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In Translation
The Pathogenesis of IgA Nephropathy: What Is New and
How Does It Change Therapeutic Approaches?
Jürgen Floege, MD
Immunoglobulin A (IgA) nephropathy is the most common glomerulonephritis worldwide. For example, in Japan,
full-blown IgA nephropathy has been detected in ⬃1.5% of all allograft kidneys at the time of transplant. Genetic and
environmental modifiers, as well as generic progression factors (eg, hypertension), must have a major role in
determining who will become clinically overt and who will experience progression. In patients with clinically overt IgA
nephropathy and/or progressive disease, it now is relatively well established that the pathogenesis involves 6 major
steps: (1) Increased occurrence of IgA1 with poor galactosylation in the circulation. This might relate to the migration
of mucosal B cells to bone marrow, where they produce “correct” poorly galactosylated IgA. Modulation of mucosal
immunity may offer new therapeutic options. (2) Generation of IgG antibodies against poorly galactosylated IgA1.
This could lay the foundation for immunosuppression, whereas detection of such IgG autoantibodies may
accommodate the noninvasive monitoring of IgA nephropathy. (3) Mesangial deposition and/or formation of
IgG-IgA1 or IgA1-IgA1 complexes. (4) Activation of mesangial IgA receptors and/or complement; both lend
themselves to therapeutic interference. (5) Mesangial cell damage and activation of secondary pathways, such as
overproduction of platelet-derived growth factor, which can be targeted specifically. (6) Activation of pathomechanisms that are not specific for IgA nephropathy and that drive glomerulosclerosis and tubulointerstitial fibrosis.
Although at present our therapeutic armamentarium is still limited largely to supportive care and immunosuppression in some instances, these new insights can be expected to yield novel, perhaps individualized, therapeutic
options in primary and recurrent IgA nephropathy.
Am J Kidney Dis. 58(6):992-1004. © 2011 by the National Kidney Foundation, Inc.
INDEX WORDS: Immunoglobulin A (IgA) nephropathy; mesangioproliferative glomerulonephritis; recurrence;
progression; hypertension; proteinuria.
BACKGROUND
Immunoglobulin A (IgA) nephropathy is very common. Studies of nonselected autopsy series or zero-hour
allograft biopsies have reported that glomerular IgA
deposits are detected in up to 20% of all cases.1,2 In a
Japanese study, glomerular IgA and C3 deposits plus
mesangioproliferative changes, in other words, IgA nephropathy, were noted in 1.6% of presumably healthy
donor kidneys.2 Thus, in contrast to the selected patients that we encounter in clinical practice, most patients
likely do not come to clinical attention and these patients
must run a benign course and/or some IgA nephropathy
must resolve spontaneously. In a report of Chinese
patients with IgA nephropathy with isolated microhematuria, resolution occurred in 14% and less than one third
experienced progression in up to 12 years of follow-up.3
Others also have reported the spontaneous or therapyFrom the Division of Nephrology and Immunology, RWTH
University of Aachen, Germany.
Received March 25, 2011. Accepted in revised form May 26,
2011. Originally published online August 29, 2011.
Address correspondence to Jürgen Floege, MD, Department of
Nephrology and Clinical Immunology, RWTH University Hospital
Aachen, Pauwelsstr 30, 52074 Aachen, Germany. E-mail:
[email protected].
© 2011 by the National Kidney Foundation, Inc.
0272-6386/$36.00
doi:10.1053/j.ajkd.2011.05.033
992
induced disappearance of IgA nephropathy in native4-6
and transplanted kidneys.7 There are 2 important implications of these observations: IgA nephropathy is a
dynamic disease and the defect(s) driving the persistence
or progression of IgA nephropathy appear to reside
largely outside the kidney.
CASE VIGNETTE
A 42-year-old man presented to the Division of Nephrology of
the Aachen Medical School after the discovery of an elevated
serum creatinine level (4.3 mg/dL [380.1 ␮mol/L], corresponding
to an estimated glomerular filtration rate (eGFR of 30 mL/min/
1.73 m2 [0.5 mL/s/1.73 m2], calculated by the MDRD [Modification of Diet in Renal Disease] Study equation), and hypertension
during a routine checkup. He had been completely asymptomatic
and no medical history was present. Both parents had hypertension, but the family history otherwise was unremarkable. His body
mass index was 23 kg/m2 and he did not smoke. A routine checkup
7 years earlier was unremarkable, with no hypertension and a
serum creatinine level within the reference range. However, a urine
dipstick test had not been performed. Working as a teacher, he had
assumed intermittent headaches to be job related. On admission, he
had already been started on treatment with ramipril, 5 mg/d. Blood
pressure was 155/90 mm Hg, urinalysis showed microhematuria,
and urine protein-creatinine ratio was 1.5 g/g. A kidney biopsy
specimen (Fig 1) showed IgA nephropathy with mesangial hypercellularity, endocapillary hypercellularity, focal glomerulosclerosis of 5 of 8 glomeruli, and tubular atrophy and tubulointerstitial
fibrosis involving ⬃80% of the renal interstitium. His angiotensinconverting enzyme–inhibitor dosage was uptitrated and a diuretic,
␤-blocker, and low-dose spironolactone were added, resulting in a
Am J Kidney Dis. 2011;58(6):992-1004
Pathogenesis of IgA Nephropathy
Figure 1. Renal pathologic characteristics of the patient described in the case vignette. Glomerulus has one small area of a
segmental increase in mesangial cell number and mesangial matrix (arrow) in the region of a segmental adhesion. Globally sclerosed
glomeruli can be seen in the upper part of the image (arrowhead). Preglomerular vessels (asterisk) are regular. Detached tubular cells
can be observed in many damaged tubules (star). Note the division of biopsy tissue into an upper half with a fibrosed interstitium and
atrophic tubules, whereas the neighboring tubulointerstitium in the lower half of the image is relatively preserved. (Periodic acid–Schiff
stain; original magnification, ⫻40.) Courtesy of H.J. Gröne, DKFZ, Heidelberg, Germany.
decrease in blood pressure to 125-130/75-80 mm Hg. Serum
creatinine level increased to 4.7 mg/dL (415.5 ␮mol/L; eGFR, 28
mL/min/1.73 m2 [0.47 mL/s/1.73 m2]), and urinary proteincreatinine ratio decreased to 0.6 g/g. Other interventions to retard
the progression of kidney disease included native vitamin D, oral
bicarbonate, dietary counseling, and low-dose allopurinol, but no
immunosuppression. Three years later, in late 2010, his serum
creatinine remained at 4.9 mg/dL (433.16 ␮mol/L; eGFR, 25
mL/min/1.73 m2 [0.42 mL/s/1.73 m2]). In early 2011, he acutely
presented with progressive weakness, with serum creatinine level
of 8.8 mg/dL (777.9 ␮mol/L; eGFR, 14 mL/min/1.73 m2 [0.23
mL/s/1.73 m2]) and worsening of renal anemia. Blood pressure
was still well controlled and there was no obvious explanation,
such as infection or nephrotoxic drugs, for this abrupt deterioration. His condition did not resolve, peritoneal dialysis therapy
finally was started, and the patient was scheduled for a living
donor kidney transplant.
PATHOGENESIS AND RECENT ADVANCES
This patient illustrates a number of problems regularly encountered in patients with IgA nephropathy:
(1) patients usually are asymptomatic and IgA nephropathy often is a chance finding; (2) a patient often is
first seen when disease has already progressed considerably; (3) despite optimized care, patients still experience progression; and (4) we have no adequate
means to assess disease activity.
The first issue implies that IgA nephropathy in the
worst case may never be identified and that patients,
for example, may be mislabeled based on clinical
Am J Kidney Dis. 2011;58(6):992-1004
grounds as “hypertensive nephrosclerosis.” Thus,
screening programs and adequate follow-up in cases
of positive urine findings, including nephrology referral and kidney biopsy, will strongly determine whether
such cases become apparent. The remaining issues
need to be addressed by the nephrology community:
we need better understanding of how IgA nephropathy manifests initially, how it progresses, and how it
can be monitored. Better insight into pathophysiologic processes should provide clues to develop
therapies, possibly even causative therapy, for the
early stages. However, we also need better therapies
for advanced stages. Thus, the purpose of this review
is to summarize our current understanding of the
pathogenesis of IgA nephropathy and discuss potential therapeutic consequences that derive from the
various steps involved in IgA nephropathy progression.
GENETIC AND/OR GENERIC
PROGRESSION FACTORS
From the few facts mentioned in the introduction, it
is clear that powerful genetic, environmental, or other
modifiers must determine in whom IgA nephropathy
is progressive and who is protected.
Hypertension is a potent predictor of outcome in
IgA nephropathy.8-10 Whether renoparenchymal or
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Jürgen Floege
primary hypertension is a more potent driver of injury
is still unresolved, but it must not be assumed that
uncontrolled primary hypertension would not contribute to damage in IgA nephropathy. Apart from hypertension, renal prognosis is worse in obese patients
with IgA nephropathy,11 and nonsurgical weight loss
can lead to a decrease in proteinuria.12
A large number of studies have investigated individual single-nucleotide polymorphisms (SNPs) and
their relation to the manifestation or course of IgA
nephropathy. Many of these studies focused on genes
related to the renin-angiotensin system13-18 or mesangial cell-specific genes such as megsin.19,20 Others,
including hemoxygenase, proinflammatory cytokines,
transforming growth factor, and uteroglobin, also have
been studied.21-26 Despite the plethora of investigations, no consistent picture has evolved. Most of these
studies are too small to provide definitive answers or
have studied ethnically heterogeneous populations.
Rarely has the role of a particular SNP been confirmed
independently in another population or even ethnic
group,27 and even then, results have not necessarily
been consistent. For example, in our German study,
renal survival was extended significantly in patients
with the CCR5⌬32 polymorphism compared with
those who did not have the deleted version of this
chemokine receptor,28 whereas a similar large French
study subsequently reported the exact opposite.29
In terms of HLA associations, earlier studies were
inconclusive, but some consistently have pointed to
an association of the HLA-DQ loci with the course of
IgA nephropathy.30 This recently has been confirmed
by a genome-wide association study in which a strong
association of a DQ locus with susceptibility to IgA
nephropathy was noted in British patients.31 Another
very large study confirmed a DQ association and
identified further loci, in particular in the complement
factor H region.32 Genetic associations suggesting
autosomal-dominant traits with highly variable penetrance also have been reported in cases of familial
IgA nephropathy.33-35 One of these loci was confirmed in a mouse strain prone to develop an IgA
nephropathy–like disease.36 However, no strong or
consistent signal was seen in the critical interval of
chromosome 6q22 in a high-throughput SNP association study involving a large set of patients with IgA
nephropathy.37 At present, none of these genetic associations is useful for clinical decision making. The
hope is that they will yield new insights into the
pathogenesis of IgA nephropathy and thus identify
new therapeutic approaches. It also needs to be realized that any genetic study in IgA nephropathy is
hampered by the problem of finding true non–IgA
nephropathy controls (in view of the high prevalence
of “covert” IgA nephropathy) and thus genetic studies
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may in reality examine factors involved in the clinical
manifestation of IgA nephropathy rather than the
susceptibility to it.
Environmental conditions also must have a strong
impact on the manifestation of IgA nephropathy, illustrated best by the inverse relationship between the
prevalence of IgA nephropathy and membranoproliferative glomerulonephritis (MPGN). In areas such as
Northern Europe, Japan, or Argentina with a relatively
high socioeconomic standard, IgA nephropathy prevalence far exceeds that of MPGN, whereas in regions
with a lower socioeconomic standard, such as some
Balkan countries, Peru, or South Africa, MPGN is the
dominant glomerulonephritis type. It has been hypothesized that overcrowding and poor hygiene early in
life may predispose to a T helper cell type 1 (TH1)dominant response, as observed in MPGN, whereas
dominance of the TH2 subset is related to the increased incidence of allergies, IgA nephropathy, and
minimal change disease in industrialized nations.38
When IgA nephropathy has manifested, its course
is modulated by inflammatory and infectious complications. For example, we have shown that subclinical
induction of the acute-phase response is present in
those with progressive IgA nephropathy.39 Macrohematuria is associated with upper respiratory tract
infections. In rare cases, spontaneous complete resolution of IgA nephropathy followed the resolution of
viral infections, for example, hepatitis A.40 Experimentally, infections and housing conditions, in other words,
conventional versus specific pathogen-free conditions, of mouse strains with an IgA nephropathy–like
pathologic state, exacerbated renal damage.41 This
correlated with higher levels of Toll-like receptor 9
(TLR9).42 Moreover, nasal challenge with CpG oligodeoxynucleotides (ie, synthetic DNA molecules containing cytosine-guanine motifs), which are ligands
for TLR9, also has been shown to worsen kidney
injury. Staphylococcus aureus cell envelope antigen
has been implicated in the induction of IgA nephropathy.43 Although this cannot be excluded, the alternative hypothesis is that microbial superantigens, such
as other infectious stimuli, can trigger IgA nephropathy disease activity. In agreement with this hypothesis, peripheral monocytes of patients with IgA nephropathy showed overexpression of TLR4, which,
among other ligands, is activated by bacterial lipopolysaccharide.44 Activation of TLR4 by bacterial lipopolysaccharide also has been implicated in methylation of
Cosmc, the chaperone of a major enzyme involved in
IgA1 glycosylation, and this may contribute to the
decreased galactosylation of IgA1 (discussed later).45
Although this latter observation would suggest a specific role of TLRs in IgA nephropathy, it is more likely
that TLR activation in patients with IgA nephropathy
Am J Kidney Dis. 2011;58(6):992-1004
Modifiers (genetic or environmental generic progression factors)
Pathogenesis of IgA Nephropathy
Increased occurrence of
IgA1 with poor galactosylation in the circulation
Manipulation of
mucosal immune
responses
IgG response against
poorly galactosylated
IgA1, IgA-IgG, or IgA-IgA
complex formation
Immunosuppression
Mesangial deposition of
IgA1 and/or immune
complexes
Removal of
glomerular IgA
IgA
receptors
Blockade of Fc-α
receptors or complement activation
Complement
activation
Mesangial cell damage
& activation of secondary
pathways
Growth factor
antagonists, etc
Glomerulosclerosis
Tubulointerstitial fibrosis
Antifibrotic agents
Figure 2. Overview of the major steps in the pathogenesis of
immunoglobulin A (IgA) nephropathy, in which each of the key
steps (center) likely is affected by potent genetic or environmental modifiers. Potential therapeutic consequences are shown on
the right. For further explanations, see text.
represents yet another generic progression mechanism given that there is ample evidence that TLR
activation represents a universal mode by which glomerular diseases are aggravated.46
Against the background of these potent modifiers, I
discuss a 6-step model of the pathogenesis of idiopathic IgA nephropathy (Fig 2), realizing that, as
always, some details may be oversimplified. This is
particularly true in IgA nephropathy, which may not
run in defined phases, rather with many mechanisms
operating in parallel, as illustrated by heavily destroyed and normal-appearing nephrons occurring side
by side simultaneously (Fig 1).
A major problem in investigating the pathogenesis
of IgA nephropathy is the absence of a good animal
model,47 mainly because of major differences between the rodent and human IgA systems. IgA is
mostly monomeric in human serum versus polymeric
in mice. Mice lack an IgA hinge region and dominant
hepatobiliary IgA clearance, 2 features seen in humans.48
Step 1: Increased Levels of Misglycated IgA1 in
the Circulation
The major difference between the 2 IgA subclasses,
IgA1 and IgA2, is the presence of an 18–amino acid
hinge region in IgA1. This difference explains why
IgA1, but not IgA2, is a substrate for proteases of
Streptococcus, Neisseria, and Haemophilus species.49
More than 85% of serum IgA is monomeric in humans. Di- and polymeric IgA are characterized by the
presence of a joining chain (J chain). Secretory IgA on
mucosal surfaces contains an additional protein, secretory component (Fig 3). IgA1 is heavily glycosylated,
with carbohydrates accounting for ⬃6% of its weight.
The IgA1 hinge region contains several sites of Olinked glycan attachments. The tight clustering and
variability of sialic acid, galactose, and N-acetylgalac-
Figure 3. Schematic illustration of the various
forms of immunoglobulin A
(IgA). Monomeric IgA consists of 2 heavy chains (with
CH1-CH3 domains and the
heavy chain V-domain), 2
light chains (with a light
chain C- and V-domain),
and a flexible heavily Oglycated hinge region. In dimeric IgA, 2 IgA monomers
are coupled through 1 J
chain. In secretory IgA, an
additional molecule (secretory component) is bound to
dimeric IgA. In addition, various high-molecular-weight
forms of IgA exist. Abbreviation: MBL, mannose-binding
lectin.
Am J Kidney Dis. 2011;58(6):992-1004
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Jürgen Floege
Figure 4. Immunoglobulin
A1 (IgA1) hinge region with its
potential glycosylation sites. NAcetylgalactosamine (GalNAc)
can be linked to galactose in
the ␤1,3 position by core ␤1,3
galactosyltransferase. Sialyltransferases can couple sialic
acid in the ␣2,3- or ␣2,6-position. In patients with IgA nephropathy (IgAN), the hinge region contains fewer galactose
residues due to reduced core
␤1,3 galactosyltransferase activity and/or “premature” (and
excessive) sialylation of GalNAc due to increased N-acetylgalactosamine–specific ␣2,6
sialyltransferase activity. The
latter precludes the subsequent
addition of a galactose residue
to the glycan side chain.
tosamine residues may significantly affect the physicochemical properties of IgA1.50
Elevated levels of circulating IgA1 and IgA1containing circulating complexes are observed in primary51 and recurrent IgA nephropathy after kidney
transplantation.52 Increased levels of circulating IgAcontaining complexes have even been detected in
urine.53 However, given that IgA serum levels can be
higher in IgA myeloma, although IgA nephropathy is
uncommon in such patients, the mere abundance of
IgA may not drive its mesangial deposition. IgA1
overproduction in IgA nephropathy probably locates
to the bone marrow rather than mucosal surfaces.54,55
In support of this, IgA nephropathy has been described as developing after allogeneic bone marrow
transplant,56 and pre-existing IgA nephropathy has
been observed to disappear after bone marrow transplant.57 Similarly, in a murine IgA nephropathy model,
renal changes are attenuated by a bone marrow transplant from healthy control mice.58 Tonsillar polymeric IgA1 production in particular poorly galactosylated IgA (discussed later) also is increased,59,60
although IgA nephropathy can occur after tonsillectomy and the tonsils produce a trivial amount of IgA.
Data about the effect of tonsillectomy on the further
course of IgA nephropathy are inconsistent, with
some reporting benefit61,62 and others failing to note
an effect.63,64
IgA deposited in glomeruli in IgA nephropathy is
mostly polymeric with ␭ light chains and more acidic
than normal serum IgA.65 The former may contribute
to a tendency of the deposited IgA to aggregate.66
However, correlation of levels of circulating polymeric IgA in patients with IgA nephropathy with
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clinical features of the disease is inconsistent.67,68
Some patients with IgA nephropathy also have elevated circulating levels and mesangial deposits of
secretory IgA,69,70 and these patients show more
hematuria.71,72
The most noteworthy finding in IgA nephropathy is
an elevation in circulating poorly galactosylated IgA1
O-glycoforms (Fig 4).73-76 The amount of poorly
galactosylated IgA1 in glomeruli significantly exceeds that occurring in serum,76,77 in particular in
patients with active IgA nephropathy78 and proliferative mesangial changes.79 In Henoch-Schönlein purpura, poorly galactysolated IgA is observed only in
patients with renal involvement, in other words, IgA
nephropathy.80 Experimentally, enzymatically cleaving oligosaccharides from the hinge region of normal
IgA significantly enhanced IgA deposition in the mesangium.81 These observations strongly imply that the
composition of IgA1 hinge-region glycans is a key
contributor to mesangial deposition.
The production of poorly galactosylated IgA1 in
patients with IgA nephropathy results from a defect in
B lymphocytes. Decreased activity of the key enzyme, core ␤-1,3-galactosyltransferase (C1␤3Gal-T),
has been shown in both freshly isolated82 and immortalized83 B cells. The poor galactosylation of IgA1 is
not shared by the other O-glycated immunoglobulin,
IgD, suggesting that it may appear at a later stage in
the development of B cells and may be secondary to
aberrant immunoregulation.84 The TH2 cytokine interleukin 4 decreases messenger RNA and activity levels
of C1␤3Gal-T and its chaperone Cosmc.85 However,
others have reported a heritable contribution to poor
IgA galactosylation. Thus, patients with IgA nephropAm J Kidney Dis. 2011;58(6):992-1004
Pathogenesis of IgA Nephropathy
athy and their first-degree relatives, but not patients’
spouses, show significantly higher IgA1 levels with
poorer galactosylation than healthy controls.86-88 These
observations in asymptomatic first-degree relatives
again support the notion that potent modifiers must
exist that determine who develops overt IgA nephropathy. In addition to C1␤3Gal-T, the chaperone Cosmc
is specifically required for O-galactosylation of the
IgA1 hinge region. Cosmc gene mutations will result
in secondary loss of C1␤3Gal-T function with undergalactosylation of glycoproteins and autoimmunity.89
However, no evidence for Cosmc gene mutations has
been detected in patients with sporadic or familial IgA
nephropathy.45,90
What exactly triggers the overproduction of poorly
galactosylated IgA1 in IgA nephropathy is unknown.
No evidence for specific viral, bacterial, or alimentary
antigens has been found in sera or mesangial deposits91-93; rather, all polymeric IgA responses to systemic immunization with common antigens are increased, possibly related to a switch to an
immunoproteasome, whereas the response to mucosal
immunization is impaired.94-96 The primary abnormality in IgA nephropathy could be compromised mucosal IgA responses, permitting enhanced antigen challenge to the marrow, in other words, defective oral
tolerance.97 A disrupted tolerance model has been
produced by transgenic overexpression of lymphotoxin-like inducible protein in mice. These animals
develop T-cell–mediated intestinal inflammation and
show elevated production of polymeric IgA, as well
as some IgA nephropathy–like pathologic characteristics.98 Further evidence for an altered mucosal barrier
function is the observation that approximately onethird of Swedish patients with IgA nephropathy had
rectal mucosal sensitivity to gluten99 and ovalbumin,100 suggesting there is generalized reactivity with
food antigens.
A key finding in the context of this discussion is
that poor galactosylation is particularly apparent in
IgA1 produced against mucosal antigens (Helicobacter pylori) compared with systemic antigens (tetanus
toxoid).101 Why levels of mucosal and systemic Oglycosylation of IgA1 are different has yet to be
clarified. However, this observation suggests the fascinating possibility that in IgA nephropathy, there is no
real defect in IgA1 O-glycosylation, but rather an
increase in “mucosal-type” IgA1 in serum, possibly
related to migration of mucosal B cells to bone
marrow, where they produce their “correct” poorly
galactosylated IgA.102 This is consistent with the
observation that homing of lymphocytes between mucosal and systemic sites is altered in IgA nephropathy.103,104
Am J Kidney Dis. 2011;58(6):992-1004
Understanding the early events involved in this
translocation of B cells may offer new therapeutic
options. If there is a mucosal defect and hyperreactivity to antigens, topical rather than systemic
immunosuppression may be beneficial in patients with
IgA nephropathy. First evidence for this is emerging.105
Step 2: Generation of Antibodies Against
Misglycated IgA1
Aberrantly glycated IgA1 may be nephritogenic by
self-aggregation and binding to mesangial matrix.
Defective glycosylation alone can be sufficient to
inflict glomerular damage, as shown in murine studies
in which the genetic lack of ␤-1,4-galactosyltransferase I resulted in an IgA nephropathy–like kidney
disease.106
Autoimmunity also may contribute to IgA nephropathy. Whereas an autoimmune response to mesangial
cells in IgA nephropathy107 has not been confirmed,
the misglycated IgA1 hinge region is aberrantly exposed108 and may induce a humoral immune response.109,110 Lymphocytes from patients with IgA
nephropathy produce IgG that forms complexes with
poorly galactosylated IgA1 in a glycan-dependent
manner and triggers the formation of IgA1-IgG immune complexes.111 The presence of glycan-specific
IgG antibodies can differentiate patients with IgA
nephropathy from healthy and diseased controls with
high specificity and sensitivity. This confirms prior
data that poorly galactosylated IgA1 O-glycoforms
occur mainly in circulating high-molecular-weight
IgA complexes in IgA nephropathy.112 Currently, little
is known about the kinetics of IgG antiglycan antibodies in IgA nephropathy. It is unclear whether the
presence of mesangial IgG deposits in a fraction of
patients with IgA nephropathy could reflect fluctuations of IgG autoantibody levels or identifies a particular subgroup of patients. Presently, the value of IgG
antiglycan antibodies as a tool to monitor the disease
and/or guide therapy in IgA nephropathy remains to
be established.
The development of IgG antiglycan autoantibodies
may relate to prior infections with viruses (eg, EpsteinBarr virus) or Gram-negative bacteria (eg, Streptococcus) that express GalNAc-containing moieties, inducing an IgG response against the glycans. These IgG
antibodies subsequently might cross-react with glycans on IgA1.112 This “molecular mimicry” also could
explain the association of macroscopic hematuria with
upper respiratory tract infections, in which serum
levels of microbial-specific IgG increase postinfection and, in error, also bind to poorly galactosylated
IgA1, resulting in the formation of IgA1-IgG complexes with mesangial cell activation and hematuria.
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Jürgen Floege
IgA-containing immune complexes in the circulation
increase during clinical relapses of IgA nephropathy.68
An autoimmune component in the pathogenesis of
IgA nephropathy currently provides the best rationale
for immunosuppressive therapy. As reviewed elsewhere,113 there is now compelling evidence that corticosteroids are beneficial in proteinuric patients with
IgA nephropathy at risk of progression. At least in
Asian patients, there also is evidence for a benefit
from mycophenolate mofetil, but to date, no benefit
has been observed in white patients. However, 2
caveats have to be kept in mind. First, there is no
evidence that immunosuppressive combination therapy
is more beneficial than corticosteroids alone.113 This
contrasts with most other autoimmune glomerular
diseases, such as membranous nephropathy, in which
corticosteroid monotherapy generally is less effective
than immunosuppressive combinations. Second, the
efficacy of any immunosuppressive regimen used
after kidney transplant to prevent recurrence of IgA
nephropathy has not yet been shown.7
Step 3: Mesangial Deposition of Misglycated IgA1
and/or Immune Complexes
Mesangial IgA consists at least in part of di- and
polymeric IgA.65,114 However, glomerular deposition
of polymeric IgA alone cannot explain the pathogenesis of IgA nephropathy: glomerular amounts of polymeric IgA are not associated with disease severity and
glomerular eluates of patients with IgA nephropathy
do not differ from disease controls.115 Thus, in addition to size, molecular alterations also likely contribute to the IgA1 localization in glomeruli in IgA
nephropathy. Binding of IgA1 to mesangial cells
depends on anionic charge.116
Poorly galactosylated IgA1 may be sequestered in
the mesangium in IgA nephropathy by self-aggregation, which seems to be related to insufficient conformational stiffness of the hinge peptide.74,117,118 In
addition, galactose-depleted IgA1 has been reported
to have the highest affinity for a number of extracellular matrix proteins.119 Whether poor galactosylation
also may impair IgA1 clearance by impeding IgA1
interactions with hepatic IgA receptors120 is uncertain
because IgA1 in general shows little hepatic clearance.121
In addition to aggregated IgA1, mesangial deposition likely derives from circulating IgA1-containing
immune complexes. Poorly galactosylated IgA1 has
been detected in complexes with IgG.122 Both mesangial deposition of circulating immune complexes and
their in situ formation are compatible with observations that mesangial IgA deposits are cleared when an
IgA nephropathy kidney is inadvertently transplanted
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Box 1. Characteristics of IgA Receptors
●
●
●
●
●
Fc␣R1 (CD89)
〫 Binds IgA1 and IgA2
〫 Association with FcR␥ chain determines inhibitory or
activating signals
Fc␣/␮R
〫 Binds IgA and IgM
Polymeric immunoglobulin receptor
〫 Mediates immunoglobulin transport across epithelial barriers
Asialoglycoprotein receptor
〫 Alternative receptor for IgA
Transferrin receptor (CD71)
〫 Alternative receptor for IgA
Abbreviation: IgA, immunoglobulin A.
into a patient without IgA nephropathy.123 When
formed, IgA-containing immune complexes, like
poorly galactosylated IgA1 alone, show a high affinity
for mesangial matrix proteins.124 Finally, formation
of IgA1-IgG complexes may alter serum IgA1 levels
by decreasing the rate at which it is eliminated and
catabolized by the liver.122
An interesting approach at the stage of mesangial
IgA deposition might be its therapeutic removal. As
mentioned, IgA1 is susceptible to degradation by
bacterial proteases. In a passive mouse model of IgA
nephropathy, treatment with Haemophilus influenzae–
derived protease removes both the antigen and antibody components of glomerular IgA immune complexes.125 Although this approach works in an acute
passively induced model, its relevance to the slow and
chronic human IgA nephropathy and its potential
antigenicity render predictions on the clinical usefulness difficult.126
Step 4: Binding of Mesangial IgA Receptors and/or
Activation of Complement
Two key events after the mesangial deposition of
IgA1 and/or IgA1-containing immune complexes include binding of IgA to mesangial receptors and
complement activation.
Five types of IgA receptors exist in humans (Box
1): Fc␣R1 (CD89), polymeric immunoglobulin receptor, Fc␣/␮R, asialoglycoprotein receptor, and transferrin receptor (CD71).127 Patients with IgA nephropathy show overexpression of CD71 in the mesangium,
which colocalizes with IgA deposits, and polymeric
and misglycated IgA1 were identified as a major
inducers of CD71 in mesangial cells.128-131 Early data
for human mesangial cells also suggested that polymeric IgA and/or IgA immune complexes activate the
cells through Fc␣R132 or the asialoglycoprotein receptor.133 Several other studies subsequently failed to
detect Fc␣R1, asialoglycoprotein receptor, or polymeric immunoglobulin receptor on human mesangial
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Pathogenesis of IgA Nephropathy
cells.134-138 However, on monocytes of patients with
IgA nephropathy, CD89 is downregulated, in particular by polymeric IgA1,139 and there is reduced binding of monomeric IgA.140 Both may contribute to
impaired degradation of IgA1, in particular polymeric
IgA1, and IgA1 immune complexes.
Transgenic mice expressing human CD89 on macrophage/monocytes shed soluble CD89 into the circulation and develop an IgA nephropathy–like renal
pathologic state.141 However, the relevance of this
pathway for human IgA nephropathy has been questioned.142,143 Patients with IgA nephropathy with progressive kidney disease show lower soluble CD89
levels than stable patients.144
Although to date, these insights have not yet been
translated into clinical therapy, first approaches are
emerging. For example, monovalent targeting of CD89
by anti-Fc␣RI Fab stimulates potent inhibitory signaling through the associated FcR␥ chain and can experimentally decrease renal inflammation.145,146
Polymeric IgA and IgA-containing immune complexes activate complement through the alternative
and lectin-binding pathways,72,147 and using very
sensitive methods, systemic complement activation
can be detected in patients with IgA nephropathy.148
Mesangial IgA deposits frequently are associated with
complement C3, C5, and properdin.149 Mesangial
secretory IgA deposits are associated with the detection of mannose-binding lectin (MBL) and C4d.69
Glomerular expression of the components of the MBL
pathway is particularly notable in younger patients
and those with more severe disease.150-152 Activation
of C4 with mesangial C4d deposits also identifies
patients with IgA nephropathy with a worse prognosis.153 Activation of the MBL pathway also can be
detected in Henoch-Schönlein–related nephritis.154
These data suggest that inhibitors of complement
activation may have a role in the treatment of highrisk patients with IgA nephropathy.
Step 5: Mesangial Cell Damage and Activation of
Secondary Pathways
Binding of polymeric IgA1 or IgA1-containing
immune complexes to mesangial cells has many biological consequences, for example, increased production of cytokines,72,130 macrophage migration-inhibitory factor,155 growth factors,130,156 inducible nitric
oxide synthase,156 and renin,157 as well as changes in
proliferation and apoptosis.158,159 In kidney biopsy
specimens, the extent of IgA deposition in glomeruli
correlates with that of neutrophil infiltration and mesangial hypercellularity. Consistent with this, injection
of misglycated IgA1 into rats leads to glomerular
deposits and neutrophil infiltration.81 Finally, inducAm J Kidney Dis. 2011;58(6):992-1004
tion of oxidative stress in IgA nephropathy predicts
the prognosis.160
Glomerular IgA also can induce a number of paracrine effector mechanisms. For example, mesangial
cells activated by IgA release tumor necrosis factor ␣,
transforming growth factor ␤, and platelet-activating
factor, all of which can damage podocytes and/or
tubular cells.161-163 Consistent with this, podocyte
loss correlates with disease severity and outcome in
IgA nephropathy164,165 and both focal segmental glomerulosclerosis and tubulointerstitial damage predict
outcome in IgA nephropathy.166-169
Whereas most of these factors lend themselves to
therapeutic intervention, few intervention studies in
models of IgA nephropathy or mesangioproliferative
glomerulonephritis models are available. The single
best-established factor responsible for driving proliferation of mesangial cells is platelet-derived growth
factor (PDGF). Mice lacking PDGF-B fail to develop
a mesangium, and antagonism of PDGF-B or -D is a
highly effective approach to inhibit pathologic mesangial cell proliferation matrix accumulation in vivo as
well as secondary focal segmental glomerulosclerosis
and tubulointerstitial damage.170 Elevated serum
PDGF-DD levels also may serve as a biomarker of
IgA nephropathy.171 As reviewed elsewhere,171 the
rationale to test anti-PDGF therapy in IgA nephropathy is now extensive.
Step 6: Activation of Nonspecific
Profibrotic Pathomechanisms
Space limitations prevent a detailed discussion of
potential therapeutic targets in glomerular and tubulointerstitial fibrosis. We and others recently have reviewed this topic in general172-175 and with particular
focus on PDGF.176 In particular, factors such as PDGF,
which operate in both the active mesangioproliferative processes and secondary tubulointerstitial damage, lend themselves to therapeutic trials because as
mentioned, in IgA nephropathy, both active glomerular inflammation and more degenerative tubulointerstitial damage may coexist.
SUMMARY
Although our therapeutic armamentarium at present is still largely limited to optimal supportive care
and immunosuppression in some instances, these new
insights into the pathogenesis can be expected to yield
novel, perhaps individualized, therapeutic options in
patients with primary or recurrent IgA nephropathy.
ACKNOWLEDGEMENTS
Prof H.J. Gröne, DKFZ Heidelberg, Germany, kindly provided
Figure 1.
999
Jürgen Floege
I apologize to all authors whose important work I could not cite
due to space restrictions.
Support: This work was funded by grants from the Deutsche
Forschungsgemeinschaft (DFG; SFB 542/C7 and SFB TRR57).
Financial Disclosure: The author declares that he has no relevant financial interests.
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