review

http://www.kidney-international.org
& 2014 International Society of Nephrology

Microalbuminuria: target for renoprotective

therapy PRO
Sara S. Roscioni1,2, Hiddo J. Lambers Heerspink1,2 and Dick de Zeeuw1
1

Department 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, 4049; doi:10.1038/ki.2013.490;
published online 23 April 2014
KEYWORDS: diabetic nephropathy; diabetes mellitus; end-stage renal
disease; microalbuminuria; randomized controlled trial

Correspondence: Hiddo J. Lambers Heerspink, Department of Clinical

Pharmacology, University Medical Centre Groningen, University of Groningen, Antonius Deusinglaan, 1, Groningen 9713 AV, The Netherlands.
E-mail: h.j.lambers.heerspink@umcg.nl
2

These 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

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 compared
with late intervention.
To study the efficacy of new drugs, clinically meaningful
outcomes 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 therefore 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 a
certain 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 performance 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. Moreover, the change in albuminuria after treatment initiation
with angiotensin-converting enzyme inhibitors or angiotensin receptor blockers is frequently used to monitor renal
and/or cardiovascular -protective response to therapy. Microalbuminuria could therefore be used as target for treatment
and as a surrogate end point in clinical trials. However, there
is growing awareness that surrogate end points should be
used in clinical trials only after they have been sufficiently
validated and reflect a true clinical end point. In the past, a
number of promising potentially valid surrogate end points
(e.g., hemoglobin) have failed to reflect a true clinical end
Kidney International (2014) 86, 4049

review

Baseline urinary
excretion (g/min)

Baseline urinary albumin

excretion (mg/24 h)
30

0
>3
0

50
15

1
30

15

0
15

00
30

<3
0

2
>1
0

1
66

General population

02

Hypertension
Baseline urinary
albumin excretion
(mg/24 h)

4
5
45
6
6

Type 2 diabetes

30

<3
0

SS Roscioni et al.: Microalbuminuria: target for therapy

1.0
1.5
2.0
2.5
P for trend < 0.013
3.0

P < 0.03

Annual rate of eGFR decline

(ml/min per 1.73 m2)

Annual rate of eGFR decline

(ml/min per 1.73 m2)

5.0

Decline of creatinine clearance

(ml/min per year)

0.0

P for trend < 0.01

3.5

Figure 1 | Higher albuminuria associates with faster decline in renal function in different populations. The annual decline in glomerular
filtration rate (GFR) relative to the levels of baseline albuminuria in patients with (a) type 2 diabetes, (b) hypertension, and in the (c) general
population. Data on type 2 diabetes patients are from the Irbesartan Microalbuminuria-2 (IRMA-2) study,90 data on hypertensive patients are
from 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.

point.4,5 Therefore, rigorous validation of a surrogate end

point is necessary before it can be implemented in clinical
practice. The criteria for validation of surrogacy have been
described in the statistical principles for clinical trials
of the International Conference on Harmonization.6 First,
prognostic evidence of the surrogate end point with patient
outcome must be available. Second, a biologically plausible
relationship between the surrogate and outcome should exist,
and third, clinical trial data must demonstrate that the effect
of interventions that change the surrogate end point is
directly associated with the same change in clinical outcomes.
Herein, we provide new updates that support the concept
that microalbuminuria is a valid surrogate renal end point
and a target for treatment in renal disease.
MICROALBUMINURIA IS ASSOCIATED WITH RENAL
OUTCOMES

Twenty-four-hour urine collection represents the gold standard method for determining the presence of microalbuminuria. However, as 24-hour urine collection is an inconvenient
procedure for patients, more practical alternatives have been
proposed, such as measurement of the albumin:creatinine
ratio (UACR) derived from a first morning void or a spot
urine sample. Of these, the measurement of UACR in a first
morning void appears to be the most reliable alternative to the
24-hour urinary albumin excretion (UAE) in determining
the presence of microalbuminuria and also in predicting the
progression of disease.7,8
For practical purposes albuminuria is categorized into
different classesnamely, normoalbuminuria (o30 mg albumin per day or per g creatinine), microalbuminuria (30300 mg
albumin per day or per g creatinine), and macroalbuminuria
(4300 mg albumin/day or per g creatinine). The changes
Kidney International (2014) 86, 4049

between these albuminuria states represent a hallmark of the

progression or regression of disease.9 Emerging evidence shows
that individuals with high grades of albuminuria are at
increased risk of accelerated loss of renal function.10 Whereas
the association between the severity of albuminuria and renal
disease progression was initially described in individuals with
high 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 different
populations.
In patients with type 2 diabetes followed up for at least 5
years, higher UACR at baseline was associated with a faster
decline in renal function. Importantly, although within the
normal range, a UACR of X10 mg/g in women or X5 mg/g
in men was associated with a significantly greater rate of renal
function decline.12 Similar data were found in patients with
type 2 diabetes and microalbuminuria participating in the
Irbesartan Microalbuminuria-2 (IRMA-2) trial. Subjects in
the highest quintile of baseline albuminuria excretion
(between 102 and 300 mg/min, which equals a UACR of
B150 and 450 mg/g) had approximately 2.5-fold greater rate
of renal function decline compared with subjects with
urinary albumin excretion between 20 and 30 mg/min13
(which equals a UACR of B30 and 45 mg/g) (Figure 1a).
The association between the increases in albuminuria and
hard renal outcomes in type 2 diabetes was established in the
ADVANCE 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 the
progression to renal outcomes, and even subtle changes in
albuminuria in the normal range were strongly associated
with disease progression.
41

review

42

14.6 (11.219.1)

20

8.0 (6.310.1)

10
Hazard ratio ESRD

Similar associations between albuminuria and renal

function decline have been described in the non-diabetic
hypertensive population. In 1998, Bigazzi et al.14 showed that
subjects with essential hypertension and microalbuminuria
had a faster rate of renal function decline (assessed by
creatinine clearance) compared with subjects with
normoalbuminuria (Figure 1b). These data were confirmed
in a larger cohort of patients with essential hypertension, of
whom the majority had normoalbuminuria (92%). Subjects
who developed a renal event had higher baseline albumin-tocreatinine ratio (ACR) compared with subjects who did not
develop a renal event (5.12 vs. 4.42 mg/g; Po0.001). Moreover, a regression analysis revealed that the ACR level at
baseline 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 the
Nord-Trndelag Health (HUNT 2) provide further insight
into the relationship between levels of albuminuria and renal
disease in the general population.1618 In the PREVEND
cohort, higher UACR levels were associated with a faster
rate of estimated glomerular filtration rate (eGFR) decline and
an increased risk for ESRD (Figure 1c).16 As observed in
individuals with diabetes or hypertension, the relation between
albuminuria and renal disease progression persists even within
the normoalbuminuric and microalbuminuric range.
Similar association between subtle increases in albuminuria and progression to ESRD was found in the HUNT 2
study.18 Of note, in the HUNT 2 study the risk prediction
of albuminuria alone performed significantly better than a
clinical risk prediction score consisting of multiple risk
factors including age, gender, physical activity, diabetes,
systolic blood pressure, antihypertensive medication, and
high-density lipoprotein cholesterol.18 This last aspect may
be of great clinical relevance considering that albuminuria can
be easily collected (and in big amounts) by the patients
themselves.
Because the progression from microalbuminuria to ESRD
takes many years to manifest, few ESRD outcomes are
observed in observational studies. Consequently, many
studies were underpowered to investigate the association
between microalbuminuria and ESRD. A collaborative metaanalysis was therefore performed to assess whether the
severity of albuminuria associates with ESRD and whether
albuminuria provides additional prognostic information
beyond eGFR.19 In this meta-analysis involving 13 cohorts
and 21,688 individuals, it was shown that albuminuria was
independently associated with a higher risk for ESRD. In
particular, compared with subjects with normoalbuminuria,
those with microalbuminuria had a threefold higher
risk for ESRD. The risk further increased with more severe
albuminuria (Figure 2). Subsequent analyses from this
collaborative initiative showed that the association between
albuminuria and ESRD is similar in non-hypertensive versus
hypertensive individuals and in non-diabetic versus diabetic
individuals.20,21 These data indicate that, in the absence of

SS Roscioni et al.: Microalbuminuria: target for therapy

1
0.8

2.9 (1.94.3)

<30

30299

300999

.1000

Albumin-to-creatinine ratio (mg/g)

Figure 2 | Albuminuria predicts renal outcome. Adjusted hazard

ratio (95% confidence interval) for end-stage renal disease (ESRD)
by albuminuria category adjusted for age, sex, race, previous
cardiovascular disease, smoking status, diabetes mellitus, systolic
blood pressure, and serum total cholesterol concentration in four
independent clinical studies in chronic kidney disease patients.
Adapted from Astor et al.19

comorbid conditions such as hypertension or diabetes, the

association between albuminuria and ESRD persists. Hence,
albuminuria is not a consequence of hypertension or diabetes
but is a valid independent marker of progressive renal
function loss. This notion is supported by another study
comparing the rate of renal function decline in diabetic
versus non-diabetic individuals.22 Subjects with diabetes had
a higher risk of progressing to ESRD than did non-diabetic
subjects. However, subjects with diabetes also had a fourfold
higher UACR level (B2000 mg/g) compared with nondiabetic subjects (B500 mg/g). When the difference in
UACR was taken into account, the difference in progression
of renal function decline in diabetic and non-diabetic
subjects disappeared, indicating that the higher rate of
renal function decline in diabetic subjects is explained by the
generally higher albuminuria level.
Not only the albuminuria level itself but also changes in
albuminuria (within the microalbuminuric range) over time
predict renal or cardiovascular risk changes. The regression or
progression of albuminuria frequently occurs in different
populations. In patients with type 2 diabetes and microalbuminuria, it has been shown that those subjects in whom
albuminuria declined by more than 50% over 2 years followup had a subsequent renal function decline of 1.8 ml/min
per year. In contrast, in subjects without a 50% reduction in
albuminuria long-term renal function decline was significantly
larger, being 3.1 ml/min per year.23 These data imply that
reduction in albuminuria is an integrated renal risk indicator.
In summary, data from multiple studies in a broad range
of patients show that subtle increases in albuminuria (even
within the normo- or microalbuminuric range) are a
determinant of renal outcome: higher exposure of albumin
to renal tissue increases the chances of losing renal function
Kidney International (2014) 86, 4049

SS Roscioni et al.: Microalbuminuria: target for therapy

review

over time, independent of the underlying renal disease or

other comorbidities. It is important to note that the strong
and consistent association between albuminuria and renal
outcome does not mean that albuminuria is the sole factor
associated with renal progression. Studies showing that
subjects without microalbuminuria progress to ESRD demonstrate that other renal risk factors are involved as well.24
More important is the fact that, whenever albuminuria is
increased for a certain period of time, it inevitably leads to
progressive renal function decline. Thus, despite the fact that
the susceptibility of progressive renal function decline may be
dictated by multiple factors including environmental factors,
concurrent diseases, or genetic variability, albuminuria predicts renal function loss in most circumstances,16,17,2528 indicating that close monitoring of albuminuria and its change
over time will help identify subjects at increased renal risk.

albuminuria to vascular dysfunction, supporting the concept

that microalbuminuria is not only a marker of renal damage
but also a more generalized marker of endothelial damage.39
A new technique was recently validated to measure the
endothelial glycocalyx dimension in humans using imaging of
the sublingual microcirculation by orthogonal polarization
spectroscopy.40 Importantly, treatment with sulodexidea
commercially available compound, which leads to an increase
in glycosaminoglycan synthesisprovided an increase in both
the sublingual and retinal glycocalyx dimensions in patients
with type 2 diabetes and reduced the transcapillary escape
rate of albumin (a measure of general vascular leakage
of albumin in the body and an indirect measure of
albuminuria).41 Long-term studies are needed to prove
whether restoration of glycocalyx size and function translates
into better disease prognosis.

MICROALBUMINURIA IS A CAUSE AND A CONSEQUENCE OF

RENAL DISEASE
Cause of high urinary albumin excretion

Renal consequences of high urinary albumin excretion

Given its size and charge characteristics, it is believed that

under physiological circumstances albumin is only minimally
filtered in the glomeruli. The increased leakage of albumin
should therefore be the result of glomerular damage.29,30
Glomerular (micro) albuminuria can be physiological
owing to an increase in hydrostatic pressure or an altered
glomerular filtration coefficient, as in stress, exercise, and
inflammationor it can be pathologicalfor example, due to
hypertension or renal disease. The integrity of the glomerulus
depends on the function and interaction of at least three
distinct layersnamely, the inner glomerular endothelial cell
layer, the outer layer of glomerular epithelial cells or
podocytes, and, between them, the glomerular basement
membrane.2931 Furthermore, mesangial cells and extracellular
matrix surround the nephrons and help in maintaining the
structure and function of the glomerular barrier.2932 Damage
to each individual component affects the excretion of albumin
and may compromise the function of the other components
and ultimately affect the whole nephron.31 Emerging recent
data provided renewed interest in the importance of another
component of the glomerular barriernamely, the glycocalyx.
The glycocalyx is a thin layer of proteoglycans with their
associated glycosaminoglycans that covers the outer endothelial 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 the
glomerular filtration barrier, leading to increased leakage of
albumin in the ultrafiltrate. The glycocalyx layer is not
restricted 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 urine
albumin excretion have been associated with general albumin
leakage throughout the body.3537 Salmon et al.38 recently
demonstrated that loss of endothelial glycocalyx links
Kidney International (2014) 86, 4049

Within the past few decades, the classical assumption of

albuminuria as merely a reflection of disease has been
challenged by consistent evidence that albumin is not an inert
molecule but actually affects the function of several cell types
in the kidney and may have a pathogenic role in renal
disease.4244 Several lines of evidence suggest a role for
albuminuria and albumin-associated factors of the
ultrafiltrate in chronic tubulointerstitial damage.45 Once
filtrated by the glomerulus, albumin undergoes reuptake by
the tubular cells, and it is degraded. However, in case of
higher albumin concentrations this system may be
overloaded, leading to increased albumin exposure in the
tubular compartment, which triggers toxic effects and
inflammatory responses.46,47 In vitro studies show that an
overload of albumin exerts cytotoxic effects on proximal and
distal tubular cells by activating a wide array of intracellular
signaling pathways (e.g., extracellular signal-regulated kinase,
nuclear factor-kB, protein kinase C),4853 which induce the
release of inflammatory (monocyte chemotactic protein-1,
RANTES (regulated on activation normal T-cell expressed
and secreted)),5355 vasoactive (reactive oxygen species, endothelin),5658 and fibrotic (tumor growth factorb, collagens)
substances,5962 causing interstitial damage and ultimately
leading to irreversible renal deterioration. Moreover, albumin
overload may also cause cellular apoptosis,63,64 leading to
decreased nephron functionality. Next to albumin itself,
substances bound to albumin, such as free fatty acid, other
proteins, or glycated albumin, can act as profibrotic and
proinflammatory stimuli in the tubule and aggravate renal
damage provoked by albuminuria.46,6570 Importantly, treatment that reduces albuminuria also prevents inflammation
and renal function deterioration.71
Intriguingly, most of the deleterious effects driven by
albumin seem to be mediated by its tubular uptake59 and
may explain renal disease progression in the presence of
intact glomerular structure and permeability. Tubular
reabsorption of albumin was demonstrated more than 40
years ago.46,47 Briefly, the proximal tubule brush border
43

review

SS Roscioni et al.: Microalbuminuria: target for therapy

Interstitium

Bowmans
capsule

Proximal
tubule
Albumin

Glomerulus
Efferent
arteriole

Distal
tubule

Afferent
arteriole
Cortex

Blood
flow

Medulla

Proximal tubule
Tubular
lumen
Albumin

PKC, ROS
MCP-1,
RANTES
Endothelin

Cubilin
Megalin
Brush
border

NF-B
NF-B

Inflammatory
cells

Loop
of
Henle

Collecting
duct

Vascular
cells

Collagen
TGF-

Urine
Fibroblasts

Interstitium
Inflammation/fibrosis/mesangial
expansion/hypertension

Progressive renal
dysfunction

Figure 3 | Pathophysiological mechanisms of albumin-induced progressive renal dysfunction. Once albumin has passed the glomerular
barrier, it undergoes reuptake by the tubular cells because of the cubilinmegalin complex. Albumin triggers a cascade of pathogenic
mechanisms 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 factorkB (NF-kB), protein kinase C (PKC)) and release of inflammatory (monocyte chemotactic protein-1 (MCP-1), regulated on activation normal T-cell
expressed and secreted (RANTES)) vasoactive (reactive oxygen species (ROS), endothelin, and fibrotic (tumor growth factor-b (TGF-b),
collagens)) substances, leading to irreversible renal damage.

reabsorbs albumin via a clathrin-mediated endocytic

pathway,47,65 which utilizes the receptor megalin and its
binding partner cubilin.7275 Once internalized in endosomal
vesicles, albumin dissociates from the cubilinmegalin
complex. Megalin is then recycled to the apical membrane,
whereas albumin is transported to the lysosomal compartment 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 activation
of a wide array of cytotoxic signals that affect the interstitium, the fibroblast, and the nearby blood vessels, and may
cause tubulointerstitial dysfunction, fibrosis, volume expansion, and hypertension, leading to a worse renal prognosis
(Figure 3).44,45,76,77 This is supported by a study from Okada
et al.78 showing that in type 2 diabetes patients with overt
proteinuria the degree of tubular damage and tubulointerstitial inflammation was a strong determinant of renal
outcome, whereas glomerular damage did not associate with
renal prognosis. These experimental data of increased
glomerular leakage followed by proximal reabsorption and
damage suggest a couple of important things: first,
albuminuria may increase because of diminished tubular
albumin reabsorption, which will not damage the tubule or
interstitium, and will thus not lead to increased renal
function loss. Only when the filtered albumin is reabsorbed
with it lead to renal damage. Indeed, in a recent experimental
study it was shown that bardoxolone methyl, a known
44

suppressor of the detrimental nuclear factor-kB pathway, also

inhibited tubular uptake of albumin. This was associated
with increased albuminuria but did not provoke histological
renal damage.79 Second, the degree of renal damage likely
depends on the exposure of albumin in the tubular compartment over time rather than on a certain albumin concentration at a fixed time point. In other words, leakage of a
large amount of albumin during a relatively short time frame
could have a different prognosis compared with leakage of a
small amount of albumin for a prolonged period of time.
Indeed, in case of minimal change disease, massive amounts
of albumin may pass the glomerulus without inducing
directly visible damage. In most cases, the leakage of high
amounts 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 through
therapy), focal segmental glomerulosclerosis or membranous
nephropathy can develop. Indeed, various studies have shown
that the average albuminuria level over time is the strongest
determinant of ESRD. Third, considering that albuminuria
causes renal damage, the renoprotective effects of drugs that
decrease albuminuria are explained by their ability to
decrease the exposure to high albuminuria. They do not
cause a direct improvement in structural renal function.
Treatment discontinuation of antialbuminuric drugs will lead
to a re-establishment of the albuminuria level to the pretreatment situation. This should happen as antialbuminuric
Kidney International (2014) 86, 4049

SS Roscioni et al.: Microalbuminuria: target for therapy

drugs are not developed to cure high albuminuria but they

just decrease the level. There is a clear analogy with blood
pressurelowering drugs. They are not developed to cure
hypertension but are developed to decrease the exposure to
high blood pressure and thereby improve renal/cardiovascular function. Discontinuation of blood pressurelowering
agents will lead to a rise in blood pressure to the pretreatment
situation, 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 baseline
value. To summarize, there is a growing body of evidence
demonstrating that an excess of albumin delivered to the
tubular compartment is deleterious for the kidney and
severely affects renal function. These data underpin the
validity of albuminuria not only as a risk indicator but also as
an important causal factor in the initiation and progression
of renal disease.
MICROALBUMINURIA REDUCTION PREDICTS RENAL
PROTECTION

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

review

the albuminuria reduction, the slower the rate of renal

function decline.13 This association was independent of
changes in blood pressure or other clinical characteristics. In
another study, Gaede et al.80 showed that intensive treatment
reduced albuminuria and slowed the progression of nephropathy compared with standard intervention. Interestingly, in
that study the rate of GFR decline was significantly
lower in patients who regressed from microalbuminuria to
normoalbuminuria compared with those who remained
microalbuminuric or progressed to macroalbuminuria. Moreover, long-term follow-up of this study showed that subjects in
the intensive treatment arm experienced significantly fewer
ESRD events compared with standard intervention.81 Similar
results were obtained in non-diabetic patients with
hypertension participating in the AASK trial: modifying
proteinuria levels even in the very low range ameliorated the
rate of GFR decline and attenuated the risk of progression to
ESRD.25
The above-mentioned studies demonstrate that the degree
of albuminuria control, mainly with A angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, is
associated with the degree of long-term renoprotection.
Importantly, this association has been observed with other
drugs or dietary interventions as well. For example, intensive
glucose control decreased albuminuria and delayed the
progression of renal function loss in subjects with type 1
diabetes, of whom the majority had normo- or microalbuminuria.82 Interestingly, statistical adjustment for the
difference in albuminuria between the intensive and conventional glucose therapy arms fully attenuated the treatment

Figure 4 | Albuminuria, blood pressure, and low-density lipoprotein (LDL) cholesterol reduction predict renal protection. Reduction in
end-stage renal disease consequent to (a) albuminuria reduction, (b) blood pressure reduction, and (c) LDL cholesterol reduction. Pooled
analysis 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, AngiotensinConverting Enzyme Inhibition in Progressive Renal Insufficiency; ARBs, angiotensin receptor blockers; DIAB-HYCAR, The Non-Insulin-Dependent
Diabetes, 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, Reduction
of 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 vs
Enalapril 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, Hypertension
in Diabetes Study Group; HOPE, Heart Outcomes Prevention Evaluation; IDNT, Irbesartan Diabetic Nephropathy Trial; LIFE, Losartan Intervention
For Endpoint reduction in hypertension study; PART, Prevention of Atherosclerosis with Ramipril; PEACE, Prevention of Events with Angiotensin
Converting 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-2
study; UKPDS, UK Prospective Diabetes Study Group; Val-HeFT, The Valsartan Heart Failure Trial. (c) AFCAPS/TexCAPS, Air Force/Texas Coronary
Atherosclerosis 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 New
Cardiac 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 Diabetes
Study; GISSI, Gruppo Italiano per 10 Studio della Sopravvivenza nelllnfarto Miocardico; GREACE, GREek Atorvastatin and Coronary heart-disease
Evaluation 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 in
Ischaemic 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 Aggressive
Reduction in Cholesterol Levels; TNT, Treating to New Targets; WOSCOPS, West of Scotland Coronary Prevention Study; 4D, German Diabetes
and Dialysis Study; 4S, Scandinavian Simvastatin Survival Study.

Kidney International (2014) 86, 4049

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SS Roscioni et al.: Microalbuminuria: target for therapy

Diet in Renal Disease trial.11 In that trial, subjects with the

largest reduction in proteinuria experienced the largest
renoprotective benefit. Thus, for most drugs that reduce
albuminuria, the change in albuminuria is associated with a

effect, suggesting that the reduction in albuminuria is a

driving parameter for the renal protective effect conferred by
intensive glucose control. Dietary protein restriction has also
been shown to decrease proteinuria in the Modification of

ARBs
ACEi
ARBs and ACEi
Ca2+antagonist

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STOP2 d/bb

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2.0

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ARB trial

0.25
4

2
0
2
4
6
8
Difference in SBP reduction (mm Hg) between randomized groups

% Reduction of major vascular events

0
ALLHAT-LLT
IDEAL

10
AZ

20

GISSI

PROVE IT
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30

MEGA

40
ALLIANCE

Post-CABG
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PROSPER
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WOSCOPS
ASCOT-LLA SPARCL
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0

10

20

30

40

50

60

70

80

Mean LDL-cholesterol reduction (mg/dl)

Figure 4 | For caption see page 45.

46

Kidney International (2014) 86, 4049

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SS Roscioni et al.: Microalbuminuria: target for therapy

proportional effect on renal outcome: the greater the

reduction in albuminuria, the greater the risk reduction.
Although the association between changes in albuminuria
and renal outcomes within trials lends support to valid
surrogacy, 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 were
adjusted for a range of potential confounders, the influence
of unmeasured confounders cannot be ignored. To avoid this
type of bias, it is necessary to perform a combined analysis of
multiple randomized controlled trials and link the treatment
effect of a drug on albuminuria with the treatment effects on
the clinical end point. The clear advantage of this so-called
trial-level approach is that the estimated treatment effects
on albuminuria and the hard end point are based on
randomized comparison, thereby reducing the chance of bias.
A joint analysis of multiple randomized clinical trials
investigating the effects of reninangiotensin system (RAAS)
blockade on renal disease progression illustrates the association between the treatment effects on albuminuria and the
treatment effects on hard renal end point: the larger the
reduction of albuminuria in a trial, the larger the treatment
effect on the hard renal end point (Figure 4a).83 The scatter
plot for albuminuria closely resembles similar scatter plots of
the accepted surrogate markers, blood pressure and cholesterol (Figures 4b and c).84,85 Collectively, these data indicate
that the degree of albuminuria control, independent of the
intervention that is used, determines the degree of renal
protection.
Not all studies unambiguously demonstrate that the
change in albuminuria during therapy is associated with
improved outcomes, and exceptions can always be found.
Dual RAAS-blockade in the ONTARGET and ALTITUDE
trial did not afford the expected cardiorenal protection
despite the fact that dual RAAS-blockade decreased albuminuria.86,87 Possible explanations for these findings may be
several. First, the ONTARGET study included only a small
percentage of people with increased albuminuria levels. Of
note, a post hoc analysis showed that, in patients with a larger
reduction in albuminuria, treatment was associated with a
significantly better cardiovascular and renal prognosis.88
Importantly, a similar analysis from the ALTITUDE trial
showed that not only baseline albuminuria but also the
6-month change in albuminuria was an independent
predictor of renal and cardiovascular outcomes: subjects
with the largest reductions in albuminuria in the first 6
months showed a subsequent higher renal and cardiovascular
risk reduction (HJ Lambers Heerspink et al. Lowering
albuminuria reduces cardiorenal events: insights from
ALTITUDE; American Society Nephrology Atlanta 2013).
The second and most important point is that both
ONTARGET and ALTITUDE suggest that the side effects of
combined therapy (i.e., hyperkalemia or hypotension) offset
the potential benefit of albuminuria lowering and ultimately
result in adverse outcomes. Finally, it should be noted that the
Kidney International (2014) 86, 4049

achieved blood pressure in both the ONTARGET and

ALTITUDE trials was lower with dual RAAS-blockade than
with monotherapy. This has never been a reason to dismiss
blood pressure as a valid surrogate marker, nor should it be a
reason to negate the value of microalbuminuria as a useful
surrogate.
Despite piling evidence that albuminuria development
and progression is associated with worse renal prognosis,
regulatory agencies have still not accepted albuminuria as a
valid surrogate end point. This is apparently justified by the
limited evidence from intervention trials showing that a drug
effect on renal outcomes can be predicted by its effect on
albuminuria. Although large trials have been conducted
with RAAS-blockade in patients with diabetic nephropathy,
these data cannot be easily extrapolated to other drugs
or diseases.89 Given the substantial risks to public health
if a surrogate end point fails to provide accurate information about drug efficacy on clinical end points, additional
prospective high-quality data are needed.89 To our
knowledge, one trial that targets albuminuria directly is
currently ongoing (NCT01858532) and results are awaited.
CONCLUSION

The validity of microalbuminuria as a renal surrogate marker

is supported by a strongly growing rationale. Numerous large
clinical studies showed that albuminuria associates with renal
outcome 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 on
albuminuria and hard renal outcome is similar to the
association between drug effects on well-accepted surrogate
end points such as blood pressure and cholesterol and hard
clinical outcomes. Moreover, emerging experimental data
demonstrate that albumin is not an inert molecule but causes
and contributes to renal disease pathogenesis. In other words,
reduction in albuminuria decreases the exposure to a
proinflammatory and profibrotic molecule, thereby resulting
in less structural worsening of the nephron, leading to a more
preserved renal functionality. Thus, we amply demonstrated
that microalbuminuria fulfills the criteria for valid surrogacy
as described in the statistical principles for clinical trials of the
International Conference on Harmonization and should be
accepted as a surrogate end point by regulatory agencies.
Accepting microalbuminuria as a surrogate marker for renal
outcomes would lead to less resourceconsuming hard
outcome trials, would accelerate the development of drugs
for chronic renal impairment, and enable earlier access of these
drugs to individual patients.
DISCLOSURE

All the authors declared no competing interests.

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