Current Therapy for IgA Nephropathy
Ju¨rgen Floege and Frank Eitner
Division of Nephrology and Immunology, RWTH University of Aachen, Aachen, Germany
Although IgA nephropathy (IgAN) is the
most common noninfectious glomeru-
lonephritis worldwide, there are remark-
ably few randomized controlled trials
and very rarely do patient numbers ex-
ceed 200. Consequently, most guidelines
relating to IgAN in the KDIGO Clinical
Practice Guideline for Glomerulonephritis
(to be published in late 2011) will be
based on a low to very low level of evi-
dence and, in many cases, suggestions
cannot even be offered. Thus, the major-
ity of patients will continue to be treated
based largely onopinion. This reviewwill
attempt to incorporate evidence-based
recommendations, but it will also cover
areas founded exclusively on opinion.
We have based the review on four classi-
cal clinical scenarios encountered in
IgAN patients: that is, the coincidental
discovery of minor urinary abnormali-
ties (the majority); the typical patient
who requires close follow-up and treat-
ment; atypical manifestations including
overt nephrotic syndrome, acute or rap-
idly progressive kidney injury, or sec-
ondary forms of IgAN; and finally recur-
rent IgAN after renal transplantation. A
synopsis of our suggested approach is
given in Figure 1. Supportive care
throughout the manuscript refers to
measures listed in Table 1, which are not
specific for IgAN and which have been
shown to retard progression of chronic
glomerular diseases.
THE SILENT MAJORITY
Most IgAN Likely Goes Unnoticed,
Is Very Benign, and Does Not Need
Treatment
In autopsy series1 and zero-hour allo-
graft biopsies,2 glomerular IgA deposits
are detected in 5 to 20% of all cases. Full-
blown IgANwith glomerular IgA plusC3
deposits as well as mesangioproliferative
changes were noted in 1.6% of Japanese
graft kidneys before implantation.2 Thus,
the majority of patients with IgAN must
run a clinically inconspicuous course
and spontaneous remissions of the dis-
ease must exist. Indeed, in Chinese IgAN
patients with isolated microhematuria
followed for up to 12 years, microhema-
turia disappeared in 14%, and in less
than one third, proteinuria increased
above 1 g/d or GFR fell.3 Repeat biopsy
studies confirm that glomerular changes,
including IgA deposits, can completely
disappear spontaneously or after treat-
ment in both native4–6 and transplanted
kidneys.7,8 These studies have two im-
portant clinical implications: IgAN—at
least in early stages—can be spontane-
ously reversible and patients with iso-
lated urinary abnormalities, particular
those in whom IgAN has been con-
firmed, need to be followed long-term, as
there may be progressive disease in ap-
proximately 30%. Although such long-
term follow-up is often recommended,
especially in young patients, at least in our
experience it is rarelymaintained through-
out the necessary 10 or more years. Auto-
Published online ahead of print. Publication date
available at www.jasn.org.
Correspondence: Dr. Ju¨rgen Floege, Department
of Nephrology and Clinical Immunology, RWTH Uni-
versity Hospital Aachen, Pauwelsstr. 30, 52074
Aachen, Germany. Phone: �49 241 80 89530; Fax:
�49 241 80 82446; E-mail: juergen.floege@rwth-
aachen.de
Copyright © 2011 by the American Society of
Nephrology
ABSTRACT
IgA nephropathy (IgAN) is a very common glomerulonephritis worldwide. In this
review, we discuss therapeutic options in four clinical scenarios encountered in
patients with IgAN: first is the patient with minor urinary abnormalities where the
mainstay of treatment is long-term, regular follow-up to detect renal progression
and hypertension. Second is the typical patient presenting with microhematuria,
significant but non-nephrotic proteinuria, hypertension, and variable degrees of
renal failure. Here the mainstay of treatment is optimized supportive care. If this
does not lower proteinuria below 1 g/d, corticosteroid monotherapy may be
effective, as long as the GFR is above 50 ml/min. There is insufficient data to
advocate the use of other immunosuppressive drugs or even combination therapy
in such patients. Third is the atypical patient with overt nephrotic syndrome, or
acute or rapidly progressive kidney injury where a possible vasculitic form of IgAN
should be sought and, if present, treated with immunosuppression. In other
atypical patients with secondary IgAN, treatment should target the underlying
primary disease. And fourth is the transplanted patient with recurrent IgAN where
the mainstay of treatment is optimized supportive care.
J Am Soc Nephrol 22: 1785–1794, 2011. doi: 10.1681/ASN.2011030221
BRIEF REVIEW www.jasn.org
J Am Soc Nephrol 22: 1785–1794, 2011 ISSN : 1046-6673/2210-1785 1785
mated reminder systems might provide
some help here.
THE TYPICAL PATIENT WITH IgAN
Proteinuria, Hypertension, and GFR
Are Key Determinants of the Type
of Treatment
The degree of proteinuria is one of the
strongest predictors of outcome in
IgAN.9–11 The risk for renal failure in-
creases with higher proteinuria. Vice
versa, lowering proteinuria markedly de-
creases risk regardless of whether the ini-
tial proteinuria is mild or in the ne-
phrotic range.9,11 Whereas most studies
use a proteinuria cutoff of 1 g/d, above
which increased risk for renal failure de-
velops,9–11 others contend that an in-
creased risk starts above 0.5 g/d.12 Fur-
thermore, it unresolved, which is the best
predictor, proteinuria at initial presenta-
tion or the level maintained over the first
year or at year 1.12 Uncontrolled hyper-
tension has an additive effectwithprotein-
uria in driving progression of disease.9,11
The third consistent indicator of risk is a
decrease in GFR at presentation.10 This is
expected since loss of renal function likely
identifies the subgroup of IgAN patients
who are already progressive. Finally, renal
prognosis is worse in obese IgAN pa-
tients,13,14 possibly related to superim-
posed obesity-related renal changes.15
Nonsurgical weight loss can indeed lead to
a reduction of proteinuria.16
In terms of histologic parameters
(Figure 2), the IgAN Oxford classifica-
tion17,18 may offer important advances
by providing evidence that not only
chronic fibrotic changes, particularly
glomerulosclerosis and tubulointersti-
tial fibrosis, but also mesangial and en-
docapillary hypercellularity predict
prognosis. Various validation studies,
such as the VALIGA study of the Euro-
pean Renal Association (ERA-EDTA),
are ongoing. Whether it is beneficial to
base clinical decisions on this classifica-
tion system, in particular, the novel pa-
rameters of mesangial and endocapillary
hypercellularity, has not yet been tested.
Finally, how the presence of cellular cres-
cents in a patient who does not exhibit a
rapidly progressive (vasculitic) course of
IgAN should ultimately affect treatment
modality is unresolved. There is relative
consensus, however, that crescents in
�50% of the glomeruli in an otherwise
stable patient should not automatically
prompt immunosuppression since insti-
tution of adequate supportive therapy
may indeed lead to resolution of cres-
cents.
One Size Fits All: Optimized
Supportive Therapy Is the
Cornerstone for All Patients at Risk
of Progression
There is no doubt that an optimized sup-
portive regimen constitutes the corner-
Optimize supportive therapy
Nephrotic syndrome
or RPGNGFR < 30–50 ml/min
Continue supportive therapy
for at least 3–6 months
Add corticosteroid,
if proteinuria > 1g/day or
progressive GFR-loss
despite blood pressure control
Add immunosuppression
Continue supportive therapy
No immunosuppression
(except if RPGN)
LOW RISK
(minor urinary abnormalities,
GFR normal, no hypertension)
MODERATE TO HIGH RISK
(proteinuria > 0.5–1 g/d and/or
GFR reduced and/or hypertension)
ACUTE OR RAPID
GFR LOSS
AKI due to macro-
hematuria or other
common cause
Supportive
therapy
BIOPSY-PROVEN, PRIMARY IgAN
Proteinuria >0.5–1 g/day
GFR normal or slowly ,
but > 30–50 ml/min
Monitor annually
for at least 10 years
Continue supportive
therapy alone,
if proteinuria < 1g/day and
GFR-decline < 30%/6 months
Figure 1. Synopsis of suggested therapeutic approaches to patients with IgAN depending on the clinical setting.
BRIEF REVIEW www.jasn.org
1786 Journal of the American Society of Nephrology J Am Soc Nephrol 22: 1785–1794, 2011
stone of any therapeutic approach to
IgAN patients at risk for progression. In
fact, this will be the only area where there
will be KDIGO recommendations (as op-
posed to suggestions with lower degree
evidence). These measures are summa-
rized in Table 1. In view of space limita-
tions, we will not discuss this issue in de-
tail. The reader is referred to excellent
reviews on this topic.19–21 Of note, most
randomized trials in IgAN suffer from
lack of optimized and comprehensive
supportive care. We therefore initiated
the STOP-IgAN trial,22 which will test in
high-risk IgAN patients whether immu-
nosuppression exerts an added benefit
after the supportive therapy has been op-
timized over 6 months. We recently fin-
ished recruitment and data are expected
by 2014.
Nonestablished and Controversial
Nonimmunosuppressive Treatment
Approaches
In a meta-analysis of fish oil therapy in
patients with IgAN, no statistically sig-
nificant benefit was noted, although
there was a 75% probability of at least a
minor effect.23 Long-term follow-up of
the largest randomized trial so far24
noted a better preservation of renal
function in the fish oil group. In a
smaller Italian randomized trial in pro-
teinuric IgAN patients with preserved
renal function, proteinuria decreased
by 75% in the fish oil group but re-
mained stable in controls;25 however, a
tendency of the control group toward
worse prognostic features at baseline
(numerically lower mean GFR, higher
proteinuria, and more men) was nota-
ble. Essentially no side effects were
noted. In contrast, another more re-
cent randomized trial failed to detect a
benefit from fish oil;26 whether this was
related to a slightly higher baseline
proteinuria in the fish oil group re-
mains unresolved. At present, fish oil
in IgAN is literally a matter of taste.
Antiplatelet and anticoagulant
drugs are mostly used in Asia for the
treatment of IgAN. A small random-
ized trial suggested benefit from dipy-
ridamole (75 mg three times daily and
warfarin [INR 1.3 to 1.5]) compared
with no treatment, but angiotensin-
converting enzyme (ACE) inhibitors
were avoided in these patients.27 Most
other studies on this topic suffer from
the fact that antiplatelet therapy was
not standardized (aspirin, warfarin, or
dipyridamole were used), often com-
bined with immunosuppression, and
were retrospective and nonrandom-
ized. At present, no recommendation
on the use of such drugs is possible in
IgAN patients.
Tonsillectomy, combined with im-
munosuppression, in patients at risk
for progressive IgAN, is mostly recom-
mended in Japan, based largely on ret-
rospective data.28,29 A recent small Jap-
anese study in transplanted patients
with recurrent IgAN30 reports that ton-
sillectomy reduces proteinuria from
880 to 280 mg/d, whereas little change
was noted in a non–operated control
group. Another recent Japanese study
in primary IgAN also reports that ton-
sillectomy combined with immuno-
suppression is more effective in induc-
ing remission of proteinuria and/or
hematuria than immunosuppression
alone.31 Limitations of both studies in-
clude their small size, nonrandomized
nature, and nonsystematic renin-ang-
iotensin blockade. Given that other
studies have been unable to document
a benefit in IgAN patients who are
Caucasian,32,32a we feel that an ade-
quately powered randomized con-
trolled trial will be required before
tonsillectomy can be routinely re-
commended in the care of IgAN pa-
tients. An exception may be when there
is a clear temporal relationship be-
tween tonsillitis episodes and bouts of
macrohematuria.
A recent Finnish study investigated
the relationship between alcohol con-
sumption and progression of IgAN.33
Better kidney function was associated
with light-to-moderate alcohol con-
sumption after correction for hyper-
tension and 24-hour protein excretion.
Light consumption (one drink per day)
in women and moderate consumption
(1 to 3 drinks per day) in men appears
optimal. Although this certainly does
Table 1. Supportive therapy of IgAN
Level 1 recommendations
● Control blood pressure (sitting systolic BP in the 120s)
● ACE inhibitor or ARB therapy with uptitration of dosage or combination ACE inhibitor
and ARB therapy
● Avoid dihydropyridine calcium-channel blockers unless needed for BP control
● Control protein intake
Level 2 recommendations
● Restrict NaCl intake/institute diuretic therapy
● Control fluid intake
● Non–dihydropyridine calcium-channel blocker therapy
● Control each component of the metabolic syndrome
● Aldosterone antagonist therapy
● Beta-blocker therapy
● Smoking cessation
● Allopurinol therapy
● Empiric NaHCO3 therapy, independent of whether metabolic acidosis is present or not
Other measures to retard IgAN progression
● Avoid NSAIDs altogether, or no more than once or twice weekly at most
● Avoid prolonged severe hypokalemia
● Avoid phosphate cathartics
● Ergocalciferol therapy to correct vitamin D deficiency
● Control hyperphosphatemia and hyperparathyroidism; in animal models and in human
studies, controlling hyperphosphatemia slows CKD progression
Recommended supportive therapy options in patients with, or at risk of, progressive IgAN (modified after
reference 20). The goal is to implement all level 1 recommendations and as many level 2
recommendations as feasible. ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blocker;
CKD, chronic kidney disease; NSAID, non-steroidal anti-inflammatory drug.
BRIEF REVIEWwww.jasn.org
J Am Soc Nephrol 22: 1785–1794, 2011 IgA Nephropathy 1787
not establish a causal or even therapeu-
tic relationship, patients should be
made aware of these findings.
Proteinuric Patients, Despite
Optimized Supportive Care, Should
Be Given a 6-Month Course of
Corticosteroids If GFR Is Above
50 ml/min
Three randomized controlled trials have
shown that a 6-month course of cortico-
steroids in IgAN patients with relatively
preserved renal function, and a GFR
above 50ml/min, can reduce proteinuria
and decrease the risk of subsequent renal
failure.34–37Whereas corticosteroid ther-
apy in the first trial consisted of com-
bined pulse and oral steroids, a purely
oral regimen was used in the subsequent
trials and appeared effective as well (Ta-
ble 2). In contrast, in a smaller United
States trial,26 using a much longer but
strictly alternating steroid regimen, no
benefit was noted at 2 years (Table 2).
Similarly, a low-dose corticosteroid reg-
imen (20 mg/d, tapered over 2 years)
from Japan was ineffective in a random-
ized trial.38
Corticosteroid-related side effects, even
with the more aggressive Pozzi regimen,
were reported to be minor. This is in con-
trast to the orthopedic literature in which
9 g of methylprednisolone markedly ex-
ceeded the threshold of 2 g ofmethylpred-
nisolone administered within 3 months,
abovewhich the incidenceof aseptic osteo-
necrosis starts to rise.39,40
Supportive therapy in the IgAN pa-
tients was not optimal by current stan-
dards in the study of Pozzi et al.36; a sim-
ilar benefit was noted after instituting an
ACE inhibitor alone.41,42 This is consis-
tent with a retrospective analysis in 702
IgANpatients where corticosteroid pulse
therapy as well as ACE-inhibitor therapy
independently reduced progression of
disease.43 Both the trial of Manno et al.
and Lv et al. 35,34 (Table 2) suffer from
their study design, as patients were re-
quired to discontinue prior ACE inhibi-
tor or angiotensin receptor blocker
(ARB) therapy. Then, in the combina-
tion groups, they started receiving simul-
taneously an ACE inhibitor and cortico-
steroids. Consequently, a high number
of patients whowould have ended up in a
low-risk category with ACE inhibitor
treatment alonewere assigned additional
immunosuppression.44 In our own on-
going STOP-IgAN study,22 we noted
that, during the 6-month run-in phase,
which is meant to uptitrate renin-angio-
tensin blockers to their maximum anti-
proteinuric effect, proteinuria decreased
to�0.75 g/d in most patients with IgAN
(unpublished data).
A pragmatic approach suggests first
optimizing supportive therapy in IgAN
patients at risk for progression (see
above). If this is not sufficient to lower
proteinuria below about 1 g/d, patients
should be offered a 6-month trial of cor-
ticosteroids as long as their GFR is higher
than 50 ml/min (Figure 1). Table 2 sug-
gests that strictly alternating or low-dose
corticosteroid therapy is ineffective. It is
unresolved which of the three high-dose
daily regimens is more beneficial. The
longest follow-up data are available for
BA
DC
FE
Figure 2. The range of histologic findings in IgA nephropathy with an evaluation based
on the Oxford classification.17,18 All sections are PAS stains. (A) Glomerulus without
mesangial proliferation and matrix increase (M0 with the majority of glomeruli showing
this phenotype). (B) Glomerulus with segmental mesangial hypercellularity (arrow) (M1
with the majority of glomeruli showing such a phenotype). (C) Endocapillary hypercellu-
larity (E1). (D) Glomerulus with segmental necrosis and extracapillary proliferation. (E)
Overview of a case with sclerotic and atrophic changes. Right-sided glomerulus with
segmental glomerulosclerosis and a focal adhesion (arrow) surrounded by increased
interstitial matrix and tubules with segmental dedifferentiation (tubular atrophy) (S1 for
glomerular sclerosis and T1 for tubular atrophy and interstitial fibrosis). (F) Higher mag-
nification of the glomerulus illustrated in Figure 2E with segmental glomerulosclerosis
and an adhesion (arrow) (S1).
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1788 Journal of the American Society of Nephrology J Am Soc Nephrol 22: 1785–1794, 2011
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