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Microalbuminuria: target for renoprotectivetherapy PROSara S. Roscioni1,2, Hiddo J. Lambers Heerspink 1,2 and Dick de Zeeuw1

1Department of Clinical Pharmacology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands

Drug efficacy is ascertained using clinically meaningful

outcomes that directly affect the well-being of patients.

However, in studies of chronic kidney disease progression,

clinically meaningful outcomes like end-stage renal disease

take a long time to occur. The use of surrogate end points/

markers as replacement for clinical outcomes is tempting as it

may reduce sample size requirements, shorten follow-up

time, facilitate trial conduct, and allow the performance of intervention trials in earlier stages of kidney disease to be

carried out. We here reviewed recent data supporting the use

of microalbuminuria as a valid surrogate end point in clinical

trials of chronic kidney disease. We provide data that

albuminuria is associated with worse renal prognosis and

that pharmacological treatment aimed to reduce albuminuria

levels delays the progression of renal disease and the

occurrence of clinical outcomes. Furthermore, we review new

studies showing that albumin is not only an inert molecule

but also directly affects the function of several cell types in

the kidney and may have a pathogenic role in renal disease.

Accepting microalbuminuria as a surrogate marker for renal

outcomes will lead to less resource-consuming hard outcome

trials, will accelerate the development of drugs for chronic

kidney disease, and enable earlier access of these drugs to

individual patients.

Kidney International (2014) 86, 40–49; doi:10.1038/ki.2013.490;published online 23 April 2014

KEYWORDS: diabetic nephropathy; diabetes mellitus; end-stage renal

disease; microalbuminuria; randomized controlled trial

Despite the availability of effective treatments to delay the

progression of renal function loss, the prevalence of end-stage

renal disease (ESRD) continues to rise.1 Novel strategies are

needed to lessen the burden of this devastating condition.

Health campaigns have focused on early detection of chronic

kidney disease on the basis of the rationale that early

intervention and appropriate treatment has a greater impact

in delaying the progression of renal function loss comparedwith late intervention.

To study the efficacy of new drugs, clinically meaningfuloutcomes that directly affect the well-being of patients are

needed. ESRD is a commonly used hard clinical end point in

drug trials in nephrology. However, the progression of kidney

disease to ESRD takes many years if not decades. Clinical

trials enrolling patients at early stages of disease would there-

fore require a long follow-up and/or an impractical large

sample size to establish drug efficacy toward ESRD. The use

of a surrogate end point may be a solution to this problem.A surrogate end point of a clinical trial is a laboratory

measurement or a physical sign that measures the effect of acertain treatment and is intended to substitute for the clinical

end point.2 Although such a surrogate end point does not

directly measure how a patient feels, functions, or survives,

it is associated with clinically meaningful outcomes so that

changes in the marker level are expected to predict benefit or

harm. The use of surrogate end points in clinical trials is

tempting as it may reduce sample size requirements, shorten

the follow-up time of clinical trials, and allow the perfor-

mance of early intervention trials to be carried out.The presence of microalbuminuria is an early sign of renal

damage and predicts an accelerated loss of renal function. 3

Clinicians currently use microalbuminuria to diagnose renal

damage and establish the prognosis of an individual. More-over, the change in albuminuria after treatment initiationwith angiotensin-converting enzyme inhibitors or angio-tensin receptor blockers is frequently used to monitor renaland/or cardiovascular -protective response to therapy. Micro-albuminuria could therefore be used as target for treatmentand as a surrogate end point in clinical trials. However, thereis growing awareness that surrogate end points should beused in clinical trials only after they have been sufficiently validated and reflect a true clinical end point. In the past, anumber of promising potentially valid surrogate end points(e.g., hemoglobin) have failed to reflect a true clinical end

r e v i e w http://www.kidney-international.org

& 2014 International Society of Nephrology

Correspondence: Hiddo J. Lambers Heerspink, Department of Clinical

Pharmacology, University Medical Centre Groningen, University of Gronin-

gen, Antonius Deusinglaan, 1, Groningen 9713 AV, The Netherlands.

E-mail: [email protected]

2These two authors contributed equally to this work.

Received 15 June 2013; revised 19 August 2013; accepted 22 August

2013; published online 23 April 2014

40 Kidney International (2014) 86 , 40–49

http://dx.doi.org/10.1038/ki.2013.490http://www.kidney-international.org/mailto:[email protected]:[email protected]://www.kidney-international.org/http://dx.doi.org/10.1038/ki.2013.490


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point.4,5 Therefore, rigorous validation of a surrogate endpoint is necessary before it can be implemented in clinicalpractice. The criteria for validation of surrogacy have beendescribed in the ‘statistical principles for clinical trials’of the International Conference on Harmonization.6 First,prognostic evidence of the surrogate end point with patientoutcome must be available. Second, a biologically plausiblerelationship between the surrogate and outcome should exist,

and third, clinical trial data must demonstrate that the effectof interventions that change the surrogate end point isdirectly associated with the same change in clinical outcomes.

Herein, we provide new updates that support the conceptthat microalbuminuria is a valid surrogate renal end pointand a target for treatment in renal disease.

MICROALBUMINURIA IS ASSOCIATED WITH RENALOUTCOMES

Twenty-four-hour urine collection represents the gold stan-dard method for determining the presence of microalbumi-nuria. However, as 24-hour urine collection is an inconvenientprocedure for patients, more practical alternatives have been

proposed, such as measurement of the albumin:creatinineratio (UACR) derived from a first morning void or a spoturine sample. Of these, the measurement of UACR in a firstmorning void appears to be the most reliable alternative to the24-hour urinary albumin excretion (UAE) in determiningthe presence of microalbuminuria and also in predicting theprogression of disease.7,8

For practical purposes albuminuria is categorized intodifferent classes—namely, normoalbuminuria (o30 mg albu-min per day or per g creatinine), microalbuminuria (30–300 mgalbumin per day or per g creatinine), and macroalbuminuria(4300 mg albumin/day or per g creatinine). The changes

between these albuminuria states represent a hallmark of theprogression or regression of disease.9 Emerging evidence showsthat individuals with high grades of albuminuria are atincreased risk of accelerated loss of renal function.10 Whereasthe association between the severity of albuminuria and renaldisease progression was initially described in individuals withhigh albuminuria (41.0 g per day),11 more recent studies show that an increase in albuminuria, even within the range that is

currently considered normal, indicates higher renal risk.10

This is a consistent finding that has been shown in differentpopulations.

In patients with type 2 diabetes followed up for at least 5 years, higher UACR at baseline was associated with a fasterdecline in renal function. Importantly, although within thenormal range, a UACR of X10 mg/g in women or X5 mg/gin men was associated with a significantly greater rate of renalfunction decline.12 Similar data were found in patients withtype 2 diabetes and microalbuminuria participating in theIrbesartan Microalbuminuria-2 (IRMA-2) trial. Subjects inthe highest quintile of baseline albuminuria excretion(between 102 and 300mg/min, which equals a UACR of

B150 and 450 mg/g) had approximately 2.5-fold greater rateof renal function decline compared with subjects withurinary albumin excretion between 20 and 30mg/min13

(which equals a UACR of B30 and 45 mg/g) (Figure 1a).The association between the increases in albuminuria andhard renal outcomes in type 2 diabetes was established in theADVANCE trial.9 Although the majority of patients (69%)enrolled in this trial had albuminuria in the normal range,baseline albuminuria was an independent determinant of theprogression to renal outcomes, and even subtle changes inalbuminuria in the normal range were strongly associatedwith disease progression.

Type 2 diabetes Hypertension General population

Baseline urinary

excretion (µg/min)

Baseline urinary

albumin excretion

(mg/24 h)

Baseline urinary albumin

excretion (mg/24 h)

3 0 0

P < 0.03 P for trend< 0.01P for trend< 0.013

Figure 1 | Higher albuminuria associates with faster decline in renal function in different populations. The annual decline in glomerularfiltration rate (GFR) relative to the levels of baseline albuminuria in patients with ( a) type 2 diabetes, (b) hypertension, and in the (c) generalpopulation. Data on type 2 diabetes patients are from the Irbesartan Microalbuminuria-2 (IRMA-2) study,90 data on hypertensive patients arefrom Bigazzi et al ,14 and data on the general population are from Prevention of Renal and Vascular End-stage Disease (PREVEND).16 eGFR,estimated GFR.

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Similar associations between albuminuria and renalfunction decline have been described in the non-diabetichypertensive population. In 1998, Bigazzi et al.14 showed thatsubjects with essential hypertension and microalbuminuriahad a faster rate of renal function decline (assessed by creatinine clearance) compared with subjects withnormoalbuminuria (Figure 1b). These data were confirmedin a larger cohort of patients with essential hypertension, of whom the majority had normoalbuminuria (92%). Subjectswho developed a renal event had higher baseline albumin-to-creatinine ratio (ACR) compared with subjects who did notdevelop a renal event (5.12 vs. 4.42mg/g; P o0.001). More-over, a regression analysis revealed that the ACR level atbaseline predicted renal events independent of other renal risk markers.15

Finally, studies from the community cohorts Prevention of Renal and Vascular End-stage Disease (PREVEND) and theNord-Trndelag Health (HUNT 2) provide further insightinto the relationship between levels of albuminuria and renal

disease in the general population.16–18 In the PREVENDcohort, higher UACR levels were associated with a fasterrate of estimated glomerular filtration rate (eGFR) decline andan increased risk for ESRD (Figure 1c).16 As observed inindividuals with diabetes or hypertension, the relation betweenalbuminuria and renal disease progression persists even withinthe normoalbuminuric and microalbuminuric range.Similar association between subtle increases in albumi-nuria and progression to ESRD was found in the HUNT 2study.18 Of note, in the HUNT 2 study the risk predictionof albuminuria alone performed significantly better than aclinical risk prediction score consisting of multiple risk

factors including age, gender, physical activity, diabetes,systolic blood pressure, antihypertensive medication, andhigh-density lipoprotein cholesterol.18 This last aspect may be of great clinical relevance considering that albuminuria canbe easily collected (and in big amounts) by the patientsthemselves.

Because the progression from microalbuminuria to ESRDtakes many years to manifest, few ESRD outcomes areobserved in observational studies. Consequently, many studies were underpowered to investigate the associationbetween microalbuminuria and ESRD. A collaborative meta-analysis was therefore performed to assess whether theseverity of albuminuria associates with ESRD and whether

albuminuria provides additional prognostic informationbeyond eGFR.19 In this meta-analysis involving 13 cohortsand 21,688 individuals, it was shown that albuminuria wasindependently associated with a higher risk for ESRD. Inparticular, compared with subjects with normoalbuminuria,those with microalbuminuria had a threefold higherrisk for ESRD. The risk further increased with more severealbuminuria (Figure 2). Subsequent analyses from thiscollaborative initiative showed that the association betweenalbuminuria and ESRD is similar in non-hypertensive versushypertensive individuals and in non-diabetic versus diabeticindividuals.20,21 These data indicate that, in the absence of

comorbid conditions such as hypertension or diabetes, theassociation between albuminuria and ESRD persists. Hence,albuminuria is not a consequence of hypertension or diabetesbut is a valid independent marker of progressive renalfunction loss. This notion is supported by another study comparing the rate of renal function decline in diabeticversus non-diabetic individuals.22 Subjects with diabetes hada higher risk of progressing to ESRD than did non-diabetic

subjects. However, subjects with diabetes also had a fourfoldhigher UACR level (B2000 mg/g) compared with non-diabetic subjects (B500 mg/g). When the difference inUACR was taken into account, the difference in progressionof renal function decline in diabetic and non-diabeticsubjects disappeared, indicating that the higher rate of renal function decline in diabetic subjects is explained by thegenerally higher albuminuria level.

Not only the albuminuria level itself but also changes inalbuminuria (within the microalbuminuric range) over timepredict renal or cardiovascular risk changes. The regression orprogression of albuminuria frequently occurs in differentpopulations. In patients with type 2 diabetes and micro-

albuminuria, it has been shown that those subjects in whomalbuminuria declined by more than 50% over 2 years’ follow-up had a subsequent renal function decline of 1.8 ml/minper year. In contrast, in subjects without a 50% reduction inalbuminuria long-term renal function decline was significantly larger, being 3.1 ml/min per year.23 These data imply thatreduction in albuminuria is an integrated renal risk indicator.

In summary, data from multiple studies in a broad rangeof patients show that subtle increases in albuminuria (evenwithin the normo- or microalbuminuric range) are adeterminant of renal outcome: higher exposure of albuminto renal tissue increases the chances of losing renal function

H a z a r d r a t i o E S R D

Albumin-to-creatinine ratio (mg/g)

14.6 (11.2–19.1)

8.0 (6.3–10.1)

2.9 (1.9–4.3)


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over time, independent of the underlying renal disease orother comorbidities. It is important to note that the strongand consistent association between albuminuria and renaloutcome does not mean that albuminuria is the sole factorassociated with renal progression. Studies showing thatsubjects without microalbuminuria progress to ESRD dem-onstrate that other renal risk factors are involved as well.24

More important is the fact that, whenever albuminuria isincreased for a certain period of time, it inevitably leads toprogressive renal function decline. Thus, despite the fact thatthe susceptibility of progressive renal function decline may bedictated by multiple factors including environmental factors,concurrent diseases, or genetic variability, albuminuria pre-dicts renal function loss in most circumstances,16,17,25–28 indi-cating that close monitoring of albuminuria and its changeover time will help identify subjects at increased renal risk.

MICROALBUMINURIA IS A CAUSE AND A CONSEQUENCE OFRENAL DISEASE

Cause of high urinary albumin excretionGiven its size and charge characteristics, it is believed thatunder physiological circumstances albumin is only minimally filtered in the glomeruli. The increased leakage of albuminshould therefore be the result of glomerular damage.29,30

Glomerular (micro) albuminuria can be physiological—owing to an increase in hydrostatic pressure or an alteredglomerular filtration coefficient, as in stress, exercise, andinflammation—or it can be pathological—for example, due tohypertension or renal disease. The integrity of the glomerulusdepends on the function and interaction of at least threedistinct layers—namely, the inner glomerular endothelial cell

layer, the outer layer of glomerular epithelial cells orpodocytes, and, between them, the glomerular basementmembrane.29–31 Furthermore, mesangial cells and extracellularmatrix surround the nephrons and help in maintaining thestructure and function of the glomerular barrier.29–32 Damageto each individual component affects the excretion of albuminand may compromise the function of the other componentsand ultimately affect the whole nephron.31 Emerging recentdata provided renewed interest in the importance of anothercomponent of the glomerular barrier—namely, the glycocalyx.The glycocalyx is a thin layer of proteoglycans with theirassociated glycosaminoglycans that covers the outer endothe-lial layer and its fenestrae in a gel-like diaphragm and excludes

(charged) macromolecules from the ultrafiltrate. Thus,glycocalyx damage may affect the charge selectivity of theglomerular filtration barrier, leading to increased leakage of albumin in the ultrafiltrate. The glycocalyx layer is notrestricted to the kidney but is present in all capillary beds.Indeed, alterations in the endothelial glycocalyx, for example,due to hyperglycemia,33 are implicated in the pathogenesis of atherosclerosis and have been associated with the onset of microalbuminuria in diabetes.34 Moreover, changes in urinealbumin excretion have been associated with general albuminleakage throughout the body.35–37 Salmon et al.38 recently demonstrated that loss of endothelial glycocalyx links

albuminuria to vascular dysfunction, supporting the conceptthat microalbuminuria is not only a marker of renal damagebut also a more generalized marker of endothelial damage.39

A new technique was recently validated to measure theendothelial glycocalyx dimension in humans using imaging of the sublingual microcirculation by orthogonal polarizationspectroscopy.40 Importantly, treatment with sulodexide—acommercially available compound, which leads to an increasein glycosaminoglycan synthesis—provided an increase in boththe sublingual and retinal glycocalyx dimensions in patientswith type 2 diabetes and reduced the transcapillary escaperate of albumin (a measure of general vascular leakageof albumin in the body and an indirect measure of albuminuria).41 Long-term studies are needed to provewhether restoration of glycocalyx size and function translatesinto better disease prognosis.

Renal consequences of high urinary albumin excretion

Within the past few decades, the classical assumption of

albuminuria as merely a reflection of disease has beenchallenged by consistent evidence that albumin is not an inertmolecule but actually affects the function of several cell typesin the kidney and may have a pathogenic role in renaldisease.42–44 Several lines of evidence suggest a role foralbuminuria and albumin-associated factors of theultrafiltrate in chronic tubulointerstitial damage.45 Oncefiltrated by the glomerulus, albumin undergoes reuptake by the tubular cells, and it is degraded. However, in case of higher albumin concentrations this system may beoverloaded, leading to increased albumin exposure in thetubular compartment, which triggers toxic effects and

inflammatory responses.46,47

In vitro studies show that anoverload of albumin exerts cytotoxic effects on proximal anddistal tubular cells by activating a wide array of intracellularsignaling pathways (e.g., extracellular signal-regulated kinase,nuclear factor-kB, protein kinase C),48–53 which induce therelease of inflammatory (monocyte chemotactic protein-1,RANTES (regulated on activation normal T-cell expressedand secreted)),53–55 vasoactive (reactive oxygen species, endo-thelin),56–58 and fibrotic (tumor growth factor–b, collagens)substances,59–62 causing interstitial damage and ultimately leading to irreversible renal deterioration. Moreover, albuminoverload may also cause cellular apoptosis,63,64 leading todecreased nephron functionality. Next to albumin itself,

substances bound to albumin, such as free fatty acid, otherproteins, or glycated albumin, can act as profibrotic andproinflammatory stimuli in the tubule and aggravate renaldamage provoked by albuminuria.46,65–70 Importantly, treat-ment that reduces albuminuria also prevents inflammationand renal function deterioration.71

Intriguingly, most of the deleterious effects driven by albumin seem to be mediated by its tubular uptake59 andmay explain renal disease progression in the presence of intact glomerular structure and permeability. Tubularreabsorption of albumin was demonstrated more than 40

years ago.46,47 Briefly, the proximal tubule brush border




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reabsorbs albumin via a clathrin-mediated endocyticpathway,47,65 which utilizes the receptor megalin and its

binding partner cubilin.72–75

Once internalized in endosomalvesicles, albumin dissociates from the cubilin–megalincomplex. Megalin is then recycled to the apical membrane,whereas albumin is transported to the lysosomal compart-ment in which it is degraded.47 Excessive tubular reuptake of albumin has been shown to be detrimental for the kidney.In fact, tubular uptake of albumin triggers the activationof a wide array of cytotoxic signals that affect the inter-stitium, the fibroblast, and the nearby blood vessels, and may cause tubulointerstitial dysfunction, fibrosis, volume expan-sion, and hypertension, leading to a worse renal prognosis(Figure 3).44,45,76,77 This is supported by a study from Okadaet al.78 showing that in type 2 diabetes patients with overt

proteinuria the degree of tubular damage and tubulo-interstitial inflammation was a strong determinant of renaloutcome, whereas glomerular damage did not associate withrenal prognosis. These experimental data of increasedglomerular leakage followed by proximal reabsorption anddamage suggest a couple of important things: first,albuminuria may increase because of diminished tubularalbumin reabsorption, which will not damage the tubule orinterstitium, and will thus not lead to increased renalfunction loss. Only when the filtered albumin is reabsorbedwith it lead to renal damage. Indeed, in a recent experimentalstudy it was shown that bardoxolone methyl, a known

suppressor of the detrimental nuclear factor-kB pathway, alsoinhibited tubular uptake of albumin. This was associated

with increased albuminuria but did not provoke histologicalrenal damage.79 Second, the degree of renal damage likely depends on the exposure of albumin in the tubular compar-tment over time rather than on a certain albumin concen-tration at a fixed time point. In other words, leakage of alarge amount of albumin during a relatively short time framecould have a different prognosis compared with leakage of asmall amount of albumin for a prolonged period of time.Indeed, in case of minimal change disease, massive amountsof albumin may pass the glomerulus without inducingdirectly visible damage. In most cases, the leakage of highamounts of albumin does not persist for a long period of time. Yet, in case the albuminuria does not remit in a

relatively short period of time (spontaneously or throughtherapy), focal segmental glomerulosclerosis or membranousnephropathy can develop. Indeed, various studies have shownthat the average albuminuria level over time is the strongestdeterminant of ESRD. Third, considering that albuminuriacauses renal damage, the renoprotective effects of drugs thatdecrease albuminuria are explained by their ability todecrease the exposure to high albuminuria. They do notcause a direct improvement in structural renal function.Treatment discontinuation of antialbuminuric drugs will leadto a re-establishment of the albuminuria level to the pre-treatment situation. This should happen as antialbuminuric

Efferentarteriole

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Figure 3 | Pathophysiological mechanisms of albumin-induced progressive renal dysfunction. Once albumin has passed the glomerularbarrier, it undergoes reuptake by the tubular cells because of the cubilin–megalin complex. Albumin triggers a cascade of pathogenicmechanisms leading to inflammation, fibrosis, mesangial expansion, and hypertension, which ultimately cause progressive renal dysfunction.These mechanisms encompass the activation of intracellular signaling pathways (e.g., extracellular signal-regulated kinase (ERK), nuclear factor-kB (NF-kB), protein kinase C (PKC)) and release of inflammatory (monocyte chemotactic protein-1 (MCP-1), regulated on activation normal T-cellexpressed and secreted (RANTES)) vasoactive (reactive oxygen species (ROS), endothelin, and fibrotic (tumor growth factor- b (TGF-b),collagens)) substances, leading to irreversible renal damage.


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drugs are not developed to cure high albuminuria but they just decrease the level. There is a clear analogy with bloodpressure–lowering drugs. They are not developed to curehypertension but are developed to decrease the exposure tohigh blood pressure and thereby improve renal/cardiovas-cular function. Discontinuation of blood pressure–loweringagents will lead to a rise in blood pressure to the pretreatmentsituation, just like discontinuation of antialbuminuric drugs(even in the normo- or microalbuminuria range after years of treatment) will lead to a return in albuminuria to the baselinevalue. To summarize, there is a growing body of evidencedemonstrating that an excess of albumin delivered to thetubular compartment is deleterious for the kidney andseverely affects renal function. These data underpin thevalidity of albuminuria not only as a risk indicator but also asan important causal factor in the initiation and progressionof renal disease.

MICROALBUMINURIA REDUCTION PREDICTS RENAL

PROTECTIONAn important criterion for valid surrogacy is that a drug-induced change in the surrogate marker (albuminuria)predicts the same change in clinical outcomes (e.g., ESRD).Analyses from different clinical trials in different populationswith different interventions have shown that drug-inducedchanges in albuminuria (within the microalbuminuria range)decrease the rate of renal function decline. Data from theIRMA-2 trial demonstrated that the reduction in albuminuriaduring angiotensin receptor blocker treatment was inversely associated with the rate of renal function decline: the higher

the albuminuria reduction, the slower the rate of renalfunction decline.13 This association was independent of changes in blood pressure or other clinical characteristics. Inanother study, Gaede et al.80 showed that intensive treatmentreduced albuminuria and slowed the progression of nephrop-athy compared with standard intervention. Interestingly, inthat study the rate of GFR decline was significantly lower in patients who regressed from microalbuminuria tonormoalbuminuria compared with those who remainedmicroalbuminuric or progressed to macroalbuminuria. More-over, long-term follow-up of this study showed that subjects inthe intensive treatment arm experienced significantly fewerESRD events compared with standard intervention.81 Similarresults were obtained in non-diabetic patients withhypertension participating in the AASK trial: modifyingproteinuria levels even in the very low range ameliorated therate of GFR decline and attenuated the risk of progression toESRD.25

The above-mentioned studies demonstrate that the degree

of albuminuria control, mainly with A angiotensin-convert-ing enzyme inhibitors or angiotensin receptor blockers, isassociated with the degree of long-term renoprotection.Importantly, this association has been observed with otherdrugs or dietary interventions as well. For example, intensiveglucose control decreased albuminuria and delayed theprogression of renal function loss in subjects with type 1diabetes, of whom the majority had normo- or microalbu-minuria.82 Interestingly, statistical adjustment for thedifference in albuminuria between the intensive and conven-tional glucose therapy arms fully attenuated the treatment

Figure 4 | Albuminuria, blood pressure, and low-density lipoprotein (LDL) cholesterol reduction predict renal protection. Reduction inend-stage renal disease consequent to (a) albuminuria reduction, (b) blood pressure reduction, and (c) LDL cholesterol reduction. Pooledanalysis is adapted from Lambers Heerspink et al.,83 the Treatment Trialists’ Collaboration,84 and Delahoy et al.,85 respectively. (a) ACEi,angiotensin-converting enzyme inhibitors; ADVANCE, Action in Diabetes and Vascular Disease, preterAx and diamicroN-MR; AIPRI, Angiotensin-Converting Enzyme Inhibition in Progressive Renal Insufficiency; ARBs, angiotensin receptor blockers; DIAB-HYCAR, The Non-Insulin-DependentDiabetes, Hypertension, Microalbuminuria, Cardiovascular Events and Ramipril Study; IDNT, Irbesartan Diabetic Nephropathy Trial; ONTARGET,Ongoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial; REIN, Ramipril Efficacy in Nephropathy; RENAAL, Reductionof Endpoints in NIDDM with the Angiotensin II Antagonist Losartan. (b) AASK, The African American Study of Kidney Disease and Hypertension;ACEi, angiotensin-converting enzyme inhibitors; ALLHAT, the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial;ANBP2, Second Australian National Blood Pressure Study; ARBs, angiotensin receptor blockers; CAMELOT, The Comparison of Amlodipine vsEnalapril to Limit Occurrences of Thrombosis study; CHARM, Candesartan in Heart Failure Assessment of Reduction in Mortality and Morbidity;EUROPA, the EUropean trial on Reduction Of cardiac events with Perindopril in patients with stable coronary Artery disease; HDS, Hypertensionin Diabetes Study Group; HOPE, Heart Outcomes Prevention Evaluation; IDNT, Irbesartan Diabetic Nephropathy Trial; LIFE, Losartan InterventionFor Endpoint reduction in hypertension study; PART, Prevention of Atherosclerosis with Ramipril; PEACE, Prevention of Events with AngiotensinConverting Enzyme Inhibition; PROGRESS, The Perindopril Protection against Recurrent Stroke Study; RENAAL, Reduction of Endpoints in

NIDDM with the Angiotensin II Antagonist Losartan; SBP, systolic blood pressure; STOP2, the Swedish Trial in Old Patients with Hypertension-2study; UKPDS, UK Prospective Diabetes Study Group; Val-HeFT, The Valsartan Heart Failure Trial. (c) AFCAPS/TexCAPS, Air Force/Texas CoronaryAtherosclerosis Prevention Study; ALERT, Assessment of Lescol in Renal Transplants; CARE, Cholesterol And Recurrent Events; ALLHAT-LLT,Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial; ALLIANCE, Aggressive Lipid-Lowering Initiation Abates NewCardiac Events; ASCOT-LLA, AngloScandinavian Cardiac Outcomes Trial-Lipid Lowering Arm; ASPEN, Atorvastatin Study for Prevention of Coronary Heart Disease Endpoints in Non-Insulin Dependent Diabetes Mellitus; A-Z, A to Z Trial; CARDS, Collaborative Atorvastatin DiabetesStudy; GISSI, Gruppo Italiano per 10 Studio della Sopravvivenza nell’lnfarto Miocardico; GREACE, GREek Atorvastatin and Coronary heart-diseaseEvaluation Study; HPS, Heart Protection Study; IDEAL, Incremental Decrease in End Points Through Aggressive Lipid Lowering; JUPITER,Justification for the Use of Statins in Prevention, An Intervention Trial Evaluating Rosuvastatin; LIPID, Long-Term Intervention with Pravastatin inIschaemic Disease; LIPS, Lescol lntervention Prevention Study; MEGA, Primary prevention of cardiovascular disease with pravastatin in Japan(MEGA Study); Post-CABG, post-coronary artery bypass graft; PROSPER, PROspective Study of Pravastatin in the Elderly at Risk; PROVE-IT,Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis in Myocardial Infarction; SPARCL, Stroke Prevention by AggressiveReduction in Cholesterol Levels; TNT, Treating to New Targets; WOSCOPS, West of Scotland Coronary Prevention Study; 4D, German Diabetesand Dialysis Study; 4S, Scandinavian Simvastatin Survival Study.




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effect, suggesting that the reduction in albuminuria is adriving parameter for the renal protective effect conferred by intensive glucose control. Dietary protein restriction has alsobeen shown to decrease proteinuria in the Modification of

Diet in Renal Disease trial.11 In that trial, subjects with thelargest reduction in proteinuria experienced the largestrenoprotective benefit. Thus, for most drugs that reducealbuminuria, the change in albuminuria is associated with a

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proportional effect on renal outcome: the greater thereduction in albuminuria, the greater the risk reduction.

Although the association between changes in albuminuriaand renal outcomes within trials lends support to validsurrogacy, it does not definitely prove the surrogacy concept.All of the aforementioned analyses were conducted post hoc and were no longer based on randomized comparisons.In addition, although these within-trial analyses wereadjusted for a range of potential confounders, the influenceof unmeasured confounders cannot be ignored. To avoid thistype of bias, it is necessary to perform a combined analysis of multiple randomized controlled trials and link the treatmenteffect of a drug on albuminuria with the treatment effects onthe clinical end point. The clear advantage of this so-calledtrial-level approach is that the estimated treatment effectson albuminuria and the hard end point are based onrandomized comparison, thereby reducing the chance of bias.A joint analysis of multiple randomized clinical trialsinvestigating the effects of renin–angiotensin system (RAAS)

blockade on renal disease progression illustrates the associa-tion between the treatment effects on albuminuria and thetreatment effects on hard renal end point: the larger thereduction of albuminuria in a trial, the larger the treatmenteffect on the hard renal end point (Figure 4a).83 The scatterplot for albuminuria closely resembles similar scatter plots of the accepted surrogate markers, blood pressure and choles-terol (Figures 4b and c).84,85 Collectively, these data indicatethat the degree of albuminuria control, independent of theintervention that is used, determines the degree of renalprotection.

Not all studies unambiguously demonstrate that the

change in albuminuria during therapy is associated withimproved outcomes, and exceptions can always be found.Dual RAAS-blockade in the ONTARGET and ALTITUDEtrial did not afford the expected cardiorenal protectiondespite the fact that dual RAAS-blockade decreased albumi-nuria.86,87 Possible explanations for these findings may beseveral. First, the ONTARGET study included only a smallpercentage of people with increased albuminuria levels. Of note, a post hoc analysis showed that, in patients with a largerreduction in albuminuria, treatment was associated with asignificantly better cardiovascular and renal prognosis.88

Importantly, a similar analysis from the ALTITUDE trialshowed that not only baseline albuminuria but also the

6-month change in albuminuria was an independentpredictor of renal and cardiovascular outcomes: subjectswith the largest reductions in albuminuria in the first 6months showed a subsequent higher renal and cardiovascularrisk reduction (HJ Lambers Heerspink et al. Loweringalbuminuria reduces cardiorenal events: insights fromALTITUDE; American Society Nephrology Atlanta 2013).The second and most important point is that bothONTARGET and ALTITUDE suggest that the side effects of combined therapy (i.e., hyperkalemia or hypotension) offsetthe potential benefit of albuminuria lowering and ultimately result in adverse outcomes. Finally, it should be noted that the

achieved blood pressure in both the ONTARGET andALTITUDE trials was lower with dual RAAS-blockade thanwith monotherapy. This has never been a reason to dismissblood pressure as a valid surrogate marker, nor should it be areason to negate the value of microalbuminuria as a usefulsurrogate.

Despite piling evidence that albuminuria developmentand progression is associated with worse renal prognosis,regulatory agencies have still not accepted albuminuria as avalid surrogate end point. This is apparently justified by thelimited evidence from intervention trials showing that a drugeffect on renal outcomes can be predicted by its effect onalbuminuria. Although large trials have been conductedwith RAAS-blockade in patients with diabetic nephropathy,these data cannot be easily extrapolated to other drugsor diseases.89 Given the substantial risks to public healthif a surrogate end point fails to provide accurate informa-tion about drug efficacy on clinical end points, additionalprospective high-quality data are needed.89 To our

knowledge, one trial that targets albuminuria directly iscurrently ongoing (NCT01858532) and results are awaited.

CONCLUSION

The validity of microalbuminuria as a renal surrogate markeris supported by a strongly growing rationale. Numerous largeclinical studies showed that albuminuria associates with renaloutcome and that reduction of albuminuria, independently of the class of drug used, lowers the risk of renal events.Importantly, the association between a drug effect onalbuminuria and hard renal outcome is similar to theassociation between drug effects on well-accepted surrogate

end points such as blood pressure and cholesterol and hardclinical outcomes. Moreover, emerging experimental datademonstrate that albumin is not an inert molecule but causesand contributes to renal disease pathogenesis. In other words,reduction in albuminuria decreases the exposure to aproinflammatory and profibrotic molecule, thereby resultingin less structural worsening of the nephron, leading to a morepreserved renal functionality. Thus, we amply demonstratedthat microalbuminuria fulfills the criteria for valid surrogacy as described in the ‘statistical principles for clinical trials’ of theInternational Conference on Harmonization and should beaccepted as a surrogate end point by regulatory agencies.

Accepting microalbuminuria as a surrogate marker for renaloutcomes would lead to less resource–consuming hardoutcome trials, would accelerate the development of drugsfor chronic renal impairment, and enable earlier access of thesedrugs to individual patients.

DISCLOSUREAll the authors declared no competing interests.

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