Original Investigation

Effects of Hydroxychloroquine on Proteinuria in IgA

Nephropathy: A Randomized Controlled Trial
Li-Jun Liu, Ya-zi Yang, Su-Fang Shi, Yun-Fei Bao, Chao Yang, Sai-Nan Zhu, Gui-Li Sui, Yu-Qing Chen,
Ji-Cheng Lv, and Hong Zhang

Rationale & Objective: Despite optimization of
renin-angiotensin-aldosterone system (RAAS)
inhibition, patients with immunoglobulin A
nephropathy (IgAN) and persistent proteinuria
remain at risk for kidney failure. We evaluated
the efficacy and safety of hydroxychloroquine
(HCQ), an immunomodulator, when added to
the treatment regimen of patients with IgAN.
Study Design: Double-blind, randomized,
placebo-controlled, phase 2 clinical trial.
Setting & Participants: Participants had
IgAN (proteinuria with protein excretion of
0.75-3.5 g/d and estimated glomerular filtration
rate > 30 mL/min/1.73 m2) and were receiving
optimized RAAS inhibitor therapy.
(n = 30) or placebo (n = 30). Percentage change Complete author and article
in proteinuria at 6 months was significantly information provided before
references.
different between the HCQ group and the pla-
cebo group (−48.4% [IQR, −64.2%, −30.5%] vs Correspondence to L.-J. Liu
10.0% [IQR, −38.7%, 30.6%]; P < 0.001, (lijun.liu@aliyun.com)
respectively). At 6 months, median proteinuria Am J Kidney Dis. XX(XX):
level was significantly lower in the HCQ group 1-8. Published online Month
than in the placebo group (0.9 [IQR, 0.6, 1.0] g/ X, XXXX.
d vs 1.9 [IQR, 0.9, 2.6] g/d; P = 0.002, respec- doi: 10.1053/
tively). No serious adverse events were recorded j.ajkd.2019.01.026
during the study in either study group. © 2019 by the National
Kidney Foundation, Inc.
Limitations: The short treatment period and lack
of postwithdrawal observations limit conclusions
about long-term renoprotective efficacy and
safety.

Interventions: Patients were randomly assigned Conclusions: HCQ in addition to optimized

1:1 to receive daily oral HCQ or a placebo for 6
months.
Outcomes: The primary outcome was percent-
age change in proteinuria between baseline and
6 months.
Results: 60 participants (mean estimated
glomerular filtration rate, 53.8 mL/min/1.73 m2;
median urine protein excretion, 1.7 g/d) were
recruited and randomly assigned to receive HCQ
RAAS inhibition significantly reduced proteinuria
in patients with IgAN over 6 months without evi-
dence of adverse events. These findings require
confirmation in larger treatment trials.
Funding: This study was supported by grants
from a government entity, the Capital of Clinical
Characteristics, and the Applied Research Fund.
Trial Registration: Registered at ClinicalTrials.
gov with study number NCT02942381.

I mmunoglobulin A (IgA) nephropathy (IgAN) is the most

prevalent form of primary glomerular disease world-
wide.1 Patients with IgAN usually develop chronic slowly
progressive kidney injury; however, up to 30% will
eventually progress to end-stage kidney failure.2 Protein-
uria is one of the strongest risk factors correlated with
kidney function decline.3 Corticosteroids are suggested for
patients with IgAN and persistent proteinuria despite
optimized renin-angiotensin-aldosterone system (RAAS)
inhibitor therapy.4 However, the efficacy of corticosteroids
is controversial, while the adverse side effects are well
documented.5,6 Identification of new therapies for this
common cause of kidney disease is a priority. To date,
there is limited evidence for the use of rituximab and
eculizumab in IgAN.7,8 Recent data for the use of targeted-
release budesonide have raised the possibility that
mucosal-associated lymphoid tissue might be a potential
therapeutic target in IgAN.9
Hydroxychloroquine (HCQ), a well-known immuno-
modulator, has been little studied in IgAN. A non-
randomized controlled trial found that HCQ treatment in
addition to losartan improved proteinuria remission
probability compared to losartan alone, although there was
no statistically significant difference in proteinuria levels
between the 2 groups at 6 months.10 Previously, we re-
ported that the combination of HCQ and routine RAAS
inhibitor treatment effectively decreased urinary protein
excretion in patients with IgAN compared to RAAS in-
hibitor therapy alone over 6 months in a retrospective,
propensity score–matched cohort study.11 However, these
studies were limited by being nonrandomized or
retrospective.
The present study was designed to provide an estimate
of the efficacy and safety assessment of HCQ in IgAN and
help in the determination of whether a larger multicenter
trial with clinical outcomes is warranted.
Methods
Study Design and Patients
This study was a double-blind randomized clinical trial
comparing oral HCQ to placebo in patients with IgAN
receiving maximal supportive treatment, including
RAAS inhibitor therapy and blood pressure control

AJKD Vol XX | Iss XX | Month 2019 1


according to the KDIGO (Kidney Disease: Improving
Global Outcomes) glomerulonephritis guideline.4 The
study was conducted at Peking University First Hospital.
The main study inclusion criteria were age 18 to 75
years, a diagnosis of biopsy-proven primary IgAN,
estimated glomerular filtration rate (eGFR) > 30 mL/
min/1.73 m2 (calculated using the Chronic Kidney
Disease Epidemiology Collaboration [CKD-EPI] creati-
nine equation12), and proteinuria with protein excre-
tion of 0.75 to 3.5 g/d despite receiving a maximum
tolerable dose of RAAS inhibitor for at least 3 months.
Principal exclusion criteria were the use of systemic
immunosuppressive therapy in the previous year, an
indication for corticosteroids (crescentic IgAN or min-
imal change disease with IgA deposits), current or
planned pregnancy or lactation, and contraindications
for HCQ therapy.
The protocol was approved by an independent ethics
committee at the Peking University First Hospital (no.
2016[1057]). The study was conducted in accordance
with the principles contained in the Declaration of Hel-
sinki. All participants provided written informed consent
before enrolling in the study. The full inclusion and
exclusion criteria are detailed in Table S1. This trial is
registered with ClinicalTrials.gov (number
NCT02942381).
Randomization and Masking
Patients were randomly assigned 1:1 to receive oral HCQ
(hydroxychloroquine sulfate tablets; Fenle, provided by
Shanghai SPH Zhongxi Pharmaceutical Co, Ltd.) or a
matching placebo using a blocked randomization scheme
with 2 HCQ treatments and 2 control allocations per every
block, which aimed to balance the number of participants
between the HCQ treatment and control groups.
HCQ and matched placebo were uniformly packaged
and numbered by an independent company according to
the random numbers generated by an independent statis-
tician. Study medication was dispensed and provided to
trial participants face to face individually by trained blin-
ded study staff. The numbers of distributed and recovered
study medication were recorded to calculate medication
adherence. Taking 80% to 120% of the prescribed treat-
ment dose was considered good adherence. Patients, in-
vestigators, site staff, and the sponsor were blinded to
treatment assignment for the duration of the study.
Treatment and Follow-up
Patients received their assigned treatment for 6 months.
The treatment dose was 0.2 g orally (2 tablets) twice daily
for patients with eGFRs > 60 mL/min/1.73 m2, 0.1 g
orally (1 tablet) 3 times daily for patients with eGFRs
between 45 and 59 mL/min/1.73 m2, and 0.1 g orally (1
tablet) twice daily for patients with eGFRs between 30 and
44 mL/min/1.73 m2. The investigational medication or
the placebo dose was decreased by 0.1 g (1 tablet) per day
2 AJKD Vol XX | Iss XX | Month 2019
Original Investigation
for patients with eGFR reduction by >25% or to <30 mL/
min/1.73 m2. Treatment was discontinued in participants
with a >30% decline in eGFR. Patients were continuously
receiving a maximum or tolerable dose of RAAS inhibitor
and no new treatments were added during the study.
Patients were assessed at baseline and every 2 months
during the study. Assessments included blood pressure,
adverse event reporting, routine hematology, routine uri-
nalysis, serum chemistry, 24-hour urine protein excretion,
and first-morning urine albumin-creatinine ratio (UACR).
eGFR was calculated using the CKD-EPI equation using
serum creatinine level. Fundus examinations were per-
formed at baseline and at the last visit.
Outcomes
The prespecified primary outcome was percentage change
in proteinuria from baseline to 6 months. Prespecified
secondary outcomes included percentage change in pro-
teinuria from baseline to 2 and 4 months, frequency of
patients with a 50% decrease in proteinuria, and percent-
age change in eGFR. Exploratory secondary outcomes
included percentage change in UACR, the disappearance of
hematuria, and blood pressure at each visit.
Adverse Events and Safety
Predefined safety outcomes were total serious adverse
events (SAEs), ophthalmologic events, serious allergies,
gastrointestinal symptoms, dermatologic changes, neuro-
muscular symptoms, cardiovascular or respiratory disor-
ders, leukopenia, agranulocytosis, or aplastic anemia
requiring hospitalization. SAEs were defined according to
the International Conference on Harmonization Guideline
for Clinical Safety Data Management.
Statistical Analysis
Based on data from our previous study11 and assuming that
proteinuria level did not change in the placebo group, if
mean baseline proteinuria had protein excretion of
2.0 ± 0.8 g/d, a sample of 28 participants per arm would
provide 80% power of detecting a 30% reduction in
proteinuria (protein excretion, 0.6 g/d) with HCQ treat-
ment, with a type I error rate of 0.05. Assuming 10%
dropout, we planned to recruit 60 participants (30 per
group) to the study.
All analyses were conducted according to the intention-
to-treat principle. Normally distributed data are presented
as mean ± standard deviation, and non-normally distrib-
uted data are presented as median with interquartile range
(IQR). Categorical data are summarized as count and
percentage. Variables of the 2 groups were compared us-
ing independent-samples t tests (for normally distributed
continuous variables), Wilcoxon rank sum tests (for
non-normally distributed continuous variables), or χ 2 tests
(for nominal variables) as appropriate. Missing primary
outcome data were filled by carrying the last observation
forward. The frequency of patients with a 50% decrease in
Original Investigation

proteinuria at each time point was evaluated using a simple
proportion calculation.
Predefined subgroups were used for the primary
outcome in stratified analyses, including proteinuria
(protein excretion < 2 vs ≥2 g/d) and eGFR (<45
vs ≥45 mL/min/1.73 m2). P < 0.05 was considered
statistically significant. Statistical analyses were per-
formed using SAS, version 9.4 (SAS Institute Inc).
Results
Baseline Characteristics
From September 2016 to July 2017, a total of 100
potentially eligible patients were screened, of whom 60
(60.0%) were eligible for the study and underwent
random assignment (30 to the HCQ group and 30 to the
placebo group; Fig 1). Four patients in the HCQ group
and 2 in the placebo group discontinued the interven-
tion (Fig 1). The investigational medication dose was
decreased in 3 patients in the HCQ group for a slightly
decreased eGFR (n = 1) or adverse events (n = 2)
including occasional dizziness and pruritus and 1 patient
in the placebo group for a slightly decreased eGFR. The
2 randomized groups had similar characteristics at
baseline (Table 1). For the entire cohort, baseline
characteristics were as follows: proteinuria, protein
excretion of 1.7 (IQR, 1.2, 2.5) g/d; UACR, 920.1
(IQR, 678.0, 1,491.8) mg/g; and eGFR,
53.8 ± 19.1 mL/min/1.73 m2.
Primary End Point
In the primary outcome analysis, percentage change in
proteinuria from baseline to 6 months was higher in the
HCQ group than in the placebo group (−48.4% [IQR,
−64.2%, −30.5%] vs 10.0% [IQR, −38.7%, 30.6%];
P < 0.001). At 6 months, median proteinuria level in the
HCQ group was significantly lower than that in the pla-
cebo group (protein excretion, 0.9 [IQR, 0.6, 1.0] g/d vs
1.9 [0.9, 2.6] g/d; P = 0.002). A prespecified subgroup
analysis defined by baseline proteinuria (protein excre-
tion < 2 vs ≥2 g/d) and eGFR (<45 vs ≥45 mL/min/
1.73 m2) did not show significant differences in the effects
of HCQ between the different subgroups (Table S2). We
do not detect interactions between HCQ treatment and
baseline proteinuria or eGFR subgroups in prediction of

Enrollment Assessed for eligibility (n=100)

Excluded (n=40)
d participant decision (n=19)
d proteinuria<0.75g/d (n=15)
d received corticosteroids (n=1)
d unlikely to comply with the study protocol (n=3)
d fundus anomaly (n=1)
d IgA vasculitis nephritis (n=1)
d proteinuria<0.75g/d (n=15)

Randomized (n=60)

Allocation
Allocated to HCQ (n=30) Allocated to placebo (n=30)
d Received allocated intervention (n=30) d Received allocated intervention (n=30)

Follow-Up
Discontinued intervention (n=4)
- allergy (rashes) (n=1)
Discontinued intervention (n=2)
- pregnancy during study (n=1)
- patient decision (n=2)
- eGFR reduction (n=1)
Received corticosteroids (n=1)
- patient decision (n=1)
Exceeded follow-up time window (n=1)
Stopped taking RAASi (n=1)
Poor medication adherence (not within 80%-120%) (n=4)
Did not tolerate RAASi (n=1)
Poor medication adherence (not within 80%-120%) (n=2)

Analysis
Analyzed (n=30) Analyzed (n=30)

Figure 1. Flow chart of the trial. Abbreviations: eGFR, estimated glomerular filtration rate; HCQ, hydroxychloroquine; IgA, immuno-
globulin A, RAASi, renin-angiotensin-aldosterone system inhibitor.

AJKD Vol XX | Iss XX | Month 2019 3

 Original Investigation

Table 1. Baseline Characteristics of the HCQ Group and Placebo Group

HCQ Group Placebo Group Total
(n = 30) (n = 30) (N = 60) P
Age, y 37.6 ± 11.6 35.6 ± 9.6 36.6 ± 10.6 0.5
Male sex 19 (63%) 20 (67%) 39 (65%) 0.8
Period from biopsy to randomization, mo 18.1 [8.6, 69.1] 41.6 [12.7, 77.0] 30.5 [9.6, 77.0] 0.4
Systolic BP, mm Hg 123.9 ± 10.2 121.9 ± 10.7 122.9 ± 10.4 0.5
Diastolic BP, mm Hg 79.4 ± 6.7 77.2 ± 7.5 78.3 ± 7.1 0.2
Scr, μmol/L 127.9 ± 41.9 120.2 ± 32.8 124.0 ± 37.5 0.6
Baseline eGFR, mL/min/1.73 m2 52.1 ± 19.7 55.5 ± 18.7 53.8 ± 19.1 0.5
Serum albumin, g/L 41.6 ± 2.9 41.6 ± 3.8 41.6 ± 3.4 0.9
Baseline proteinuria, g/d 1.6 [1.1, 2.2] 1.9 [1.3, 2.6] 1.7 [1.2, 2.5] 0.4
UACR, mg/g 888.8 [717.2, 1,464.5] 962.8 [629.7, 1,564.0] 920.1 [678.0, 1,491.8] 0.9
Hematuria 27 (90.0%) 24 (80.0%) 51 (85.0%) 0.5
Oxford histologic score36
M 0.6
0a 9 (35%) 12 (43%) 21 (39%)
1a 17 (65%) 16 (57%) 33 (61%)
E 0.5
0 16 (62%) 20 (71%) 36 (67%)
1 10 (39%) 8 (29%) 18 (33%)
S 0.01
0 3 (12%) 12 (43%) 15 (28%)
1 23 (89%) 16 (57%) 39 (72%)
T 0.6
0 13 (50%) 14 (50%) 27 (50%)
1 8 (31%) 13 (46%) 21 (39%)
2 5 (19%) 1 (4%) 6 (11%)
C 0.4
0 8 (31%) 7 (25%) 15 (28%)
1 14 (54%) 14 (50%) 28 (52%)
2 4 (15%) 7 (25%) 11 (20%)
Therapy with RAASib 29 (97%) 30 (100%) 59 (98%) 0.9
ACEi without ARB 7 (24.1%) 8 (26.7%) 15 (25.4%)
ARB without ACEi 19 (66%) 18 (60%) 37 (63%)
ACEi plus ARB 3 (10%) 4 (13%) 7 (12%)
Therapy with RAASi 0.7
No. treated 13 12 25
% of maximum labeled dose 43% 40% 42%
Therapy with spironolactone 3 (10%) 1 (3%) 4 (7%) 0.6
Previous corticosteroid/immunosuppressive 4 (13%) 6 (20%) 10 (17%) 0.5
therapy
Note: Continuous data are shown as mean ± standard deviation or median [interquartile range].
Abbreviations: ACEi, angiotensin-converting enzyme inhibitor; ARB, angiotensin II receptor blocker; BP, blood pressure; C, crescents (C0: absent; C1, 0%-25% of
glomeruli; C2, ≥25% of glomeruli); E, endocapillary hypercellularity (E0, no endocapillary hypercellularity; E1, any glomeruli show endocapillary hypercellularity); eGFR,
estimated glomerular filtration rate; HCQ, hydroxychloroquine; M, mesangial hypercellularity (M0, <50% of glomeruli show mesangial hypercellularity; M1, >50% of
glomeruli show mesangial hypercellularity); RAASi, renin-angiotensin-aldosterone system inhibitor; S, segmental glomerulosclerosis (S0, absent; S1, present in any
glomeruli); Scr, serum creatinine; T, tubular atrophy/interstitial fibrosis (T0, 0%-25% of cortical area; T1, 26%-50% of cortical area; T2, >50% of cortical area); UACR, urine
albumin-creatinine ratio.
a
Six histologic scores unavailable because 4 patients underwent kidney biopsy in other clinics, and glomeruli were fewer than 8 on the kidney specimen of the other 2
patients.
b
One patient in the HCQ group did not tolerate RAASi.

the primary outcome (P for interaction = 0.7 and 0.9,
respectively).
Secondary End Points
In the secondary outcome analysis, percentage changes in
proteinuria decrease from baseline to 2 and 4 months were
higher in the HCQ group than in the placebo group (at 2
months: −28.4% [IQR, −46.4%, −11.4%] vs −1.4% [IQR,
−29.2%, 31.9%]; P = 0.003; at 4 months: −38.0% [IQR,
−58.4%, −26.5%] vs −3.5% [IQR, −30.6%, 29.2%];
P < 0.001). Effects on primary and secondary outcomes are
listed in Table 2. Of 26 patients who completed the month
6 visit, 13 (50%) patients in the HCQ group showed a
50% decrease in proteinuria at 6 months compared with 4

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Original Investigation

Table 2. Effects of HCQ on Primary and Secondary Outcomes

Outcome HCQ Group Placebo Group P
Protocol-specified primary outcomea
Change in proteinuria at 6 mo −48.4% [−64.2%, −30.5%] 10.0% [−38.7%, 30.6%] <0.001
Proteinuria at 6 mo, g/d 0.9 [0.6, 1.0] 1.9 [0.9, 2.6] 0.002
Protocol-specified secondary outcomes
Change in proteinuria at 2 mo −28.4% [−46.4%, −11.4%] −1.4% [−29.2%, 31.9%] 0.003
Proteinuria at 2 mo, g/d 1.2 [0.8, 1.7] 1.9 [1.5, 2.5] 0.001
Change in proteinuria at 4 mo −38.0% [−58.4%, −26.5%] −3.5% [−30.6%, 29.2%] <0.001
Proteinuria at 4 mo, g/d 1.0 [0.7, 1.4] 2.0 [1.1, 2.5] <0.001
Frequency of patients with 50% decrease in
proteinuria
2 mo timepoint 5 (18%) 1 (3%) 0.1
4 mo timepoint 12 (43%)b 3 (10%)c,d 0.005
6 mo timepoint 13 (50%)d 4 (15%)e 0.006
Change in eGFR
2 mo timepoint −1.5% [−12.3%, 3.4%] 1.5% [−4.4%, 11.4%] 0.1
4 mo timepoint −3.2% [−11.6%, 10.9%] 2.5% [−7.0%, 9.4%] 0.3
6 mo timepoint 4.5% [−12.3%, 23.1%] 0.0% [−12.6%, 19.3%] 0.9
Exploratory secondary outcomes
Change in UACR
2 mo timepoint −20.0% [−42.4%, 4.3%] −9.3% [−25.9%, 24.9%] 0.07
4 mo timepoint −36.3% [−56.9%, −12.0%] −3.1% [−26.8%, 19.1%] 0.007
6 mo timepoint −50.3% [−61.9%, −28.6%] 1.9% [−30.4%, 46.2%] <0.001
Frequency of hematuria disappearancef
2 mo timepoint 4 (16%) 3 (14%) 0.9
4 mo timepoint 3 (12%) 5 (22%) 0.4
6 mo timepoint 6 (26%) 1 (5%) 0.1
Note: Continuous data given as median [interquartile range].
Abbreviations: eGFR, estimated glomerular filtration rate; HCQ, hydroxychloroquine; UACR, urine albumin-creatinine ratio.
a
Four proteinuria values in the HCQ group and 3 proteinuria values at 6 months were missing. Missing primary outcome data were filled by carrying the last observation
forward.
b
One patient who had achieved a 50% reduction in proteinuria at 2 months was no longer present at 4 months for the HCQ group.
c
One patient who had achieved a 50% reduction in proteinuria at 2 months was no longer present at 4 months for the placebo group.
d
Five patients who had achieved a 50% reduction in proteinuria at 2 or 4 months were no longer present at 6 months for the HCQ group.
e
Two patients who had achieved a 50% reduction in proteinuria at 2 or 4 months were no longer present at 6 months for the placebo group.
f
Comparison of frequency of hematuria disappearance using χ2 tests.

of 27 (14.8%) patients in the placebo group (P = 0.006; study drug withdrawal. One patient showed occasional
Fig 2). Percentage change in UACR showed a similar trend dizziness and 1 reported pruritus; in both instances,
to that of proteinuria in the 2 groups. No statistically the problems resolved following dose reduction.
significant differences were observed in percentage change One patient developed skin pigmentation, transient
in eGFR or frequency of hematuria disappearance between
the 2 groups. Individual proteinuria and eGFRs during
follow-up are shown in Figures S1 and S2.
Blood pressure was stable and well controlled, and there
were no statistically significant differences in blood pres-
sure between the HCQ group and the placebo group
during the study (Table S3).

Safety and Adverse Events

There were no SAEs in the 2 groups during the study.
Adverse events in both groups are listed in Table 3.
Seven patients experienced adverse events in the HCQ
group. One patient presented with an eGFR reduction of
29.0% from baseline at 4 months and dropped out of the
study, and 1 patient presented with a 33.4% reduction
in eGFR at 6 months. One patient was allergic to HCQ Figure 2. Percent with >50% reduction in 24-hour urine protein
(rash on neck and limbs), which resulted in early excretion during follow-up in the hydroxychloroquine (HCQ)
withdrawal from the study; the symptoms resolved after group and the placebo group. *P < 0.05.

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 Original Investigation

Table 3. SAEs and Adverse Events in the HCQ Group and frequency of repeat kidney biopsy,15 and contribute to
Placebo Group sustained renal remission in lupus nephritis.16 HCQ is
HCQ Group Placebo Group believed to have pleiotropic immunomodulatory ac-
(n = 30) (n = 30) tions, including inhibiting the activation of inflamma-
SAEs 0 0 tory cells, suppressing autoantigen presentation, and
Adverse events inhibiting Toll-like receptors and the production of
No. of events cytokines or chemokines.17-24
0 23a 28 IgAN is believed to arise as a consequence of multiple
1 6 2 pathogenic hits, which include a significant contribution from
≥2 1 0 mucosal-associated lymphoid tissue.25 It is hypothesized that
Event details antigens at mucosal surfaces activate both monocytes and
eGFR reduction 2 0 lymphocytes through ligation of Toll-like receptors. This in
Abdominal pain 0 1 turn results in B-cell proliferation, IgA class switching, and an
Nauseab 1 0 abnormal IgA response characterized by the synthesis and
Palpitationsb 1 0 release into the circulation of galactose-deficient IgA1.26,27 The
Eye swelling pain 0 1 synthesis and binding of autoantibodies to galactose-deficient
Dizziness 1 0 IgA1 leads to the formation of pathogenic IgA1-containing
Pruritus 1 0 immune complexes, which deposit in the glomerulus and
Skin pigmentationb 1 0 result in mesangial cell and complement activation resulting in
Allergy (rashes on neck 1 0 kidney injury.28 We speculate that the proteinuria reduction
and limbs)
Pregnancy 1 0
seen with HCQ may be a direct response to HCQ-mediated
Note: Data are shown as counts. P = 0.2 for comparison of proportion of patients
inhibition of mucosal and intrarenal Toll-like receptor
with at least 1 event using Fisher exact test. signaling, resulting in alleviation of intrarenal inflammation
Abbreviations: eGFR, estimated glomerular filtration rate; HCQ, hydroxy- and reduction in galactose-deficient IgA1 synthesis.
chloroquine; SAE, serious adverse event.
a
The numbers in the table represent number of patients at risk. Antimalarial drugs can also stimulate nitric oxide
b
These adverse events occurred in the same patient. synthesis in endothelial cells through impairment of
iron metabolism, and it has been reported that some of
palpitations, and nausea, which resolved spontaneously. the protective effect of HCQ may be due to enhanced
One patient was pregnant during treatment and left the vasodilatation, protecting against ischemic-reperfusion
study. injury in mice and improvement in blood pressure
control.29-31 In this study we observed no differences in
blood pressure between the 2 groups or after
Discussion commencement of HCQ treatment. This may have been
In this study, we examined the antiproteinuric effect of a the result of all patients being already on maximal
6-month regimen of HCQ compared to placebo in patients tolerated doses of RAAS inhibitors. Whether HCQ in-
with IgAN who were receiving optimized RAAS inhibitor fluences the glomerular microcirculation in IgAN re-
therapy. We found that HCQ effectively reduced protein- quires further investigation.
uria and increased the frequency of a 50% reduction in Proteinuria is the strongest prognostic factor in IgAN, for
proteinuria in patients with IgAN who were on a maximal which the effect is dose dependent and independent of other
tolerated dose of an RAAS inhibitor. There was no signif- risk factors.4 Patients with IgAN with proteinuria with pro-
icant change in eGFR between the HCQ and placebo tein excretion > 1 g/d and possibly 0.5 to 1 g/d are
groups. The drug was well tolerated, and no SAEs were considered to be at a higher risk for kidney function
recorded. decline.32,33 Decreasing proteinuria is an important treatment
Consistent with these findings, a recently published target in IgAN, and early decline in proteinuria is associated
nonrandomized controlled trial10 and a retrospective with lower risk for long-term renal outcomes (hazard ratio
cohort study11 of HCQ in IgAN reported a similar bene- per 50% reduction in proteinuria, 0.40 [95% confidence
ficial antiproteinuric effect of HCQ in IgAN. HCQ interval, 0.32-0.48]; P < 0.001).34
increased the frequency of remission of proteinuria and It is perhaps not surprising that we did not observe dif-
decreased urinary protein excretion compared to RAAS ferences in percentage change in eGFR between the HCQ and
inhibitor therapy alone.10,11 Our data, together with these placebo groups. Follow-up was limited to 6 months and
earlier studies, support the efficacy and safety of HCQ in because IgAN is typically a slowly progressive disease, it is
patients with IgAN. likely that differences in eGFRs would only become apparent
HCQ is widely used in diseases associated with with more extensive follow-up.
immunologic disorders, including systemic lupus ery- However, using the data included in Inker et al,34 we
thematosus, rheumatoid arthritis, and Sj€ ogren syn- have estimated that a 6-month reduction in proteinuria
drome. HCQ has been shown to improve proteinuria of 48% equates to an 80% (IQR, 50%, 90%) reduction
remission rates,13 decrease the risk for CKD,14 lower the in risk for doubling of serum creatinine level, end-stage

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Original Investigation
kidney disease, or death at 2 to 3 years in this popula-
tion. However, in the Inker et al34 analysis, the evidence
for a reduction in proteinuria as a valid surrogate
outcome in IgAN was strongest for RAAS inhibitor and
steroid interventions and less convincing for other in-
terventions. A longer term study or poststudy follow-up
to evaluate the impact of HCQ treatment on change in
eGFR is necessary.
Corticosteroids are suggested in patients with proteinuria
with protein excretion > 1 g/d despite sufficient RAAS inhi-
bition and blood pressure control.4 Although improvement in
kidney function was found to be remarkable in patients using
oral steroids in the Therapeutic Evaluation of Steroids in IgA
Nephropathy Global (TESTING) Study, the severe adverse
events, especially infection, contributed to a less optimistic
treatment risk-benefit ratio.
In our study, HCQ was well tolerated, and no SAEs
were recorded. Seven (23.3%) participants experienced
adverse events, and 3 (10%) quit the study due to eGFR
reduction, allergy, or pregnancy. However, the study
was still too small to allow for a definitive assessment of
harms of the treatment. HCQ does not suppress the
normal immunologic response against infection. HCQ
has been shown to slightly elevate intracellular pH,
which can selectively decrease the loading of auto-
antigen self-peptides but leave the response to exoge-
nous peptides intact.35 On this basis, HCQ might serve
as an alternative treatment strategy for patients with
contraindications to steroids.
This is a single-center trial with a small sample size in an
ethnically homogeneous group of Chinese patients. The
study lacks generalizability and only included patients with
relatively preserved eGFRs. It should be noted that there
are some differences in baseline characteristics, such as
shorter time from biopsy and higher M1 and E1 percent-
age in the HCQ group than the placebo group, which did
not reach statistical difference but might introduce bias
into the result. The major limitation of this study was the
short treatment period and lack of postwithdrawal obser-
vation phase. The trial was stopped and unblinded after
finishing, and patients were not followed up according to
predefined protocol. Patients were treated depending on
their proteinuria by their physicians. Therefore, it is
difficult to draw conclusions about the long-term reno-
protective efficacy and safety of HCQ.
Because this is an early-phase trial, it should not be
viewed as providing a definitive answer to the question
about the intervention. We view this study as a proof-of-
concept study providing the justification to embark on a
larger, longer duration, multicenter, multiethnic, clinical
trial. We firmly believe that further study of HCQ and its
underlying mechanism in IgAN is warranted.
In conclusion, HCQ treatment in addition to optimized
RAAS inhibitor therapy significantly and safely reduced pro-
teinuria in patients with IgAN. HCQ may in the future be an
additional therapeutic option for the treatment of IgAN.
AJKD Vol XX | Iss XX | Month 2019
Supplementary Material
Supplementary File (PDF)
Figure S1: Individual proteinuria measurements during follow-up.
Figure S2: Individual eGFRs during follow-up.
Table S1: Full inclusion and exclusion criteria.
Table S2: Prespecified subgroup analysis of the primary outcome
according to baseline characteristics.
Table S3: Blood pressure during follow-up.
Article Information
Authors’ Full Names and Academic Degrees: Li-Jun Liu, MD, Ya-zi
Yang, MD, Su-Fang Shi, MD, Yun-Fei Bao, MS, Chao Yang, MS, Sai-
Nan Zhu, MD, Gui-Li Sui, BS, Yu-Qing Chen, MD, Ji-Cheng Lv, MD,
and Hong Zhang, MD, PhD.
Authors’ Affiliations: Renal Division, Peking University First
Hospital, Institute of Nephrology, Peking University, Key Laboratory
of Renal Disease, Ministry of Health of China (L-JL, Y-zY, S-FS, Y-
FB, CY, G-LS, Y-QC, J-CL, HZ); and Statistics Division, Peking
University First Hospital, Beijing, PR China (S-NZ).
Address for Correspondence: Li-Jun Liu, MD, Renal Division,
Peking University First Hospital, Peking University Institute of
Nephrology, Key Laboratory of Renal Disease, Ministry of Health of
China, Beijing 100034, PR China. E-mail: lijun.liu@aliyun.com
Authors’ Contributions: Research idea, study design, participants’
enrollment: L-JL; participant follow-up: L-JL, S-FS, J-CL, HZ;
database management: G-LS; ethics and regulatory document
preparation: Y-FB; data analysis/interpretation and statistical
analysis: CY, S-NZ; supervision and mentorship: Y-ZY, S-FS, Y-
QC, J-CL, L-JL, HZ. Each author contributed important intellectual
content during manuscript drafting or revision and accepts
accountability for the overall work by ensuring that questions
pertaining to the accuracy or integrity of any portion of the work
are appropriately investigated and resolved.
Support: This study was supported by grants from the Capital of
Clinical Characteristics and the Applied Research Fund
(Z171100001017124 and Z161100000516005). Study drug was
provided by Shanghai SPH Zhongxi Pharmaceutical Co, Ltd. The
funders had no role in the study design; collection, analysis, and
interpretation of data; writing the report; or the decision to submit
the report for publication.
Financial Disclosure: The authors declare that they have no
relevant financial interests.
Acknowledgements: We thank all the patients who participated in
this trial; and Jin-Wei Wang, PhD, for help with randomization and
masking.
Data Sharing Statement: The individual participant data that
underlie the results reported in this article (including data
dictionaries), after deidentification (text, tables, figures, and
appendixes), and the study protocol will be available beginning 3
months and ending 36 months following article publication. The
data will be shared with investigators whose proposed use of the
data has been approved by an independent review committee
identified for this purpose to achieve aims in the approved
proposal. Proposals may be submitted up to 36 months following
article publication. After 36 months, the data will be available in
our university’s data warehouse but without investigator support
other than deposited metadata.
Peer Review: Received July 18, 2018. Evaluated by 2 external peer
reviewers, with direct editorial input from a Statistics/Methods
Editor, an Associate Editor, and the Editor-in-Chief. Accepted in
revised form January 20, 2019.
7

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