The Case for Using Albuminuria in Staging Chronic Kidney Disease
Ron T. Gansevoort and
Paul E. de Jong
Department of Medicine, Division of Nephrology, University Medical Center Groningen, Groningen, Netherlands
Correspondence: Dr. Ron T. Gansevoort, Department of Medicine, Division of Nephrology, University Medical Center Groningen, Hanzeplein 1, 9713 EZ Groningen, Netherlands. Phone: 0031-50-3612955; Fax: 0031-50-3619310; E-mail: r.t.gansevoort{at}int.umcg.nl
The publication of the Kidney Disease Outcomes Quality Initiative(K/DOQI) guidelines for the evaluation, classification, andstratification of chronic kidney disease (CKD) in 20021 hasgreatly raised awareness of CKD and stimulated epidemiologicresearch investigating the consequences of CKD. Its publicationand distribution were also followed by critical commentaries.The authors of these commentaries questioned whether it is correctto claim someone has chronic disease without having firm evidencethat that chronic disease will lead to a worse prognosis.2,3They suggested that the CKD staging system be changed—onechange among others—by not paying attention to stages1 and 2 CKD, which are characterized by early signs of renaldamage (albuminuria, erythrocyturia, or abnormalities on ultrasonography)and normal or near-normal estimated GFR (eGFR). Critical authorsargued that this modification would make the staging systemmore simple and useful.2,3 In this commentary, we suggest thatthe discounting of stages 1 and 2 CKD is not justified on thebasis of recent evidence from various epidemiologic studiesand indicate further that there is need to examine more carefullythe clinical prognosis of individuals with stage 3 CKD.
The main value of a CKD classification system is in providinginsight regarding risk for developing ESRD. That renal functionoften declines gradually makes it more likely that a patientwho ends with ESRD will have previously gone through the fivelevels of severity of CKD; that is, from a normal GFR of >90ml/min down to a GFR of <15 ml/min. It is unreasonable toassume, however, that all patients with the earlier stages ofCKD will likely progress to ESRD. Stages 1 through 3 CKD arepresent in 10% of the population,4–6 whereas each yeargoing forward fewer than one of the 1000 of those patients willarrive at ESRD. It is also expected that the risk that a patientwith stage 1 or 2 CKD would reach ESRD in epidemiologic studiesis lower than that for a patient with stage 3 or 4 CKD, becauseit requires more time before the lowest patients will have lostall of their residual renal function. It is unclear, however,which signs of kidney damage, expressed as albuminuria (requiredfor stage 1 or 2 but not for stage 3 or 4) or the severity ofthe loss of filtration capacity (expressed as estimated eGFR)best predicts whether a patient will reach ESRD.
The incidence of ESRD increases with worsening from baselineeGFR (Figure 1). The incidence of ESRD, however, is approximately100-fold higher when a patient with a given eGFR has dipstickproteinuria compared with patients with similar eGFR but withoutdipstick proteinuria. In fact, a patient with stage 1 or 2 CKDand with dipstick proteinuria but nearly normal eGFR has a greaterrisk for reaching ESRD than a patient with stage 3 or even 4CKD and without a positive dipstick test.7 These findings wererecently confirmed by data from the Multiple Risk Factor InterventionTrial (MRFIT). Whereas the risk for reaching ESRD for a patientwith stage 3 CKD and without dipstick-positive proteinuria wasincreased only 2.4-fold compared with the population withoutCKD, it was increased 33-fold for a patient with stage 3 CKDand with a positive dipstick test.8 When interpreting thesedata, it should be realized that only 25% of patients with stage3 CKD had micro- or macroalbuminuria.9,10 Of note, the riskfor reaching ESRD was increased 12-fold for a patient with stage1 or 2 CKD, again a higher risk than for the patient with stage3 and without a positive dipstick test.8 The epidemiologic studieson this topic either used a dipstick test for proteinuria orquantitatively measured albuminuria. It is important to realizethat there is not so much difference between these two, becausemost patients with a 1+ or 2+ dipstick test have micro- insteadof macroalbuminuria, whereas patients with 3+ proteinuria mostlyhave macroalbuminuria.11
Figure 1. Incidence of new cases of ESRD according to the severity of GFR impairment and the presence or absence of a dipstick proteinuria test in a 17-yr follow-up of a cohort of 95,252 patients. Dipstick positivity is defined as 1+ proteinuria. Adapted from reference7.
RISK FOR A MORE NEGATIVE SLOPE OF EGFR OVER TIME ACCORDING TO CKD STAGE
The benefits of a staging system should not be limited justto predicting who will finally reach ESRD but should also detectpatients who are at risk for accelerated decline in renal functionwhich is associated with morbidity and mortality. For such patients,treatment could be started early to prevent progression of disease(Figure 2). Epidemiologic studies investigating risk factorsfor accelerated loss of renal function are scarce. To that purpose,one needs studies with sequential follow-up to calculate changein eGFR over time. The more data points of eGFR available andthe longer the follow-up, the more reliable the calculated changingslope of eGFR will be. To acquire such data, patients participatingin the Prevention of Renal and Vascular Endstage Disease (PREVEND)study, a Dutch population prospective cohort study with sequentialfollow-up, are screened every 3 to 4 yr. With now three datapoints available over a period of 6.2 yr, slope calculationsare possible.
Figure 2. Schematic presentation of the decline in GFR over years in a patient with albuminuria and in a patient with normal urinary albumin excretion. Indicated is the (proven) change in slope when intervention to lower albuminuria is started in a late phase and the (expected) change in slope in case intervention is started early.
The data on 6879 patients showed eGFR decline is on average0.45 ± 1.60 ml/min per 1.73 m2/yr. Adjusted for age andgender, the decline is increased stepwise for each incrementin urinary albumin excretion.12 In each CKD stage, eGFR slopesare always worse in those with albuminuria compared with thosewithout.13 The data on slopes in this cohort also allow oneto determine the risk factors associated with more progressiveloss of eGFR. For example, high BP and plasma glucose are independentpredictors of declining renal function in both genders. In menand women, albuminuria also predicted decline in renal function.14
Of course, even if we are able to identify patients with acceleratedloss of renal function in an early phase, it is not yet provedwhether the beneficial effect of renoprotective treatment workssimilarly as when such treatment is started in a later phase(Figure 2); however, assuming this indeed is true, dialysiscan be delayed for many more years. Evidence for a beneficialeffect of early intervention is sparse. There are data, however,that starting early renoprotective treatment for type 2 diabetesis as effective in retarding progression of microalbuminuriato overt diabetic nephropathy15 as the start of such treatmentin overt diabetic nephropathy to delay progression to ESRD.16From these early and late intervention trials, the early startis even more cost-effective than the late start of renoprotectivetreatment.17
RISK FOR CARDIOVASCULAR EVENTS ACCORDING TO STAGES OF CKD
There is evidence that both a higher albuminuria18 and a lowereGFR19 are independent of classical cardiovascular risk factorsassociated with occurrence of cardiovascular events. The questionhowever, is, how reliable these two variables predict cardiovascularevents and how they are interrelated, if at all. Recent datafrom a study of patients after myocardial infarction,20 as wellas from two population studies,13,21 showed that age- and gender-adjustedhazard ratios for cardiovascular events were not statisticallyelevated in patients with stage 3 CKD and without albuminuria,whereas they were clearly elevated in patients stage 3 CKD andwith albuminuria. It should be stated that some studies diddescribe a significantly increased cardiovascular risk in patientswith stage 3 CKD and without albuminuria22,23; however, thisrisk was limited to patients with more severly impaired eGFRbetween 30 and 45 ml/min per 1.73 m2. Importantly and similarlyas has been described for the risk for developing ESRD, therisk for developing a cardiovascular event in all of these studieswas significantly elevated in stages 1 and 2 CKD when comparedwith patients with no CKD.
Apart from giving evidence of an association between albuminuriaand cardiovascular events, it is also important to have evidencethat lowering albuminuria is associated with a better cardiovascularprognosis. There are indeed data that both in patients withmacroalbuminuria24 and patients with microalbuminuria,25 angiotensin-convertingenzyme inhibition results in a lowering of albuminuria and abetter cardiovascular prognosis. Moreover, the beneficial effectof BP lowering on cardiovascular events is especially due tothe effects of that treatment in patients with hypertensionand with microalbuminuria.26
The parallel between the impact of albuminuria for cardiovascularand renal risk prediction is thus remarkable. It was alwayssuggested that macroalbuminuria is evidence of a diseased glomerulus,whereas microalbuminuria was a sign of vascular damage and notalways considered an enduring renal phenomenon. It thereforewas always expected that macroalbuminuria would predict ESRD,whereas microalbuminuria would predict cardiovascular events.Today, macroalbuminuria is also associated with cardiovascularevents,27,28 and microalbuminuria also predicts ESRD and progressivedecline in renal function, both in patients with diabetes29,30and patients with hypertension31 and in the general population.12–14Figure 3 compares the association of albuminuria with both cardiovascularand renal events. This figure demonstrates that the associationbetween increasing albuminuria and renal events is at leastas steep as the association between albuminuria and cardiovascularevents.
Figure 3. Age- and gender-adjusted risk to develop a cardiovascular event (defined as a fatal or nonfatal myocardial infarction or cerebrovascular accident) and to develop a renal event (defined as an eGFR slope of more than three times the mean of the normal gender-stratified population) in the PREVEND cohort that had at least three eGFR measurements available during 7 yr of follow-up. *P < 0.05 versus patients with a urinary albumin excretion <15 mg/d. N = the number of patients with follow-up data available; n = the number of patients with an event.
We suggest that if we want to modify the CKD classificationsystem, then we should do so to improve its prognostic value.We should not emphasize so much the risk of stage 3 CKD withoutalbuminuria, especially in patients with an eGFR of 45 to 60ml/min per 1.73 m2. These patients in general are not at increasedrenal and cardiovascular risk. Conversely, we ought to givemore attention to patients with albuminuria, even when theireGFR is not impaired yet. There seems a benefit to startingcardio- and renoprotective treatments with agents interferingin the renin-angiotensin system in those patients. The gainis not only potential prevention of ESRD, but also preventionof accelerated loss of renal function and new cardiovascularevents.
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Top
Introduction
RISK FOR ESRD ACCORDING...
10% of the population,4–6 whereas each year going forward fewer than one of the 1000 of those patients will arrive at ESRD. It is also expected that the risk that a patient with stage 1 or 2 CKD would reach ESRD in epidemiologic studies is lower than that for a patient with stage 3 or 4 CKD, because it requires more time before the lowest patients will have lost all of their residual renal function. It is unclear, however, which signs of kidney damage, expressed as albuminuria (required for stage 1 or 2 but not for stage 3 or 4) or the severity of the loss of filtration capacity (expressed as estimated eGFR) best predicts whether a patient will reach ESRD. 
