Screening, Monitoring, and Treatment of Albuminuria: Public Health Perspectives
Paul E. de Jong* and
Gary C. Curhan
* Division of Nephrology, Department of Medicine, University Medical Center Groningen, Groningen, The Netherlands; and Renal Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts
Address correspondence to: Dr. Paul E. de Jong, Division of Nephrology, Department of Medicine, University Medical Center Groningen, Groningen University, Hanzeplein 1, 9713 GZ Groningen, The Netherlands. Phone: 31-50-3612955; Fax: 31-50-3619310; E-mail p.e.de.jong{at}int.umcg.nl
Microalbuminuria is an early sign of progressive cardiovascularand renal disease in individuals with and without diabetes.Despite compelling data, at present only a minority of patientswith diabetes and rarely individuals without diabetes are screenedfor albuminuria in a systematic way. All of the criteria toimplement systematic albuminuria screening are fulfilled indiabetes, and most are nearly fulfilled for microalbuminuriascreening in individuals without diabetes. Because of the growingevidence that treatment of microalbuminuria in individuals withoutdiabetes may offer a cost-effective benefit to prevent cardiovasculardisease, nephrologists and other health care providers shouldpay more attention to the early detection and subsequent treatmentof individuals with microalbuminuria.
Microalbuminuria is an early sign of progressive cardiovascularand renal disease. We discuss whether screening for albuminuriais warranted and, if so, how screening and subsequent monitoringcould be carried out.
The criteria that a screening program should fulfill have beendescribed by Wilson and Jungner (1) and are given in Table 1.As more data are available on the impact of elevated albuminuriaon renal and cardiovascular prognosis in individuals with diabetesthan in individuals without diabetes, we discuss separatelythe evidence that is available for the need for albuminuriatesting in these two groups.
Albuminuria screening first may be used as a tool to detectindividuals with undiagnosed chronic kidney disease (CKD). Elevatedalbuminuria (30 to 300 mg/d albumin is the definition of microalbuminuria)is an early predictor of progressive renal function loss intype 1 (2,3) and type 2 diabetes (4,5). At the time that microalbuminuriabecomes manifest, GFR typically is normal or elevated or onlymodestly impaired (stage 1 or 2 CKD). Increased urinary albuminexcretion (UAE) also may indicate a worse renal prognosis inindividuals without diabetes. In a Japanese study, >100,000individuals were tested for dipstick proteinuria. After a periodof >17 yr, the likelihood of being on dialysis increasedaccording to the degree of dipstick proteinuria at baseline(6). A similar finding was reported from the Prevention of Renaland Vascular End Stage Disease (PREVEND) study: After a 4.2-yrfollow-up, the number of individuals who de novo had developedstage 3 or worse CKD was related to baseline albuminuria (7)(Figure 1). By screening for elevated albuminuria, one of coursewill not only detect individuals with microalbuminuria but alsoindividuals with macroalbuminuria (>300 mg/d), who most likelyare already in stage 3 or 4 CKD.
Figure 1. The incidence of new ESRD after 17 yr of follow-up (A) and of new stage 3 chronic kidney disease after 4.2 yr of follow-up (B) according to dipstick proteinuria (A) or albuminuria (B) in a community-based screening in Japan (A) or the Netherlands (B) (references [6] and [7], respectively).
The benefits of screening for albuminuria in the short termare to detect individuals who are at risk for cardiovasculardisease in individuals with diabetes (8) and individuals withoutdiabetes (9,10). We should keep this in mind in view of thepros and cons for screening for albuminuria in the general population.Especially in individuals without diabetes, the short-term benefitswill be to prevent cardiovascular events; only in the long termmight it be found to prevent ESRD.
Does Screening for Albuminuria Help Detect Individuals at Risk for CKD and CVD in an Early Phase?
The time course of albuminuria in relation to progressive renalfunction loss has been well described. When microalbuminuriabecomes manifest, the phase of glomerular hyperfiltration isshifting to that of progressive renal function loss. This hasbeen shown in type 1 (11) and type 2 diabetes (5). This lossof GFR ultimately leads to ESRD. Evidence is accumulating thatthe same holds true for individuals who do not have diabetesand have microalbuminuria (12,13). It is a great benefit thatwe may detect individuals who are at risk for progressive diseasein an early phase, because it is widely known that CKD typicallybecomes symptomatic only in stages 4 and 5 CKD. In that respect,it is noteworthy that most patients with CKD are not aware ofhaving diseased kidneys (14). Patients with earlier stages ofCKD need increased attention because they are at increased riskfor cardiovascular disease. Because nephrologists presentlyare focusing predominantly on renal replacement therapy programsfor patients with ESRD, the International Society of Nephrologyissued a call to action to pay attention to patients with earlierCKD. Remuzzi and Weening (15) drew the parallel with an iceberg.What we are looking for presently is only the tip of what weshould look for in the future.
Is Lowering of Albuminuria, Started at an Early Phase, Associated with Better Renal and Cardiovascular Outcomes?
The trials in individuals with macroalbuminuria (16–19)showed that lowering of albuminuria by either an angiotensin-convertingenzyme (ACE) inhibitor or an angiotensin II receptor blocker(ARB) was associated with a better renal (20) and cardiovascular(21) outcome. Moreover, it has been shown that the renoprotectiveand cardioprotective effects were related to the extent to whichalbuminuria was lowered. These trials all were performed inpatients with stage 3 or 4 CKD. Recently, however, a few trialshave been carried out in individuals with earlier stages ofrenal disease. The Irbesartan in Patients with Type 2 Diabetesand Microalbuminuria (IRMA) study in patients with type 2 diabetesand microalbuminuria (GFR > 90 ml/min) showed that treatmentwith an ARB effectively prevented progression from micro- tomacroalbuminuria (22). The Bergamo Nephrologic Diabetes ComplicationsTrial (BENEDICT) showed that an ARB even effectively preventedprogression from normo- to microalbuminuria, again in type 2diabetes (23). There are few data to show that lowering of albuminuriain individuals with still normal GFR results in a better cardiovascularoutcome. Gaede et al. (24) recently showed that an interventionthat aimed to correct multiple risk factors in type 2 diabetesand microalbuminuria reduced the risk for cardiovascular andmicrovascular events by approximately 50%. In the Preventionof Renal and Vascular Endstage Disease Intervention Trial (PREVENDIT), who did not have diabetes but had UAE of 15 to 300 mg/dand a normal GFR were treated for 4 yr with fosinopril and/orpravastatin. There was a trend for fewer cardiovascular eventsin the fosinopril-treated group, in which albuminuria was loweredby 30% persistently during the 4-yr period. Pravastatin, incontrast, did not lower albuminuria and had no effect on cardiovascularevents (25). The group with the higher baseline albuminuria(50 to 300 mg/d) showed the most benefit from fosinopril forpreventing cardiovascular events.
The albuminuria screening debate is hampered by differencesin laboratory methods used, urine samples studied, and definitionsof microalbuminuria, which lead to different conclusions. Thebest approach depends on the number of individuals to be screenedand the way the screening will be organized.
Traditionally, the dipstick test was used to detect proteinin the urine. The test is semiquantitative, however, and insensitiveto detect reliably albumin concentrations in ranges <300mg/d albumin. At present, various antibody-based methods areused to measure lower levels of urinary albumin. These includeRIA, nephelometry, immunoturbidimetry, and ELISA. It is beyondthe scope of this review to evaluate these different techniquesin detail. Recently, an HPLC method was developed by which notonly immunoreactive but also immunounreactive albumin is measured(26). Using this method, more patients are found to have analbumin excretion in the microalbuminuric range (27). Whetherpatients who are detected as having microalbuminuria by HPLCare equally at risk for progressive renal and cardiovasculardisease as those who are detected by the traditional antibody-basedmethods has yet to be determined. Whichever method is chosen,it is preferable to measure albumin in fresh samples (28).
These methods all require laboratory facilities. Antibody-baseddipstick tests for microalbuminuria also are available (29,30).Although only semiquantitative, these tests have the advantagethat they can be used easily by the general practitioner orthe patient at home. A recent study in hypertensive patientsfound a sensitivity of 88%, a specificity of 80%, a positivepredictive value of 69%, and a negative predictive value of92% (30). The development of point-of-care testing systems mayprovide in the near future a quantitative urine albumin valuewithin seconds.
For the diagnosis of microalbuminuria, a 24-h urine collectionis the gold standard. Because of the effort involved, it isnot the method of choice for screening. The second best is atimed overnight urine collection. Again, because this requirescollection of urine over a given time period, this may be acceptablefor screening specific patient groups such as patients withdiabetes or hypertension, but it is less feasible for populationscreening. The next best is a first-morning urine sample. Thishas the advantage over a spot-urine sample because it is alwaysperformed at the same time of the day, and it is least influencedby hydration status and physical activity of the patient, reducingthe variability that is caused by these factors. This may bea good choice for population screening if the patient is askedto mail a urine sample, as was done in the PREVEND study (31).In clinical practice, however, a spot-urine sample is collectedwhen the patient visits either the general practitioner or thehealth care office, where the screening takes place. Some ofthe variability in timing of collection can be overcome by correctingurinary albumin concentration for urinary creatinine concentration.
Taking these considerations together, the best approach is touse a spot-urine sample (either the first-morning void or atthe time of the visit to the medical office) as a prescreening.The patients whose urine is found positive then either shoulddeliver two more samples to confirm whether the first valueindeed was abnormal or, preferably, should collect two 24-hurine samples. This latter approach was tested in the PREVENDstudy. After using just one first-morning urine sample for measurementof urinary albumin concentration, patients with a urinary albuminconcentration above a certain cutoff were invited for two 24-hurine collections. It was suggested that a cutoff value of 10mg albumin/L could be used for mass screening to identify individualswho are more likely to have a UAE >30 mg/24 h (32).
How Should We Express Albuminuria, and Which Definition Should be Used for Abnormally Elevated Albuminuria?
Preferably, the excretion of albumin per unit of time shouldbe used: UAE per 24 h or per minute (in case of timed overnightcollections). For untimed samples, the albumin-to-creatinineratio is advocated most (33). Because it corrects albumin forcreatinine concentration, it may be more reliable than justa urinary albumin concentration. The albumin-to-creatinine ratio,however, introduces the need to use different definitions foran abnormal value for men and women (Table 2). Moreover, creatinineexcretion in the urine depends not only on gender but also onage and race (34,35). This may explain why urinary albumin concentrationfrom a spot sample performs equally well for the definitionof microalbuminuria as albumin-to-creatinine ratio (32). Incase a specific individual is followed over time with serialurine samples, the albumin-to-creatinine ratio may offer anadvantage over albumin concentration alone.
Table 2. Classification of abnormal urinary albumin excretion
The definitions for microalbuminuria and macroalbuminuria aregiven in Table 2. Because the relation between albuminuria andan increased cardiovascular (or renal) risk is continuous, itis difficult to conclude what is a normal level. In general,it is desirable to define specific cutoff values that couldbe used in clinical guidelines. The lower cutoff value may changeover the years, as has been seen for BP and cholesterol valuesin the past decades. In fact, cutoff levels are defined dependingthe cost-effectiveness of screening for albuminuria and treatmentto lower albuminuria in an attempt to prevent cardiovasculardisease and CKD. If it is found to be cost-effective to loweralbuminuria from levels >15 mg/L, then it is wise to setthe definition of abnormal albuminuria at that level. It maybe appropriate to use a lower albuminuria cutoff in case ofconcomitant morbidities, such as diabetes.
What Extra Work Should Be Done When an Individual Is Found to Be Positive?
When someone is found to be positive for microalbuminuria, onefirst should confirm the positive test by repeated testing.It has been argued that two of the three tests need to be positive.After confirmation, one should look for a potential cause underlyingthe albuminuria, especially in case of macroalbuminuria. Oneshould ascertain whether there is any classical renal disease,such as glomerulonephritis or interstitial nephritis. If medicalhistory for such a disease is negative, then a urinary sedimentand measurement of renal function may be sufficient. In addition,cardiovascular risk factors (BP, cholesterol, and glucose) shouldbe screened.
Is Screening to Detect Microalbuminuria Followed by Appropriate Treatment of Positive Individuals Cost-Effective?
In diabetes, it has been shown that ACE inhibitor or ARB treatmentis cost-effective (36) for preventing ESRD. Moreover, it hasbeen shown that, in the long term, cost-effectiveness is evenmore favorable when treatment is started earlier (37). The evidencefor individuals without diabetes is limited. Boulware et al.(38) showed that screening for dipstick proteinuria by primarycare providers followed by treatment of those who were positivewas not cost-effective in terms of preventing ESRD. This isnot surprising, because it generally takes many years beforea who does not have diabetes but has dipstick-positive proteinuriawill reach ESRD. There are alternatives to the Boulware approach,however (39). First, the use of a dipstick would require screeningof many individuals to find the few who were positive, whereasscreening for microalbuminuria would detect more positive individuals;the prevalence of microalbuminuria is approximately 30 timeshigher than that of macroalbuminuria (31). Although the costsof an albuminuria measurement are higher than those of a dipsticktest, the higher yield of the test will outweigh that difference.Second, screening via the general practitioner is labor-intensive,whereas the delivery of a urine sample to a central laboratoryfacility will be cheaper. Third, although it takes many yearsfor an individual with microalbuminuria to develop stage 5 CKD,cardiovascular events may be manifest already within a few years.We therefore studied the cost-effectiveness of screening foralbuminuria and subsequent treatment of individuals with anelevated UAE with an ACE inhibitor. This approach was cost-effectiveto prevent cardiovascular events (40).
How Can a Screening Program for Albuminuria Be Organized?
Taking the evidence together, we can conclude that screeningfor albuminuria and treatment of those who are found to be positiveis well accepted in individuals with diabetes. Indeed, annualscreening for albuminuria in individuals with diabetes is recommendedin the guidelines of the American Diabetes Association (41).At present, it seems too early to recommend such an approachfor the general population: More studies to examine the beneficialeffect of albuminuria lowering are needed. It seems sensibleto screen individuals who are at higher risk for cardiovasculardisease and CKD. Besides individuals with diabetes, attentionshould focus on individuals with hypertension (42), hyperlipidemia,and obesity and those who smoke. However, a focused approachwill overlook many individuals with an elevated UAE. First,many individuals are not aware that they have diabetes, hypertension,or hyperlipidemia. Indeed, in the PREVEND study, two thirdsof those screened were found to have previously undiagnosedhypertension and/or diabetes (43). Second, it has been shownthat UAE gradually increases with increasing plasma glucoselevel or systolic or diastolic BP even within the normal ranges(44). This suggests that individuals with higher but still normallevels of plasma glucose and systolic or diastolic BP are atrisk for having microalbuminuria. They will not be detectedwhen the screening is limited only to those with manifest diabetesand/or hypertension. It is of interest that the presence ofmicroalbuminuria may even precede manifest diabetes (45,46)and hypertension (47,48). Microalbuminuria may be consideredone of the earliest manifestations of the insulin resistancesyndrome. Indeed, it has been shown that the prevalence of microalbuminuriaincreases according to the number of components of the metabolicsyndrome present (49). The aforementioned data raise doubt whetherwe should limit our screening strategies to those with knownrisk factors or preferably should screen the general population.
The composition of the population and the type of health caredelivery system will dictate the optimal design of the screeningprogram. The components to consider include who will do thetesting (e.g., physician, nurse, technician), where the screeningwill take place (e.g., clinic, health fair), and how it willbe financially supported.
How Should a Patient with Microalbuminuria Be Monitored in the Long Term?
Screening for albuminuria in individuals with diabetes has beenadvocated to be performed once every year. In case of a positivetest, it is advocated to repeat testing twice within 3 to 6mo. If two of the three tests are positive, then treatment tolower albuminuria should be started (41). Thus far, no harddata are available for the optimal time interval for albuminuriatesting in individuals with hypertension or in other groups.As progression of albuminuria may be slower in individuals withoutdiabetes than in individuals with diabetes, it seems acceptableto perform albuminuria testing in individuals with hypertensionor other risk categories every 3 yr.
Both in type 1 diabetes (50) and in the general population (51),progression and regression of albuminuria can be observed. After4.2 yr, UAE had regressed in 9.8% individuals in the generalpopulation, whereas progression was found in 11.4%. Progressionand regression of albuminuria were most prevalent in the groupof individuals with a UAE of 15 to 30 mg/d (21.3 and 47.4%,respectively). This suggests that especially in individual witha borderline elevation in UAE, repeated testing every 3 to 5yr is indicated.
Lowering of BP with agents that interfere with the renin-angiotensin-aldosteronesystem, such as ACE inhibitors or ARB is most effective forlowering UAE. It has been shown in patients with manifest renaldisease (i.e., those with overt proteinuria of >300 mg/d)that the extent to which proteinuria is lowered during treatmentpredicts the prevention of both CKD and progressive cardiovasculardisease (20,21). It is highly likely but not proved that thesame will hold true for individuals with microalbuminuria. Thusfar, however, we cannot define a certain cutoff level belowwhich albuminuria should be lowered; we suggest use of the samecutoff as for the definition of microalbuminuria: <30 mg/d.
There is compelling evidence that screening for albuminuriashould be carried out in individuals with diabetes. Evidenceis accumulating that it also should be implemented in individualswith hypertension and in individuals with increased cardiovascularand renal risk. Further studies are needed to confirm that systematicscreening for albuminuria also is cost-effective in the generalpopulation. The short-term benefits for prevention of cardiovasculardisease may outweigh those of the long-term prevention of ESRD.
Footnotes
Published online ahead of print. Publication date availableat www.jasn.org.
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A. H. Brantsma, S. J.L. Bakker, D. de Zeeuw, P. E. de Jong, R. T. Gansevoort, and for the PREVEND Study Group Extended Prognostic Value of Urinary Albumin Excretion for Cardiovascular Events
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Abstract
Introduction