). It is interesting that the vasodilatorycapacity of renal arteries that is mediated by nitric oxide(NO) of healthy kidney inversely predicts the subsequent developmentof focal glomerulosclerosis in both models of 5/6 nephrectomyand Adriamycin nephrosis. Moreover, the vasodilation that ismediated by endothelial hyperpolarizing factor (EDHF) is positivelyrelated with the renal damage. The rats with more pronouncedendothelial NO-mediated relaxation and the ones with lower EDHF-mediatedrelaxation seem to be protected against end-organ damage. Thisis in agreement with the protective role of NO against the developmentof renal damage and EDHF serving as a backup mediator underthe conditions of impaired NO availability.
Figure 1. Individual variation in endothelial function of healthy rats predicts individual development of renal damage. Nitric oxide (NO) endothelium-dependent relaxation measured in small renal arteries of healthy animals (in arbitrary units of area under dose-response curve to acetylcholine [AUC]) predicts the development of renal damage (proteinuria in mg/24 h) after induction of chronic renal disease either by subtotal nephrectomy (A) or Adriamycin injection (B). Adapted from references (44,45).
Can one find this interindividual variability in the human situation?Urinary albumin levels vary considerably between individualsalready at young age. PREVEND data show that the median and97.5th percentile of albuminuria are relatively similar throughoutlife, at least below the age of 50 (Figure 2) (46). This couldmean that the difference in albuminuria levels reflects a differentphysiologic state. However, this reasoning may be biased becausethe analysis is a cross-sectional approach starting at the relativeage of 27. However, if one looks at the pediatric literature,one may find several publications showing that the level andthe interindividual variation of albuminuria are very similarfrom birth to adolescence (47,48) (Figure 2). It seems thatone is endowed at birth with a level of albumin excretion thatmay represent a vascular state and that in turn may be associatedwith increased or reduced susceptibility to organ damage. Thiswould explain why albuminuria is such a powerful predictor ofCV and even renal disease but also why it predicts new-onsethypertension and diabetes. Obviously, this extension of theSteno hypothesis will need further experimental and clinicaltesting. A particular challenge will be to appreciate the weightof genetic and environmental factors that determine the vascularstate at birth. There is ample evidence pointing to involvementof genetic factors, such as that renal disease of patients withdiabetes clusters in families (reviewed in [49]). However, uterinelife is known to exert a major impact on development of thekidney (50) and the vascular tree in the fetus (51,52).
Figure 2. Individual variation of urinary albumin excretion is relatively constant with aging. Median and 97.5th percentile of albuminuria (mg/d) according to different age classes in a random adult cohort of the general population (PREVEND data modified from reference [46]) and in a cohort of children. Adapted from reference (48).
Microalbuminuria seems to reflect a state of (patho)physiologicvascular dysfunction that makes an individual susceptible toorgan damage. High levels of albuminuria may already be foundin young children and reflect a normal physiologic variationin endothelial function associated with CV and renal risk atlater age. Intervention strategies aimed at repairing this vascularfunction could be very useful not only in secondary but alsoin primary prevention. Albumin excretion levels may representthe primary marker for success of such therapies.
Footnotes
Published online ahead of print. Publication date availableat www.jasn.org.
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Abstract
Introduction
