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CJASN ePress. Published on February 9, 2017 as doi: 10.2215/CJN.

07420716

IgA Nephropathy
Jennifer C. Rodrigues,* Mark Haas,† and Heather N. Reich*‡

Abstract
IgA nephropathy (IgAN) is a leading cause of CKD and renal failure. Recent international collaborative efforts
have led to important discoveries that have improved our understanding of some of the key steps involved
in the immunopathogenesis of IgAN. Furthermore, establishment of multicenter networks has contributed
*Department of
to rigorous design and execution of clinical trials that have provided important insights regarding
Medicine, University
immunotherapy in IgAN. In this article, we review emerging developments in clinical and translational IgAN of Toronto and
research and describe how these novel findings will influence future strategies to improve the outcome of Division of
patients with IgAN. Nephrology,
University Health
Clin J Am Soc Nephrol 12: ccc–ccc, 2017. doi: 10.2215/CJN.07420716
Network, Toronto,
Ontario, Canada;

Department of
Epidemiology of IgA Nephropathy Pooled cohorts from the European Validation Study of Pathology and
The most common GN globally is IgA nephropathy Laboratory Medicine,
the Oxford Classification of IgA Nephropathy (VALIGA)
Cedars-Sinai Medical
(IgAN). Prevalence varies geographically, and esti- and North American cohorts indicate rates ESRD or Center, Los Angeles,
mates of disease burden vary according to whether halving of eGFR of 27% at 10 years (7). There are regional California; and

ascertained using biopsy registry data versus dialysis differences in the progression of disease, however these Gabor Zellerman
registries. Despite these caveats, biopsy and organ Chair in Nephrology
are difficult to ascertain given lead-time biases intro-
Research, University
replacement registries suggest geographic variation in duced by variation in biopsy practice. In our cohort of of Toronto, Toronto,
disease burden with a higher incidence in Pacific 669 patients, multivariable analysis demonstrated that Ontario, Canada
Asian regions. individuals of Pacific Asian origin have an increased
Biopsy registry data underestimate disease burden risk of ERSD (adjusted hazard, 1.56; 95% confidence in- Correspondence:
as patients with mild disease may not undergo biopsy, Dr. Heather Reich,
terval [95% CI], 1.1 to 2.22) (8).
and in countries lacking screening programs disease Division of
Nephrology,
may not be detected. Distinguishing the contribution University Health
of ancestry and geography to differential disease sus- Disease Pathogenesis in IgAN Network, 200 Elizabeth
ceptibility using biopsy registry data is further chal- Susceptibility to IgAN and risk of disease progres- Street, Room 8N 849,
lenged by substantial geographic variation in biopsy Toronto, ON M5G
sion are influenced by a confluence of genetic and
2C4, Canada. Email:
practice patterns (e.g., for clinical indication versus environmental factors. The immunopathogenesis of heather.reich@uhn.ca
mandatory military screening). A systematic review this disease is described as a multi-“hit” process (9).
of biopsy-based studies spanning multiple countries These “hits” reflect knowledge derived from popula-
suggests an overall population incidence of at least tion genetic studies and careful characterization of the
2.5 per 100,000 (1). Only one study in this review was IgA moieties found in biopsy specimens and circulation of
from Japan, and most were from Europe and North patients with IgAN. Figure 1 illustrates current under-
America. In children, the incidence in a Japanese biopsy standing of the pathogenesis of IgAN and steps where
registry study where broad screening programs were in therapeutic interventions may be targeted.
place was eight-fold higher compared with a Tennessee A central finding in patients with IgAN is the presence
program where biopsies were performed for-cause and of circulating and glomerular immune complexes com-
routine screening was not in place (4.5 versus 0.57 per prised of galactose-deficient IgA1, an IgG autoantibody
100,000/yr) (2,3). directed against the hinge region O-glycans, and C3. The
Compelling data from autopsy and donor registries presence of aberrantly glycosylated IgA1 is an heritable
support that there is a higher burden of IgAN in East trait (10). Galactose-deficient IgA1 levels are elevated in
and Pacific Asian countries. Lanthanic IgA deposition 25% of blood relatives of IgAN patients and segregation
is detected in 1.3% of autopsies of trauma victims in analysis suggests a major dominant gene with additional
Finland compared with 15.6% of deceased donor can- polygenic background (11). A recent review outlines
didates in Japan (4,5), suggesting that regional vari- the cellular mechanisms responsible for IgA glyco-
abilities in incidence are not simply attributable to sylation (12). The relative levels of galactose-deficient
variation in biopsy practices. These findings parallel IgA1 may also be partially influenced by environ-
geospatial differences in prevalence of genetic suscep- mental factors. For example, these antibodies are
tibility loci reported in global genome-wide association susceptible to bacteria-derived proteases (13). Re-
studies (6). cent data suggest that anti-glycan autoantibodies

www.cjasn.org Vol 12 May, 2017 Copyright © 2017 by the American Society of Nephrology 1
2 Clinical Journal of the American Society of Nephrology

Figure 1. | Understanding the pathogenesis of IgA nephropathy reveals therapeutic targets. (A) Mucosal IgA production by plasma cells
occurs by T cell–dependent and –independent processes. T cell cytokines such as APRIL promote B cell class switch to IgA1-producing plasma
cells. Inhibitors of these cytokines are potential therapeutic targets. B cell and plasma cell inhibitors (e.g., rituximab, bortezomib) may result in
decreased IgA production. (B) The IgA1 produced in patients with IgA nephropathy is underglycosylated (Gd-IgA1). Susceptible individuals will
also produce anti–Gd-IgA1 autoantibodies (auto-Ab), reviewed in (9). Antiproliferative drugs may affect production of anti-glycan autoanti-
bodies. The Gd-IgA1–auto-Ab immune complexes activate the alternative pathway of complement. Complement inhibitors may prevent
formation of immune complexes. (C) The immune complexes are nephritogenic, contributing to local inflammation, cellular proliferation, and
ultimately fibrosis. Broad-based targeting of processes implicated in glomerular and tubulo-interstitial injury (e.g., inflammation, fibrosis)
target these final common pathways of kidney damage. Anti-Gd-IgA1-auto Ab, autoantibody directed at galactose-deficient IgA1.

may be targeting IgA VH gene segments that occur as a IgA production, and this is facilitated by the presence of
result of somatic hypermutation, and not sequences pre- mediators of B cell differentiation and proliferation BAFF
sent in the host germline (14). and/or APRIL. Although application to the pathophysiol-
These immune complexes are nephritogenic, contribut- ogy of IgAN in humans must be made with caution, this
ing directly to glomerular inflammation and mesangial schema is further supported by genome-wide association
proliferation. Activation of the local and systemic renin studies and clinical studies of disease progression (19). It is
angiotensin system and complement activation also ulti- hypothesized that APRIL contributes to IgAN by promot-
mately contribute to glomerulosclerosis and tubulo-inter- ing B cell class switch to an IgA-producing plasma cell
stitial fibrosis, leading to loss of renal function. Coexistent risk through its dominant actions on the TACI receptor.
factors such as hypertension and smoking contribute to A polymorphism in the APRIL gene confers IgAN sus-
disease progression, potentially through microvascular injury ceptibility (20) and several risk alleles associated with
(15). Maladaptive hyperfiltration injury and glomerulome- IgAN are also associated with other diseases of mucosal
galy attributed to obesity are also implicated in nonimmuno- immunity and defense against mucosal microbial patho-
logically-mediated disease progression (16). gens (21). Elevated circulating APRIL levels were docu-
The triggers responsible for production of galactose- mented in a cohort of 166 patients with IgAN, and
deficient IgA1 are not known and the site of IgA produc- APRIL expression was correlated with a progressive clini-
tion in IgAN is not established. Experimental models suggest cal phenotype and elevated circulating levels of galactose-
environmental triggers may lead to excess production of deficient IgA (19).
aberrantly-glycosylated IgA in mucosal-associated lymphoid Recent studies suggesting immunotherapy primar-
tissue. A B cell activation factor of the TNF family, BAFF, is ily results in reduction in proteinuria (without change in
critical but not sufficient for development of an experimental long-term outcome) may call into question the role of anti-
IgAN phenotype (17). In this model BAFF-overexpressing glycan antibodies in disease immunopathogenesis. How-
mice reared in pathogen-free conditions develop a phenotype ever, one must consider that these are short-term treatment
similar to IgAN with detectable circulating and glomerular interventions, and the formation of anti-glycan antibodies is
underglycosylated IgA, whereas those housed in germ-free only one part of a complex disease process. Genetically-
cages do not. The related cytokine APRIL (a proliferation- influenced and environmentally-determined defects in
inducing ligand) shares some signaling receptors important mucosal immune function (and microbiota profiles) may
for B cell development with BAFF, is elevated in IgAN pa- not be altered in a sustained fashion by a brief immuno-
tients, and correlates with age, serum creatinine, and urine modulatory intervention.
protein-to-creatinine ratio (18). Activation of complement is regarded as an important
These findings suggest that, at least in mice, exposure to pathogenic contributor in IgAN. The lectin pathway of com-
commensal or pathogenic bacteria is necessary for excess plement activation is also implicated in IgAN pathogenesis.
Clin J Am Soc Nephrol 12: ccc–ccc, May, 2017 IgA Nephropathy, Rodrigues et al. 3

Polymeric IgA1 is capable of activation of this pathway in vitro, ESRD or decrease in eGFR by 50% occurred in 26% of patients
and mannose-binding lectin pathway elements are detected at 10 years. Most of the histologic variables remained
in glomerular deposits (22,23). independently associated with outcome, when adjusted for
Clinical and genetic studies link defects in regulation of the baseline and longitudinal clinical variables. Interestingly, in
alternative pathway of complement to IgAN immunopatho- the low risk group with proteinuria,0.5 g/d only endoca-
genesis (6). Circulating and immune complexes contain C3, pillary proliferation was associated with a rapid rate of re-
and this is evident on immunofluorescence of kidney biop- nal function decline by univariate analysis (hazard ratio
sies (24). Properdin and complement factor H (CFH) are also [HR], 5.2; 95% CI, 1.1 to 25.9), however, it was not signif-
detected in immune deposits (reviewed by Gharavi et al. icantly associated with outcome by multivariate analysis.
[25]). Genome-wide association studies identify an allele Mesangial and endocapillary proliferation were associated
initially localized to the CFH gene that confers protection with an increased risk of developing proteinuria$1 g/
against development of IgAN. Further analysis indicate d (HR, 2.3; 95% CI, 1.3 to 4.0) or $2 g/d (HR, 3.5; 95%
that deletion of complement factor H–related (CFHR) genes CI, 1.5 to 8.4). In patients with eGFR,30 ml/min per 1.73
one and three are in linkage disequilibrium with the iden- m2 M1 and T1–2 were associated with a lower renal sur-
tified risk allele. The CFHR1 and CFHR3 proteins titrate vival (HR, 2.3; 95% CI, 1.2 to 4.2) (28).
CFH activity, and their absence is associated with altered An important goal of deriving a histologic scoring sys-
CFH levels and enhanced CFH activity (25,26). tem is shortening the time frame of observation required
to accurately predict which patients are at risk of adverse
outcome. A recent pooled analysis of the 901 subjects from
Clinical-Pathologic Correlation in IgAN: Mesangial the VALIGA, Oxford, and North American cohorts dem-
hypercellularity (M), endocapillary hypercellularity onstrated that incorporation of MEST score into predictive
(E), segmental glomerulosclerosis (S), tubular atrophy algorithms provides timely and accurate predictive accu-
(T), MEST and Crescents racy to identify patients at highest risk of poor outcome (7).
Through rigorous design of a structured, standardized, The addition of the MEST score to clinical data at biopsy
and reproducible pathologic scoring system in IgAN, provided significant improvement in prediction compared
pathologic evaluation now adds important prognostic with considering only clinical data at biopsy (proteinuria,
information beyond what is obtained from clinical var- creatinine, mean arterial pressure). Importantly, the com-
iables alone. bination of MEST and cross-sectional clinical data at bi-
The Oxford classification schema was derived studying opsy predicted adverse outcome as well as using 2 years
patients with $0.5 g/d of proteinuria, eGFR$30 ml/min of clinical data (proteinuria and mean arterial pressure av-
per 1.73 m2 at renal biopsy, and $1 year of follow-up. eraged over a 2-year period). This was true regardless of
Histologic variables selected for inclusion demonstrated treatment with renin-angiotensin system (RAS) blockade
a high degree of interobserver reproducibility and corre- or immunosuppression.
lated with predetermined clinical endpoints including a Elucidating the relationship between histologic class and
composite outcome of ESRD or 50% reduction in eGFR treatment response is an important next step. The MEST
and rate of renal function decline. Four key pathologic studies suggest that response to corticosteroids may differ
features were consistently independently-associated with according to histology. In the original derivation cohort,
renal outcome including mesangial hypercellularity (M), use of corticosteroids confounded the relationship between
endocapillary hypercellularity (E), segmental glomerulo- endocapillary proliferation, and adverse outcome (30). In
sclerosis (S), and tubular atrophy and interstitial fibrosis the VALIGA cohort, half of subjects received immunosup-
(T) now known collectively as the MEST or Oxford score pression, mostly including corticosteroids. In a VALIGA
(27). The absence/presence of .50% of glomeruli show- substudy, Tesar et al. (31) derived a propensity-matched
ing mesangial hypercellularity is denoted M0/M1, respec- cohort of 184 pairs to evaluate additive benefits of cortico-
tively; E1 indicates any endocapillary hypercellularity; S1 steroids above RAS blockade. Use of corticosteroids affor-
denotes any segmental glomerulosclerosis; and T0, T1, and ded an improved renal survival, and the greatest reduction
T2 reflect fibrosis involving 1%–25%, 26%–50%, or .50% of in rate of renal function afforded by corticosteroids oc-
the cortical area. curred in subjects with mesangial proliferation, segmental
The clinical relevance and applicability of this score has glomerulosclerosis, and tubulo-interstitial fibrosis. Al-
now been validated across multiple populations including, though it is difficult to make firm conclusions based
most recently, the European (VALIGA) cohort (28). True upon observational data, future therapeutic trials in
validation studies (such as described by Herzenberg et al. IgAN should include stratification based upon MEST score
[29]) applied the regression models derived in the original to determine if histology can be used to tailor treatment
Oxford cohort and verified the independent contribution decisions.
of each variable to the same clinical outcomes. Although The additive effect of crescents on prediction of outcome
the individual components were not always indepen- remains a challenging question in IgAN, and new infor-
dently predictive in these validation studies the score over- mation may shed some light on clinical implications of
all consistently adds value to prognostication. these findings. Although crescents are a common finding
The largest validation study was performed in the VALIGA in IgAN biopsies, the presence of .30% of crescents is
cohort of 1147 patients. Unlike the original Oxford study, not. Early studies initially suggested that patients with
entry criteria were less restrictive; patients at both ends of the crescents involving .50% of glomeruli are at high risk of
spectrum of disease severity were included. The cohort was progression, with 75% reaching ESRD by 10 years (32).
predominantly white (97.5%) and the combined end point of Certainly, in the context of rapid progression of loss of kidney
4 Clinical Journal of the American Society of Nephrology

function, crescents portend a poor prognosis. Patients with


rapidly progressive courses were not included in the Oxford
study, therefore the study was underpowered to determine
if a high percentage of crescents is independently-associated
with adverse outcome (i.e., beyond the information that
would have been derived from clinical data alone). A meta-
analysis of the Oxford study and four validation studies did
suggest that the presence of crescents is associated with a
higher risk of adverse prognosis (HR, 2.3; 95% CI, 1.6 to
3.4; P,0.001) (33).
A working group formed in 2014 at the First Oxford Con-
ference on IgA Nephropathy examined the association
of crescents with renal outcomes in 3096 patients combined
from four published studies: the original Oxford cohort, the
VALIGA study cohort, and two large Asian cohorts, one
from China and the other from Japan. Biopsies from 1118
(36%) of the patients contained any cellular or fibrocellular Figure 2. | A novel addition to the MEST classification system iden-
crescents; 440 (14%), 221 (7%), and 96 (3%) had crescents in tifies patients at increased risk of poor outcome based on crescents: C0
$1/10, $1/6, and $1/4 of glomeruli, respectively. Over- (no crescents), C1 (<25% left panel), and C2 (‡25% right panel). The
all, the presence of any such crescents was a significant, biopsy specimen represented in the left panel had 21 total glomeruli of
independent predictor of the likelihood of developing a which two had segmental crescents; of the six complete glomeruli
combined event of ESRD or a $50% reduction in eGFR. represented in the photomicrograph one shows a fibrocellular crescent
with segmental solidification of the tuft adjacent to the crescent. There is
Other independent predictors of the combined event were
also mild mesangial hypercellularity, and the MEST scores are M1, E0,
eGFR at biopsy, time-averaged proteinuria and mean ar- S1, T0. The biopsy represented in the right panel contained 14 total
terial pressure, and Oxford M1, S1, and T1/T2 scores. The glomeruli, of which five had segmental cellular crescents; two of the
predictive value of all histologic parameters (including latter glomeruli are represented in the photomicrograph. The glomeruli
crescents) except T1/T2 was lost in patients receiving im- also show mesangial hypercellularity, and the biopsy also showed focal
munosuppression. However, the presence of cellular or and segmental endocapillary hypercellularity (not shown in the photo-
fibrocellular crescents in $1/4 of glomeruli was signifi- micrograph); the MEST scores are M1, E1, S0, T0. Periodic acid–Schiff
cantly predictive of the combined event even in patients stain; original magnification, 3100 (left panel), and original magnifi-
receiving immunosuppression. On the basis of these find- cation, 3200 (right panel).
ings, the authors proposed adding crescent scores to the
Oxford (MEST) classification as follows: C0—no cellular or
fibrocellular crescents; C1—cellular/fibrocellular crescents uria (i.e., ,0.5 g/d) may be detected through screening
in ,25% of glomeruli, identifying patients at increased programs, such as those in countries with school screen-
risk of a poor outcome (compared with C0) among those ing, military draft screens, or insurance programs. Isola-
not given immunosuppressive therapy; and C2—crescents ted microscopic hematuria with minimal proteinuria is
in $25% of glomeruli, identifying patients at increased risk regarded as having a favorable prognosis, particularly in
of a poor outcome even if given immunosuppression (34) white populations (36). Nonetheless, a proportion will ul-
(see Figure 2). timately develop hypertension and significant proteinuria,
The MEST score does not replace the detailed and in- suggesting that long-term follow-up of these patients
formative information provided by the full pathology should be instituted (37,38).
report. One should be mindful that despite the statistically- Progressive CKD is a common phenotype observed in
significant association with progression, the pathology score multiple cohorts. Renal survival ranges greatly according
combined with clinical data account for only a minority to biopsy timing and introduction of lead-time bias.
(,30%) of the variability in outcome in patients with IgAN Actuarial renal 10-year survival is reported to be 57%–
(35). Therefore, a majority of the variability in outcome is 91% (39). In addition to pathologic findings, factors asso-
attributable to unmeasured factors which would hopefully ciated with poor prognosis include hypertension, protein-
include therapeutic intervention. uria, and decreased eGFR at diagnosis (35,40). Race may
also be an important determinant of outcome (8).

Clinical Manifestations Less Frequent Manifestations


The range of clinical manifestations of IgAN is broad, Synpharyngitic macroscopic hematuria is a classic clin-
from asymptomatic microscopic hematuria to rapidly pro- ical syndrome associated with first presentation of IgAN.
gressive GN. The typical mode of presentation varies ac- The presence of gross hematuria at the time of pharyngitis
cording to age group and biopsy practice patterns. or other infection is alarming to patients and often prompts
immediate medical attention and diagnosis. This syndrome
Common Phenotypes: Asymptomatic Hematuria and occurs in approximately 10%–15% of subjects (41) and pre-
Progressive Kidney Disease dominantly in patients under the age of 40. Recurrent mac-
By far the two most common clinical presentations roscopic hematuria is associated with a favorable prognosis
are asymptomatic hematuria and progressive kidney in the short-term, potentially reflecting lead-time bias asso-
disease. Asymptomatic hematuria with minimal protein- ciated with this finding in younger populations. However,
Clin J Am Soc Nephrol 12: ccc–ccc, May, 2017 IgA Nephropathy, Rodrigues et al. 5

subsequent development of persistent proteinuria is well 21.0%, P 0.001) (50). Weight reduction may ameliorate pro-
documented and associated with potentially progressive teinuria in IgAN (51). Given the link between smoking and
disease (42). progression, smoking cessation should also be promoted (15).
Although nephrotic-range proteinuria.3 g/d is not un-
common in IgAN, coexistence of the nephrotic syndrome is Corticosteroids
rare (43,44). A rare clinical presentation more in keeping with There are several clinical trials supporting that corti-
dual diagnoses of IgAN and minimal change disease is also costeroids reduce proteinuria in IgAN. Although earlier
well described. Renal function is often preserved, and overt studies supported that this was associated with an im-
nephrotic syndrome with edema, dyslipidemia, and hypoal- provement in clinical outcome, more recent large trials
buminemia is present. Steroid responsiveness and favorable question the sustained benefits of a brief period of immu-
prognosis akin to minimal change lesions are reported (45), nosuppression.
although a steroid-sparing agent is often required to maintain One of the first randomized trials suggesting a benefit of
remission. In one cohort, only 306 patients of 11,885 with IgA corticosteroids was a study of 86 patients with biopsy-proven
met criteria for this diagnosis—diffuse IgA-dominant mesan- IgAN with proteinuria 1–3.5 g/d for at least 3 months and a
gial deposits with minimal changes in glomeruli on light serum creatinine #1.5 g/dl (52). Patients received steroid ther-
microscopy and .50% podocyte foot process effacement. apy (1 g intravenously for 3 days at months 1, 3, and 5, and
None of these patients reached ESRD at the end of a median oral prednisone at 0.5 mg/kg per day on alternate days for 6
of 2.6 years (45). months) or supportive therapy alone. Given the era of the trial,
IgAN with rapidly progressive course is rare and most use of RAS blockade was not uniform and there was no run-in
frequently associated with a pathologic finding of .50% of period of optimizing conservative therapy. In this study, 5-
glomeruli exhibiting crescents. The largest case series of year renal survival (defined as 50% increase in serum creati-
113 subjects described a rate of ESRD of 42.5% at 1 year nine) was greater in the corticosteroid group (81% versus 64%,
despite immunotherapy (46). P50.05) as was survival without a 100% increase in creatinine
(95% versus 74%, P50.001). In the multivariate analysis, re-
duction in proteinuria from baseline to 6 months was signifi-
Treatment Strategies: Current Evidence and cantly associated with renal survival (relative risk [RR], 0.48;
Novel Therapies 95% CI, 0.34 to 0.69; P,0.001). At 10 years, renal survival was
In this section, the focus of discussion will be on treating better in the steroid group as compared with controls (97%
the most common clinical variants of IgAN. versus 53%, P50.003; RR, 0.06; 95% CI, 0.01 to 0.44; P50.001).
More patients in the steroid group had a reduction in protein-
Conservative Therapy uria ,0.5 g/d after 1 year (26% versus 5%; RR, 5.50; 95% CI,
The importance of conservative therapy to reduce pro- 1.3 to 23; number needed to treat55; P50.01) (53). This finding
teinuria and slow the rate of renal function decline in IgAN suggested that exposure to corticosteroids for a 6-month pe-
cannot be overemphasized. In the recent Supportive Versus riod may have a “legacy effect,” with sustained reduction in
Immunosuppressive Therapy of Progressive IgA Nephrop- the risk of progressive renal dysfunction.
athy (STOP-IgAN) trial, nearly one third of patients who Similarly, a single-center, randomized, open-label trial of
completed a 6-month run-in phase of intensive optimiza- 97 patients with biopsy-proven IgAN, proteinuria$1 g/d,
tion of conservative therapy no longer qualified for ran- and eGFR.50 ml/min per 1.73 m2 demonstrated benefits of
domization to immunosuppressive therapy (47). corticosteroids (54). After a 3-month run-in phase during
The role of RAS blockade in IgAN is now well established. which they were required to discontinue RAS blockade pa-
Although dual RAS blockade may reduce proteinuria, reg- tients were randomized to ramipril or ramipril plus predni-
ulatory agencies have recommended against use of combi- sone 1.0 mg/kg per day for 8 weeks then tapered by 0.2 mg/
nation therapy due to risks of hyperkalemia (48). Many trials kg per day every month. The corticosteroid group had a
have examined the effects of statins in patients with CKD, higher baseline proteinuria (2.5 versus 2 g/d). More patients
however few have focused on patients with IgAN. A small, in the combined group failed to reach the combined end-
randomized, placebo-controlled trial of 21 patients with se- point of ESRD or doubling of serum creatinine at 8 years
rum creatinine ,1.8 mg/dl, with absence of severe lesions on (85.2% versus 52.1%, P50.003). Similar results were demon-
renal biopsy and without RAS blockade, received fluvastatin strated in a Chinese cohort of 63 subjects (55).
or placebo for 6 months. A decrease in proteinuria was seen A subsequent meta-analysis of 536 patients in nine trials
after 6 months (baseline 837–1100 mg/24 hours in the pla- with proteinuria.1 g/d demonstrated corticosteroids de-
cebo group versus 845–494 mg/24 hours, P,0.01) (49). creased the risk of kidney failure (RR, 0.32; 95% CI, 0.15 to
Obesity can contribute to proteinuria. In a cohort of 331 0.67; P50.002). The effects on renal outcome were dose-
patients with IgAN in whom 44.1% were either overweight or dependent, requiring .30 mg/d or high-dose pulse and
obese, the overweight/obese group were more likely to were not surprisingly associated with an increased risk of
be hypertensive (24.6% versus 52.9%, P,0.001), have worse adverse events (56). Major criticisms of these studies have
renal function (mean eGFR 69.1 versus 80.2, P50.003), and been the lack of uniform use of RAS blockade for all pa-
have proteinuria$1 g/d (22.1% versus 39.7%, P50.003). tient groups (52) and small sample size, which may have
There was no difference in the endpoint of death/dialysis been underpowered to detect adverse events associated
between those with normal body mass index (BMI) and the with corticosteroids (56).
overweight/obese group, however the overweight/obese The STOP-IgAN study (47) recently further brought
group had a worse eGFR (59.3 versus 73.4, P,0.001) and a into question the long-term benefits of a 6-month course
greater prevalence of CKD stage 3 or greater (43.4% versus of corticosteroids. This study was designed to enroll
6 Clinical Journal of the American Society of Nephrology

approximately 380 subjects to determine the benefits of is applicability in patients with low-risk renal disease. In a
immunosuppression compared with conservative therapy randomized, double-blind, placebo-controlled clinical trial,
in patients with persistent proteinuria and eGFR.30 ml/min 44 patients with persistent proteinuria.0.6–0.8 g/g and
per 1.73 m2 after a 6-month run-in period that involved eGFR.50 ml/min per 1.73 m2 were randomly assigned
adequate BP control and RAS blockade, as well as lipid con- to mycophenolate mofetil (MMF) or placebo in addition
trol. Patients allocated to the immunotherapy would receive to conservative therapy. A significant number were ex-
corticosteroids if the eGFR was .60 ml/min per 1.73 m2 cluded as they had a good response to conservative man-
whereas those with eGFR of 30–59 ml/min per 1.73 m2 agement during the run-in phase (36 of 184) and only
would receive steroid and cyclophosphamide, followed by seven patients in the treatment group and ten patients in
maintenance immunosuppression with azathioprine akin to the placebo group were analyzed at the end of the study
one of the few randomized trials in patients with severe but period after the trial was stopped early due to lack of
not rapidly progressive disease (57). The study was powered observed benefit (59).
to evaluate the effect of immunotherapy on primary end- At the other end of the spectrum is a study of myco-
points: “full clinical remission” (protein-to-creatinine ratio phenolate in patients with more advanced and high-risk
of ,0.2 and stable renal function with a decrease in the disease. A double-blind, controlled trial of 32 patients with
eGFR of ,5 ml/min per 1.73 m2 from the baseline eGFR) $1g/d of proteinuria and at least two additional risk fac-
and a decrease in the eGFR of .15 ml/min per 1.73 m2 from tors (male sex, hypertension, clearance,80 ml/min per
the baseline. Secondary endpoints related primarily to eGFR 1.73 m2, glomerulosclerosis, tubulo-interstitial fibrosis, or
changes and slope. $25% of glomeruli affected by crescents) (60). Patients re-
After the intensive 6-month optimization of conserva- ceived MMF or placebo in addition to RAS blockade. This
tive therapy, nearly one third of patients no longer qualified study was terminated early due to the finding of a trend in
for randomization. Ultimately only 162 patients were ran- worse renal outcome in the MMF group.
domized. At 3 years, a larger proportion of patients who In contrast, in a small, randomized, nonblinded trial of
received immunosuppression were in a full clinical re- 40 patients with .1 g/d of persistent proteinuria, more
mission compared with patients who received only sup- patients in the MMF group demonstrated remission of
portive care (17% versus 5%, P,0.05). However, these proteinuria (16 versus six) and had overall less proteinuria
differences in remission were not associated with signifi- (1.1460.23 g/24 hours versus 2.460.40 g/24 hours) (61).
cant difference in the rate of loss of kidney function. Not Long-term follow-up demonstrated improved renal sur-
surprisingly, more infections occurred in the immunosup- vival in MMF-treated patients (90% versus 55%, P50.01)
pression group, including one sepsis-related death. Im- (62).
paired glucose tolerance and significant weight gain These studies are limited by small sample size. It also
were also observed (47). remains possible there is race-specific variability in response
The interim results of the Therapeutic Evaluation of to MMF as in lupus nephritis (63). However systematic re-
Steroids in IgA Nephropathy Global Study were recently views and meta-analyses of the randomized trials of MMF
presented as a late-breaking clinical trial abstract at the 53rd also suggest mixed results (64–66).
meeting of the European Renal Association—European
Dialysis and Transplantation Association. This study Rituximab
was designed to evaluate the effects of a 6–8 months Although evidence for rituximab in other glomerular
course of 0.6–0.8 mg/kg per day of oral methylpredniso- diseases is promising, early results in IgAN are not encour-
lone versus placebo, with a target sample size of 1300 and aging. A pilot trial evaluated the outcome of 34 patients with
5 years of longitudinal follow-up. The primary outcome proteinuria.1 g/d and eGFR,90 ml/min per 1.73 m2 ran-
was a composite of 40% decrease in eGFR, ESRD, or domized to rituximab versus conservative management.
death. An interim analysis of 262 patients was presented. No effects on proteinuria or renal function were seen (67).
Although proteinuria was reduced with corticosteroid
treatment, and the composite outcome occurred in a lower Combination Therapy
proportion of patients in the treatment arm (8% versus Combination therapy with corticosteroid plus an addi-
15%, P50.02), there were concerning signals of risk with tional agent is generally reserved for patients with progressive
corticosteroids at a mean follow-up of 1.5 years. Serious disease. A single-center, prospective, randomized, controlled
adverse events were reported more frequently in the cor- trial of 38 patients with “high-risk” IgAN (hypertension,
ticosteroid arm (relative risk, 4.63; 95% CI, 1.63 to 13.18; .15% rise in creatinine in prior year) demonstrated im-
P50.001) mostly due to excess serious infections (14.7% proved renal survival after 2 years in patients receiving pred-
versus 3.2%, P,0.001), including two fatal infections. nisone and cyclosphosphamide/azathioprine as compared
Based upon the interim analysis the investigators con- with no immunotherapy (57).
cluded that renal benefit is likely but will need to be In contrast, dual-agent immunotherapy does not always
weighed carefully against risk. Recruitment is currently afford an advantage. A multicenter, open-label, trial of 207
on hold pending protocol revision (ClinicalTrials.gov patients with creatinine,2.0 mg/dl and proteinuria$1.0 g/d
NCT01560052). for at least 3 months randomized patients to corticosteroids
alone (1 g intravenously for three consecutive days at months
Mycophenolate 1, 3, and 5, and then continued at 0.5 mg/kg) or corticoste-
Data regarding the efficacy of mycophenolate are mixed, roids in addition to azathioprine 1.5 mg/kg. There was
such that current clinical guidelines recommend against no difference in primary outcome of time to 50% increase
use of this agent in IgAN (58). At one end of the spectrum in creatinine or secondary outcome of change in proteinuria
Clin J Am Soc Nephrol 12: ccc–ccc, May, 2017 IgA Nephropathy, Rodrigues et al. 7

over time, however major side effects were seen more com- Disease Improving Global Outcomes guidelines regarding
monly in the azathioprine group (68). The same investigators corticosteroid use in patients with .3 g/d of proteinuria
conducted a separate randomization for an additional 46 pa- persisting despite conservative therapy, although treat-
tients with advanced disease (creatinine$2.0 mg/dl) (69). There ment is not without risk.
was no difference in renal survival at 6 years, although multi- On the other end of the disease spectrum, 20% of subjects
variable survival analysis identified that azathioprine therapy ultimately randomized had under 1 g/d of proteinuria and
was associated with improved renal survival. A substantial the rate of renal function decline in the study population
number of patients did not complete the study due to compli- was low overall, as expected (72). The VALIGA analysis
cations of therapy, highlighting the potential toxicity of immu- suggests a graded benefit of corticosteroids according to
nosuppression in patients with advanced renal insufficiency. time-averaged proteinuria before treatment, with no differ-
ence in renal function decline below 1 g/d of proteinuria.
Novel Agents Therefore, patients with persistent proteinuria,1 g/d likely
A novel potential therapy for IgAN is a modified formulation do not derive significant benefit from addition of corticoste-
of oral budesonide (Nefecon). This agent is proposed to act roids. The 1–3 g/d category remains a “gray zone.” Indeed, a
locally at the mucosal lymphoid tissue in the distal ileum and long duration of follow-up will be required to demonstrate
proximal large intestine to modulate IgA production. High first- any potential benefit, based upon rates of renal function
pass metabolism also theoretically minimizes systemic effects decline typically observed in patients with this degree of
(70). The results of the phase 2 double-blind, placebo controlled persistent proteinuria (72).
trial were recently presented. After a 6-month run-in phase, pa- The rigor of design and execution of these multicenter
tients with proteinuria.0.5 g/g or 0.75 g/d and eGFR $45 trials bring a most welcome evolution in the landscape of
ml/min per 1.73 m2 were randomized to receive placebo, 8, clinical trials for IgAN. They have also highlighted urgent
or 16 mg/d of budesonide. There was a significantly greater needs in this realm. A lack of sensitive and specific early
reduction in proteinuria in patients treated with the budesonide surrogate markers of long-term outcome further challenges
—up to 27% reduction with a 3% rise in proteinuria in the execution of these studies. Although substantial observa-
placebo group. In addition, there was a significant difference tional data support an association between complete or partial
in a secondary endpoint; the change in eGFR was less in the remission of proteinuria with improved renal survival, this
budesonide group (24.7 ml/min per 1.73 m2 for placebo versus remains to be validated in controlled trials.
0.32 and 1.95 ml/min per 1.73 m2 for 8 mg and 16 mg/d, re- None of the information regarding the pathogenesis of
spectively P,0.05). More adverse events were seen in the bu- this disease suggests a curable time-limited event. Perhaps
desonide group, necessitating treatment cessation in 22% of there is a role for treatment to be divided into induction and
patients on this higher dose (ClinicalTrials.gov NCT01738035). maintenance phases, with use of steroid-sparing mainte-
An open-label efficacy/safety study is currently recruiting nance therapy to achieve sustained reductions in time-
patients with eGFR.30 ml/min per 1.73 m2 with IgAN and averaged proteinuria that ultimately affect renal survival.
nephrotic syndrome who failed previous immunosuppres- Furthermore, studies of immunotherapy in IgAN consis-
sion to treatment with Acthar gel, a purified form of adreno- tently demonstrate significant risk of toxicity. Ultimately, it
corticotropic hormone (ClinicalTrials.gov NCT02382523). is anticipated that improved understanding of the immu-
Another open-label pilot study is currently recruiting nopathogenesis of this disease will lead to development of
for efficacy/safety in patients with .1 g/d of proteinuria more targeted and less toxic treatment options.
and no eGFR restriction of bortezomib, a proteasome in-
hibitor (ClinicalTrials.gov NCT01103778). Both studies exam- Disclosures
ine proteinuria at 12 months as the primary outcome with M.H. discloses receipt of consulting fees from Shire Viro-
varying requirements for RAS blockade. A double-blind pharma (Lexington, MA) and Astra Zeneca (Wilmington, DE).
safety/efficacy study in patients with .0.5 g/d of proteinuria These disclosures are unrelated to the material presented in this
and eGFR.30 ml/min per 1.73 m2 randomized patients to paper. H.N.R. has received speaker fees from Hoffman La-Roche
either fostamatinib, an oral spleen tyrosine kinase inhibitor, (Mississauga, ON, Canada) and participated in an advisory board
or placebo with the primary outcome of proteinuria at for Hoffman-La Roche and AMGEN (Mississauga, ON, Canada).
24 weeks (ClinicalTrials.gov NCT02112838). Additional ther-
apies are reviewed by Yeo et al. (71).
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