Pediatric Nephrology (2021) 36:491–496

https://doi.org/10.1007/s00467-020-04486-7

REVIEW

Treatment of IgA nephropathy in children: a land without KDIGO

guidance
Rosanna Coppo 1

Received: 29 August 2019 / Revised: 25 September 2019 / Accepted: 20 January 2020 / Published online: 14 February 2020
# IPNA 2020

Abstract
IgA nephropathy (IgAN) in children is no longer considered a rare and benign disease but a nephritis with different presentations
and various outcomes. The decision to initiate a treatment and the therapeutic choice depend on the individual risk of progression.
The Kidney Disease: Improving Global Outcomes (KDIGO) clinical guidelines in 2012 considered that the risk factors for
progression of IgAN were similar in both children and adults and suggested in some conditions to follow the adult schedules. In
2017 a KDIGO Controversies Conference on management and treatment of glomerular diseases decided not to include an update
in children with IgAN since the level of evidence of treatments in children was too scarce. Children can follow the indications for
adults as far as the disease is similar in the various ages. This review is aimed at discussing why the KDIGO guidelines are poorly
suitable to treat children with IgAN, and there is a need to develop new prediction models for progression of IgAN in children to
guide selection of the cases to be treated. The identification of different risk levels in children with IgAN may personalize the
choice of available drugs and support the use of new targeted therapies.

Keywords IgA nephropathy in children . Treatment . KDIGO . Risk factors . MEST-C score . Prediction models

Introduction has reported that most subjects with IgAN when entering renal
replacement therapy are young adults [3]. Since their function-
The dilemma of to treat or not to treat children with IgA al decline is slow, it is reasonable to suppose that severe pro-
nephropathy (IgAN) is nowadays more complex than when gressive IgAN may begin in childhood and that a prompt
this entity was considered rare and benign, since the therapeu- diagnosis may offer the possibility for early treatment and
tic choice varies case by case according to the individual risk improvement of the natural history of the disease in adult age.
of progression to end-stage renal disease (ESRD) [1]. At the
present time, we do not have sufficient knowledge to predict
individual risk. It is still unknown why 30–60% of subjects
Kidney Disease: Improving Global Outcomes
with pediatric IgAN will never experience any decline in GFR
(KDIGO) guideline approach to treat IgAN
over a long and healthy life, while about 10% of them will
in children
progress to ESRD or severe CKD stages within 10 years after
the diagnostic renal biopsy and 20–30% after 20 years [2].
The KDIGO clinical guidelines published in 2012 were a
Moreover, several cases reach 40–50 years of age with a silent
milestone document for treatment of glomerular disease in
relentless progression of an undiagnosed IgAN, which is dis-
adults and children [4]. KDIGO commented that children with
covered by chance finding after a checkup for hypertension
IgAN were less likely to reach ESRD, probably due to an early
and reduced GFR in subjects without a known personal or
diagnosis. Since the risk factors for progression had been val-
familiar history of renal disease. The ERA-EDTA Registry
idated in both children and adults [5], a generalization of in-
dications across the ages was considered possible. The
KDIGO approach was to deliver recommendations on irrefut-
* Rosanna Coppo
rosanna.coppo@unito.it
able publication basis as Level 1 “we recommend” supported
by systematic review/meta-analysis and Level 2 “we suggest”
1
Fondazione Ricerca Molinette, Regina Margherita Hospital, supported by at least one randomized controlled trial (RCT).
Turin, Italy The data available for children with IgAN were so limited that
492
KDIGO just suggested in some conditions to follow the adult
guidelines.
The KDIGO 2012 guidelines considered the most frequent
presentation in adults with slowly progressive IgAN at risk of
ESRD, i.e., patients with proteinuria > 1 g/day (often with
hypertension and already slightly reduced GFR), and the
first-line treatment recommended was renin-angiotensin sys-
tem blockers (RASB) valid also in children. A threshold of
proteinuria > 0.5 g/day/1.73 m2 was suggested in children.
Corticosteroids (CS) were suggested only in patients with per-
sistent proteinuria, despite 3 to 6 months of optimized sup-
portive care with RASB. No additional benefit of adding other
immunosuppressive drugs (IS) was reported. In the rare event
of crescentic IgAN with > 50% of glomeruli involved, a treat-
ment as for ANCA vasculitis was suggested. In infrequent
cases of IgAN associated with minimal change disease, the
recommendation was to use the same treatment as for minimal
change disease.
In 2017, a KDIGO Controversies Conference on manage-
ment and treatment of glomerular diseases started the review
of the 2012 guidelines. Some results from the panel discussion
have already been published [6], while waiting for new guide-
lines in 2020. However, an update in children with IgAN will
not be included, since there were no new pediatric studies
meeting the requirements for “we recommend” or “we sug-
gest.” IgAN was considered similar in children and adults;
hence, the final message is once again that children may fol-
low the same treatment indications given for adults.
Application of KDIGO guidelines to children
with IgAN
There is a very moderate enthusiasm from experts in guide-
lines in dealing with an extremely limited number of RCTs, or
a few uncontrolled retrospective cohort studies often reporting
recent as well as historical patients enrolled over several de-
cades, despite the change over time of diagnostic and thera-
peutic approaches. The outcomes analyzed in the RCTs in-
volving children with CKD, including IgAN, are extremely
heterogeneous and mostly surrogate [7]. Moreover, the initial
course of several mild cases of IgAN in children may present a
spontaneous remission of urinary abnormalities, often follow-
ed by reappearance of clinical manifestations during the
follow-up [8], indicating phases of activity, recovery, and re-
lapses, which can render difficult a standardization of treat-
ments. However, the pediatric nephrologist has in charge pre-
cious cases of children with IgAN of unknown destiny and has
to make the choice: not to treat, hoping in a self-limiting evo-
lution and avoiding the trouble of pills and controls and – most
of all – dangerous drug side effects, or be worried about a
potential progression. The pediatric nephrologist is tempted
to offer the most powerful treatment as early as possible to
Pediatr Nephrol (2021) 36:491–496
avoid an irreversible decline of GFR, but is it always correct?
The benefits of therapy in children with IgAN, particularly in
mildly proteinuric cases, take years to be appreciated, and
adverse events are uncommon but may be severe [9]. IgAN
is not a life-threatening condition, and one cannot disregard
the cost-benefit balance in individual cases.
Several reports have published results obtained by various
treatments in children with IgAN, mostly CS and IS [10–16].
It is not the aim of this review to list and re-discuss all of them,
which are easily found among the references. However, most
of the reports do not meet the criteria required for producing
KDIGO guidelines in children. This review is aimed at
discussing why the KDIGO guidelines are poorly suitable to
treat children with IgAN and the need to develop new predic-
tion models for progression of IgAN in children to guide se-
lection of the cases to be treated. The identification of different
risk levels at presentation in children with IgAN will support
the choice of available drugs and indicate new targeted thera-
pies [17, 18]. This review aims at offering material for indi-
vidual decision, more than direct suggestions for treatment of
pediatric IgAN, a land unfortunately without KDIGO
guidance.
KDIGO 2012 concluded that treatment indications for
adults and children may be the same since the risk factors
are the same. However, treatment can be shared as far as the
disease is similar. It is difficult to generalize the course of
IgAN in children even more than in adults; hence, it is hard
to propose fixed treatment schedules in pediatric IgAN. Each
risk factor which is solid and well established in adults is
fragile in children. This renders difficult a generalized sched-
ule to treat children with IgAN. The possibility of a personal-
ized treatment remains a tempting promise for the future when
new risk stratification models will be available [19].
Proteinuria at renal biopsy: Is proteinuria
enough to guide treatment in children
with IgAN?
The KDIGO guidelines consider proteinuria as the only risk
factor to target therapy in IgAN. Indeed in adults with chronic
slowly progressive IgAN, when proteinuria develops and in-
creases, the risk of progression greatly increases, and there is
the need for establishing a treatment [17, 20]. The value of
baseline proteinuria as predictor of progression of IgAN in
pediatric age has been challenged by some recent observa-
tions. In children with IgAN, the clinical data at renal biopsy,
as well as at the pathology features, change according to the
variable indications to perform renal biopsy in cases with
moderate urinary abnormalities or shortly after an acute epi-
sode of macroscopic hematuria with nephritic syndrome or
nephrotic range proteinuria. In Japan there is a large preva-
lence of children diagnosed after school screening programs
Pediatr Nephrol (2021) 36:491–496
[21], which is not the case in nearby China or in other conti-
nents. The heterogeneity of features of children with IgAN at
renal biopsy is often evident, even in the same geographical
area and in different periods of the reports [22, 23].
In Europe a rather unbiased observational approach is of-
fered by the cohort gathered by the international collaborative
study to validate the Oxford classification of IgAN VALIGA
[2, 24], which enrolled 174 children aged < 18 years from 13
European countries, followed for 4.6 (2.5–7.3) years. Renal
biopsy was performed in children with median proteinuria of
0.84 g/day/1.73 m2 (in 25% of the children, proteinuria was <
0.30 g/day/1.73 m2, and in only 1%, it was of nephrotic range)
and mostly with normal eGFR. RASBs were adopted in 67%
of the cases and CS/IS treatment in 50%. In this cohort, the
eGFR decline was in median absent, due to improvement in
half of the cases, and the combined outcome of 50% reduction
in eGFR or ESRD was attained in only 6.3% of the cases. This
suggests a possibility of regression, either spontaneous - in
mildly proteinuric cases or in children biopsied shortly after
gross hematuria - or induced by the CS-IS treatment given in
more than half of children. However, the VALIGA pediatric
cohort maintained signs of risk factor persistence over long
follow-up, since a stable remission on average proteinuria to
values < 0.5 g/day/1.73 m2 was reported in only 7.5% of the
cases who had initial proteinuria > 0.5 g/day/1.73 m 2 .
Children with IgAN from the VALIGA study did not show a
rapid decline in eGFR, but during the follow-up maintained a
median proteinuria of 0.56 (0.27–1.02) g/day/1.73 m2. Any
level of persistent proteinuria is a risk factor for progression in
patients with IgAN, indicating that in the long-term, progres-
sion toward ESRD is possible [20].
In children with IgAN enrolled in VALIGA, the multiple
linear regression analysis failed to prove the value of protein-
uria at renal biopsy as a risk factor for progression (as well as
median arterial blood pressure (MAP) and eGFR). The only
risk factors for progression were proteinuria and MAP over
the follow-up. Hence, in this large European cohort, protein-
uria at renal biopsy – which is the only risk factor considered
by KDIGO to select patients to be treated – was not predictive
of outcome. Spontaneous remissions, as well as a positive
effect of early CS/IS treatment, did not allow the detection
of proteinuria at renal biopsy as a risk for progression in chil-
dren. The only significant biomarker for chronic progression
was the persistence of proteinuria and increased MAP values
during the follow-up. Children maintaining proteinuria after
management of the acute and active phase of IgAN must be
targeted for chronic therapy.
In children with IgAN, proteinuria at renal biopsy per se
does not indicate the risk of progression. Also the finding of
reduced GFR at renal biopsy, which is a strong risk factor in
adults [17], is not predictive of outcome in children [16, 24].
Some data suggest the association with microscopic hematuria
increases the value of proteinuria in assessing the clinical
493
activity of patients with IgAN [25]. No literature data support
the use of this biomarker for a therapeutic choice, but it is
common opinion that it should enter the panel of data to define
children with persistent disease activity [26].
Renal biopsy features: Should MEST-C score
be considered to establish treatment
in children with IgAN?
The Oxford clinic pathologic classification and subsequent
studies detected the independent value as risk factors for pro-
gression of mesangial hypercellularity (M), endocapillary
hypercellularity (E), segmental glomerulosclerosis (S), tubular
atrophy/interstitial fibrosis (T), and crescents (C), forming the
MEST-C score [27, 28]. Its value was independent of protein-
uria, MAP, and eGFR at renal biopsy and during the follow-
up. Notably, this was unchanged across all age groups and
decades after the renal biopsy [27, 29]. However, the
KDIGO Controversies Conference in 2019 commented that
MEST-C score was developed to predict renal outcome and
not to guide treatment or to predict treatment response [6].
Although observational data in adults suggest that E1 [30,
31] and crescents [32–34] may predict outcomes differently
in treated versus untreated patients, and the benefits of steroids
may differ in patients with M1 [19, 35] or S1 [36], KDIGO
concluded that there is currently insufficient evidence to sug-
gest that immunosuppression decisions should be based on
histology parameters. New RCTs designed to enroll patients
with similar MEST-C scores have been launched in adults but
are still ongoing (e.g., Treatment of IgA Nephropathy
According to Renal Lesions (TIGER), ClinicalTrials.gov:
NCT03188887).
In pediatric IgAN the attempts to validate the value of
MEST-C scores have always faced the problem of too few
end points (50% decline in eGFR or ESRD) in cohorts with
only a few hundred cases, and median follow-up of 5–
10 years, which is insufficient to detect functional decline in
cases with early diagnosis, such as pediatric ones [24, 37–39].
As expected, T lesions are the strongest risk factor for progres-
sion in children as well as in adults, but the support given by
this score for selecting a correct treatment may be only caution
in aggressive therapy when fibrotic changes are too extensive.
Children with IgAN show less T chronic damage and more
active lesions (M1, E1, C1) than adults. The prevalence of the
MEST-C scores varies according to the renal biopsy policy. In
the multinational European VALIGA study, for the 174 chil-
dren < 18 years of age enrolled, the distribution of frequency
was M1, 22%; E1, 14%; S1, 43%; T1–2, 6%; and C1, 15%
[24]. In comparison to the adult VALIGA cohort, children
showed lower frequency of S1 and T1 lesions and higher
frequency of crescentic lesions. M1 was more frequent in
children < 12 years of age. A recent report from the Pediatric
494
Nephrology Centers in Paris [16] presented a different fre-
quency of MEST-C score distribution in 82 children (M1,
80%; E1, 71%; S1, 61%; C, 46%) with exceptional T1–2
(1%). History of gross hematuria was reported in one third
of the cases, 25% presented with acute kidney failure and
7% with nephrotic range proteinuria at the time of biopsy.
The high frequency of active and severe lesions was likely
due to the short time elapsed between clinical onset and renal
biopsy, in median less than 2 months. The prompt indication
to perform renal biopsy may favor the detection of acute or
active renal lesions. In a Japanese pediatric cohort, the prolon-
gation of waiting time before renal biopsy was associated with
reduction in M and E lesions, with increase in T damage [40].
Children with IgAN may have onset acute kidney injury
(AKI). In a Chinese cohort, AKI with hematuria and massive
proteinuria was detected in 9.7% of 196 children with IgAN:
C1 was found in 80%, E1 in 60%, and tubular damage with
erythrocyte casts in 70% [41].
The analysis of these data, which are so different at base-
line, produced different results for risk factors needing treat-
ment. In the multinational pediatric European cohort, no
MEST-C score was predictive of progression. The number
of combined events of ESRD and 50% loss of eGFR was so
limited (6.3%) and the eGFR decline so mild (median loss
0 ml/min/1.73 m2) as to render impossible the detection of
risk factors, either clinical or histological. The prediction val-
ue of M1, S1, and T1 was attained including in the observation
216 young subjects aged less than 23 years. Until this age, a
correlation between age at renal biopsy and log hazard of the
combined end point was found [24], which then reached a
plateau, suggesting some age-related protective effect, which
seemed to be lost after the age of 23 years. Also in the French
series of rather acute and active cases, the MEST-C scores
proved the predictive value of S1 only [16]. In the Chinese
[39] and Japanese [38] cohorts, only T lesions resulted as
significantly associated with outcome upon multivariate
analysis.
These data prove the limited predictive value of active le-
sions per se in children with IgAN, due to the limited number
of events, the slow median progression rate, and the regression
of clinical features in several cases, mostly associated with the
high use of CS/IS drugs.
Association of clinical and pathology features
to predict progression of IgAN
Individual risk stratification is the starting point for the choice
of treatment, and the lack of suitable risk factors for individual
clinical and pathology data at renal biopsy in children does not
fulfill the expectation of the pediatric nephrologists. Notably, a
significant predictive value on outcome was proved in each
large cohort of children with IgAN investigated by the
Pediatr Nephrol (2021) 36:491–496
association of clinical features (mostly proteinuria) with
MEST-C scores. In the VALIGA pediatric study, a survival
tree multivariate analysis found that M1 associated with pro-
teinuria > 0.4 g/day/1.73 m2 provided a stratification of chil-
dren at higher risk for progression [24]. Similarly, in the
Swedish [37], Japanese [38], and Chinese [39] cohorts, the
association of proteinuria at renal biopsy with MES and C
lesions provided at multivariate analysis the identification of
potentially progressive patients.
In adults, an IgAN risk prediction tool valid in a large
multiethnic cohort (3297 patients of Caucasian, Chinese,
and Japanese ethnicity) was recently developed by the
International IgA Nephropathy Network [42], which al-
lows a risk calculation for individual adult patients, based
on clinical data and MEST score. The prediction model
was assessed in a derivation cohort of 2781 cases and
validated in a cohort of 1146 cases. The two cohorts had
a similar risk of reaching a composite end point of ESRD
or 50% decline in eGFR (14% and 13% at 5 years from
renal biopsy, respectively). Two full models (including
age; proteinuria; MAP; eGFR; MEST; prior use of
RASB or CS/IS drugs; Caucasian, Chinese, or Japanese
race; or the same parameters without race) better predicted
the composite end point compared to a model with clini-
cal data only (proteinuria, MAP, eGFR). A mobile app
calculator was developed by QxMD and a web-based cal-
culator is available at http://qxmd.com/calculate-by-qxmd.
Using this calculator for adult patients, a time for
prediction can be selected (up to 7 years after renal
biopsy, usually 5 years). Then data are entered,
including age, race, blood pressure, eGFR, proteinuria at
biopsy, MEST score, and use of RASB and CS/IS before
biopsy. The calculator provides the percentage of risk of
attaining the composite end point at the follow-up time
previously selected. Notably, there is a strict correlation
between the percentage of patients reaching the composite
end point at 5 years and the eGFR yearly decline. Patients
may be stratified according to the mean percentage of
subjects reaching the composite end point into low, inter-
mediate, high, and highest risk (respective risks: 1.5%, 4.
7%, 13.9%, 46.5%) and corresponding eGFR loss (− 1.24,
− 1.76, − 2.35, − 3.45 ml/min/1.73 m 2 /year). The
International IgAN network collaboration has gathered
data from 1050 children of various ethnicities, including
Caucasians, Chinese, and Japanese, among others, and the
validation of this predictive tool for risk stratification in
children is in progress.
This prediction tool is designed to assess the risk at renal
biopsy and not the response to CS/IS drugs. As an example,
patients with T2 lesions will be stratified as at high risk, but no
indication will be provided on the response to treatments.
Accurate risk stratification using this prediction tool (for chil-
dren the ongoing pediatric version) will be very useful for
Pediatr Nephrol (2021) 36:491–496
future RCTs selecting patients with similar risk for
progression.
Risk stratification will allow a personalized approach to
treatment of children with IgAN, who present with a scenario
much more complex than that defined by KDIGO in adults.
Treatment choice should consider the moment of the natural
history of the disease, the previous personal history, and the
rapidity of progression, while evaluating clinical and patholo-
gy features together. The prediction model is a step forward to
precision medicine in the treatment of IgAN, and the pediatric
community is looking forward to its development in children,
with the hope that IgAN in children will no longer be a land
without KDIGO guidelines.
Compliance with ethical standards
Conflict of interest No conflict of interest to declare.
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