Crescentic IgA Nephropathy

Nephrology Grand Rounds
March 16th, 2010
Aditya Mattoo
 Epidemiology
 Clinical Presentation
 Prognosis
 Pathogenesis
 Histology
 Treatment
 Recurrence in Transplant
First described by Berger et al in 1968.
Characterized by predominant IgA
deposition in the glomerular mesangium.
Most common form of primary
glomerulonephritis around the world.
Berger et al. J Urol Nephrol, 74:p694, 1968.
Clinical onset in second and third decades of
life. 80% of patients are between the ages of
16-35 years at the time of diagnosis.
Male predominance of 2:1 in Japan to as
high as 6:1 in northern Europe and US.
Asians and Caucasians more prone to
develop IgAN than people of African descent.
There appears to be a familial clustering of
IgAN which shows strong family predisposition
in about 10% of cases.
 In the U.S., regions in Kentucky, Alabama and
other parts of the Southeast exhibit a higher
incidence of IgAN.
 In other parts of the world, familial clustering of
IgAN seems to be more common in Southern
France and Italy.
 Many genetic studies are underway, trying to
establish common susceptibility genes in
familial IgA.
IgAN Nationwide
IgAN prevalence as a percentage of primary GN:
 In Japan, 50% of new cases of GN are IgAN (causing 40%
of all ESRD).
 30% of new GN cases in Western Europe and Australia.
 10% in general US population (exception Native Americans
from New Mexico with prevalence of rate of 38%)
Crescentic IgAN (CIgAN) is seen in approximately
7% of patients with IgAN.
However, a study conducted by Shouno et al
reported that by increasing the number of serial
sections examined for any single biopsy specimen
from the standard 20 to 100 sections, the finding of a
segmental necrotizing lesion increases to 30%.
Donadio et al. NEJM, 347:p738, 2002.
Shouno et al. Acta Pathol Jpn, 43:p723, 1993.
Clinical Presentation
IgAN is highly variable, both clinically and
Clinical features range from asymptomatic
hematuria to RPGN.
Classic flare includes painless hematuria
concurrent with the onset of viral illness (e.g.
pharyngitis, gastroenteritis, etc.)
Clinical Presentation
Approximately 40-50% of patients present with
one or recurrent episodes of gross hematuria.
Another 30-40% have microscopic hematuria
and usually mild proteinuria incidentally
detected on a routine examination.
Gross hematuria will eventually occur in 2025% of these patients.
Clinical Presentation
Of the patients with gross hematuria
secondary to IgAN, up to 40% will develop
transient renal failure.
Less than 10% present with either nephrotic
syndrome or RPGN (characterized by edema,
hypertension, and renal dysfunction).
Clinical Presentation:
Crescentic vs Non-crescentic
Crescentic IgAN
Non–crescentic IgAN
Sex male/female
Mean age years
33 ± 12.5
32 ± 13
Serum creatinine mg/dL
1.3 ± 0.5
1.2 ± 0.4
Proteinuria g/day
2.3 ± 2.1
1.1 ± 1.2
< 0.003
Number of patients
History of recurrent
P value
Hematuria % of patients
Arterial hypertension
% of patients
Ferarrio et al. 3rd Congress of Nephrology, 2003.
Between 5-30% of patients with mild proteinuria,
hematuria or mild renal dysfunction undergo
spontaneous remission of abnormal laboratory
 A Chinese study of 72 consecutive patients with
IgAN performed diagnostic biopsies on patients
with hematuria, but with no or minimal proteinuria
(defined as less than 0.4 g/day).
 After a seven year follow up period, protein
excretion >1g/d, HTN, and serum Cr ≥1.4 mg/d
developed in 33%, 26%, and 7%, respectively.
Hotta et al. AJKD, 39:p493, 2002.
Szeto et al. Am J Med. 110:434, 2001.
Approximately 25-30% of patients will reach
ESRD at 10 years.
 Clinical risk factors associated with progressive
disease are:
> 1g/d proteinuria
Male gender
Persistent microscopic hematuria
Histologic risk factors include cellular crescents
and endocapillary proliferation.
Donadio et al. NEJM, 347:p738, 2002.
Prognosis – Crescentic IgAN
Some correlation between crescents and
clinical risk factors exists (in one case series
all patients who had at least 10% cellular
crescents had hypertension and > 1g
Furthermore, prospective studies have shown
that 40% of patients with as little at 10%
cellular crescents will progress to ESRD within
3 years.
Tumlin et al. Seminars in Nephrol 24:p256, 2006.
IgA is an antibody that plays a
critical role in mucosal immunity.
 IgA has two subclasses (IgA1 and
IgA2) and can exist in a dimeric
form called secretory IgA.
 It exists in two isotypes, IgA1
(90%) and IgA2 (10%):
 IgA1 is found in serum and made by
bone marrow B cells.
 IgA2 is made by B cells located in the
mucosa and is the major
immunoglobulin found in mucosal
 IgA2 provides a key first line of
defense against invasion by inhaled
and ingested pathogens at the
vulnerable mucosal surfaces.
 IgA1 provides a second line of
defense in the serum, mediating
elimination of pathogens that have
breached the mucosal surface
Panel A – Normal IgA1 Molecule
Panel B - Structure of carbohydrates
O-linked to serine (Ser) or threonine
(Thr) residues on IgA1.
The IgA1 heavy chain contains a hinge
region (a 19-residue sequence
between CH1 and CH2, which
consisted entirely of serine, threonine
and proline).
Glycosylation is restricted to the hinge
region of IgA1.
N-acetyl galactosamine (GalNAc) is Olinked to Ser or Thr residues.
GalNAc is linked to Gal through the
action of the enzyme β1,3-galactosyl
Sialic acid is linked to Gal through an
α2,3 link and to GalNac through an
α2,6 link.
Donadio et al. NEJM, 347:p738, 2002.
Pathogenesis – Mesangial Deposition
Although the pathogenesis of IgAN is not
completely clear, it is well accepted that aberrant
glycosylation pattern of IgA is involved.
 This is supported by the fact that in IgAN,
mesangial deposits of IgA contain high
concentrations of abnormally undergalactosylated IgA1.
 Furthermore it has been demonstrated that
enzymatic removal of complex oligosaccharides
from the hinge region of IgA1 antibodies from
normal individuals significantly enhanced IgA
deposition in the mesangium.
Sano et al. NDT, 17:p50, 2002.
Pathogenesis – Mesangial Deposition
Leukocyte β1,3-galactosyl transferase activity
is decreased in patients with IgAN which may
be responsible for deficient galactosylation of
Abnormally glycosylated IgA has a higher
tendency to self-aggregate and form
complexes with IgG antibodies directed at
epitopes in the hinge region of IgA1.
Novak et al. KI 62:p465, 2006.
Allen et al. NDT. 12:p701, 1997.
Pathogenesis – Decreased Clearance
Leukocyte Fc-receptor for IgA (CD89) is
downregulated, furthermore the receptor
binding site is in the CH2 domain close the
hinge (possibly affected by deficient
Altered IgA1 clearance from circulation,
particularly via the hepatic asialoglycoprotein
receptor (ASGPR) whose chief ligand is the
terminal galactose of IgA1 (the principle site
of IgA catabolism).
Pathogenesis - Summary
Floege et al. JASN, 11:p2395, 2000.
Pathogenesis – Inflammatory Response
IgA elicits a phenotypic transformation in
mesangial cells in vitro, with mesangial cell
proliferation and secretion of extracellular
matrix component.
 IgA appears to stimulate the production of a
variety of proinflammatory and profibrotic
molecules, such as interleukin-6.
 Increased renal expression of TGF-beta which
correlates with severity of tubulointersitial
damage in IgAN.
Barratt et al. Seminars in Nephrol 24:p197, 2004.
Taniguchi et al. Scand J of Urol Nephrol. 33:p243, 1999.
Pathogenesis – Inflammatory Response
Studies have suggested that mesangial IgA
probably activates C3, leading to the
generation of C5b-9 (MAC), which then
promotes the production of inflammatory
mediators and matrix proteins by mesangial
 Systemically, low-grade complement
activation through the alternative pathway
can be seen in patient’s with IgAN as well.
Zwriner at al. KI, 51:p1257, 1997.
The suspicion of IgAN is generally based
upon the clinical history and laboratory data.
 The diagnosis can be confirmed ONLY by
kidney biopsy demonstrating IgA deposition.
 Given the generally benign course of patients
with IgAN who have isolated hematuria,
biopsies are usually performed only if there
are signs suggestive of more severe or
progressive disease (HTN, proteinuria,
elevated Cr, etc.)
A skin biopsy, looking for IgA deposition in the
dermal capillaries, has not proven to be
sufficiently predictive in IgAN.
 Plasma polymeric IgA1 levels are elevated in
30-50% of cases, but this suggestive finding is
not sufficiently specific to establish the
 Circulating IgA-rheumatoid factors and IgAimmune complexes have been tested as
diagnostic markers but are not specific nor can
they be reliably correlated with disease activity.
Susuki at al J Clin Invest. 119:p1668, 2009.
Increased serum levels of Gal-deficient IgA1,
present in IgAN, may suggest the diagnosis.
However, this assay has not been validated by
testing non-IgAN patients with GN who present
similarly to IgAN.
Gal-deficient IgA1-specific IgG may be prove to
be a clinically useful diagnostic marker as serum
levels of IgG specific for Gal-def IgA1 are
elevated in patients with IgAN.
Susuki at al J Clin Invest. 119:p1668, 2009.
(A) Gal-deficient IgA1 incubated with IgG
from healthy controls, non-IgAN disease
controls and IgAN patients.
The rIgG from an IgAN patient served as a
positive control.
Serum IgG from IgAN patients bound more
to Gal-deficient IgA1 compared with the IgG
from disease controls or healthy controls.
(B) The intensity of signal in each well was
measured by densitometry as compared
to rIgG
Serum IgG from IgAN patients has
significantly higher reactivity to Gal-def IgA1
compared with that from healthy (P < 0.0001)
and disease controls (P < 0.0001).
Serum IgG from 54 of the 60 patients with
IgAN showed values greater than the 90th
percentile of the values for healthy controls.
(C) ROC for serum IgG binding to Galdeficient IgA1. The area under the curve is
0.9644. These data indicate a sensitivity of
88.3% and a specificity of 95.0%
(D)/(E) The intensity of IgG binding to Galdeficient IgA1 correlated with urine Pr/Cr
ratio as well as with urinary IgA-IgG
immune complexes.
Susuki at al J Clin Invest. 119:p1668, 2009
The major finding on light microscopy is mesangial
proliferation and matrix expansion (arrows) that can be
focal, but more often seen diffusely.
Light microscopy of a glomerulus from a patient with IgAN
showing increased mesangial matrix and cellularity.
H&E demonstrating
hypercellularity and
matrix expansion.
H&E with mesangial cell
hypercellularity and focal
area of endocapillary
proliferation (bold arrow).
H&E demonstrating
diffuse endocapillary
proliferation and
H&E -silver
demonstrating cellular
crescent with partial
collapse of glomerular
H&E demonstrating
diffuse endocapillary
proliferation and fibrinoid
Silver stain
demonstrating crescent
and focal glomerular tuft
adhesion to Bowman’s
Tumlin et al. CJASN. 2:p1054, 2004.
Segmental crescents are relatively common,
although they may be missed by sampling
error if only a few glomeruli are obtained. (as
mentioned earlier as many of 30% of IgAN on
biopsy may have crescents).
 Although there is usually little or no
glomerulosclerosis on initial biopsy, patients
may eventually develop glomerulosclerosis,
by which time they have clinically advanced
disease (i.e. decreased GFR and increased
Histology - Immunoflourescence
IF demonstrates prominent, globular
deposits of IgA (often accompanied by C3
and IgG) in the mesangium and, to a lesser
degree, along the glomerular capillary wall.
Histology - IF
IF demonstrating large, globular mesangial IgA deposits.
Note that the capillary walls are not outlined, since the
deposits are primarily limited to the mesangium.
Histology – Electron Microscopy
EM typically reveals electron-dense
deposits that are primarily limited to the
mesangium, but may also occur in the
subendothelial and subepithelial spaces.
The number and size of these deposits
generally correlates well with the
severity of changes seen on light
Histology - EM
Low power electron micrograph in IgAN. The primary finding is electron dense
deposits that are limited to the mesangial regions (D). The glomerular basement
membrane (GBM) is normal and there are no glomerular capillary wall deposits.
Histology - EM
Higher power EM
with significant
expansion of
mesangial matrix
and presence of
large mesangial
dense deposits
Histology – Oxford Classification
A consensus on the pathologic classification of IgA nephropathy has been
developed by the International IgAN Network with the Renal Pathology Society:
Mesangial hypercellularity:
0 = < 4 mesangial cells are present per mesangial area
1 = 4-5 mesangial cells are present per mesangial area
2 = 6-7 mesangial cells are present per mesangial area
3 = >8 mesangial cells are present per mesangial area.
Scores for all glomeruli are averaged and the resulting assigned hypercellularity score is
either M0 if the mean score is less than 0.5 or M1 if the mean score is greater than 0.5.
Segmental glomerulosclerosis:
 S1 = any part of the glomerular tuft is involved in sclerosis
 S0 if no segmental glomerulosclerosis is present.
Endocapillary hypercellularity:
 E1 = if hypercellularity is present within the capillary lumina resulting in narrowing.
 E0 if no hypercellularity is present within lumina.
Tubular atrophy/interstitial fibrosis — The percentage of the cortical area
involved by tubular atrophy or interstitial fibrosis.
 A score of T0, T1 or T2 is given if the percentage of involved cortical area is 0-25; 26-50 or
>50 percent, respectively.
Histology – Haas Classification
Based on the histological features of 244
cases of IgAN over a 14 year period at one
 Class I (39 cases): minimal or no mesangial
hypercellularity, without glomerulosclerosis
Class II (18 cases): FSGS without active cellular
Class Ill (110 cases): focal proliferative GN
Class IV (42 cases): diffuse proliferative GN
Class V (35 cases): any biopsy showing > 40%
globally sclerotic glomeruli and/or > 40%
estimated cortical tubular atrophy or loss.
Haas et al. AJKD, 29:p829, 1997.
Histology – Haas Classification
Haas et al. AJKD, 29:p829, 1997.
Histology – Haas Classification
Haas showed a statistically significant correlation between histologic subclass
and renal survival, with an order I, II (greatest survival) > Ill > IV, V.
Histology – Haas
Classification with
Haas also reported the
probability of renal survival
when crescents were present
in Haas subclass III and IV.
Patients with isolated hematuria, no or
minimal proteinuria, and a normal GFR are
typically not treated (and often not biopsied),
unless they have evidence of progressive
disease such as increasing proteinuria, blood
pressure, and/or serum creatinine.
Treatment – ACE/ARB
Patients with persistent proteinuria (500-1000 mg/day),
mildly reduced GFR that is not declining rapidly, and only
mild to moderate histologic findings on renal biopsy are
traditionally managed with ACE/ARB.
In one trial, 44 patients with proteinuria (≥0.5 g/day,
mean 1.9 g/day) and a Cr ≤1.5 mg/dL at baseline were
randomly assigned to either enalapril or antihypertensive
agents other than ACE inhibitors or ARBs.
At follow-up of about six years, renal survival, defined as
<50% increase in the Cr, was significantly more likely in
the enalapril group (92% versus 55%).
A significant decrease in proteinuria was only observed
in the enalapril group (2 g/day at baseline to 0.9 g/day).
Blood pressure control was similar in the two groups.
Praga et al. JASN, 14:p1578, 2003.
Treatment - Immunosuppressives
Patients with more severe or rapidly
progressive disease (e.g. nephrotic range
proteinuria or proteinuria persisting despite
ACE/ARB therapy, rising serum creatinine,
and/or renal biopsy with more severe
histologic findings) may benefit from
immunosuppressive therapy in addition to
ACE/ARB slow disease progression.
Treatment – Glucocorticoids
Glucocorticoid therapy is recommended in patients
with clinical and histologic evidence of active
inflammation (eg, hematuria and/or proliferative or
necrotizing glomerular changes).
The potential benefit of glucocorticoid therapy
alone in IgAN has been examined in uncontrolled
studies, retrospective observations, and a few
relatively small, randomized controlled trials.
The applicability of these trials to current practice is
unclear, since most trials predated widespread use
of ACE/ARBs.
Treatment - Glucocorticoids
A prospective trial from Italy included 86 adults with
proteinuria (1 to 3.5 g/day) and at most mild renal
insufficiency (median serum creatinine 1 mg/dL).
The patients were randomly assigned to supportive
therapy alone, or glucocorticoids (1.0 gram of IV
methylprednisolone for 3 consecutive days at the
beginning of months 1, 3, and 5, combined with 0.5
mg/kg of oral prednisone given on alternate days for
6 months).
At five and ten years, the glucocorticoid treated
patients had a markedly lower incidence of the
primary end point, which was a doubling of Cr (2%
vs. 21% at five years and 2% vs. 30% at 10 years).
The effect of ACE/ARB was not assessed.
Pozzi et al. Lancet, 353:p883, 1999.
Rx – Combined Immunosuppressive Therapy
Combined immunosuppressive therapy is
recommended in patients with more severe
active disease as defined by a more rapidly
progressive clinical course and/or histologic
evidence of severe active inflammation (eg,
crescent formation).
 Several trials have suggested a possible benefit
from combined immunosuppressive therapy in
these patients, however, most did not include a
comparison group treated with prednisone
 Similarly, the studies were primarily performed
prior to the widespread use of aggressive
ACE/ARB therapy.
Rx – Combined Immunosuppressive Therapy
In a randomized control trial of 38 patients with
rapidly progressive disease (without crescents)
combined treatment with prednisone and oral
cyclophosphamide for 3 months, followed by
azathioprine for two years or more, resulted in
better preservation of renal function.
 At 2, 3, 4, and 5 years renal function was
preserved in 82%, 82%, 72% and 72% of
treatment patients, respectively, when
compared with 68%, 47%, 26%, and 6% in
controls who received placebo.
 A lower degree of proteinuria was also
observed in treatment group compared to
Ballardie et al. JASN, 13:p142 2002.
Treatment – Crescentic IgAN
Uncontrolled reports in patients with IgAN
causing crescentic RPGN suggest possible
benefit from regimens similar to those used
in other forms of crescentic GN:
 IV pulse methylprednisolone followed by oral
 IV or PO cyclophosphamide,
 and/or plasmapheresis.
Treatment – CIgAN – Roccatello et al
One report evaluated the efficacy of combination
therapy (steroids, oral cyclophosphamide and
plasmapheresis) in six patients with crescentic
glomerulonephritis due to IgAN (entry required
>40% crescents).
 After two months of therapy, there was substantial
clinical improvement characterized by reductions
in Cr and proteinuria.
 However, repeat renal biopsy at 2 months showed
persistence of crescents in all patients and 50% of
patients had progressive disease after therapy
was discontinued.
Roccatello et al. NDT, 10:p2054, 1995.
Treatment – CIgAN – Tumlin et al
A more prolonged course of aggressive
immunosuppressive therapy was evaluated in 12
patients with CIgAN who had a mean serum Cr of
2.7 mg/dL and proteinuria of 4 g/day at baseline.
The treatment regimen consisted of the following:
 Pulse methlyprednisolone (15 mg/kg/d for 3 days)
 PO prednisone
○ 1 mg/kg/d for 60 days, then slow taper
 with all patients on 10 mg/d at the time of repeat biopsy
 Monthly IV cyclophosphamide (0.5 g/m2) for six months.
Tumlin et al. NDT, 18:p1321, 2003.
Treatment – CIgAN – Tumlin et al
After the six month course, there was significant improvement in
the serum Cr concentration (from 2.7 to 1.5 mg/dL) and in
proteinuria (from 4 to 1.4 g/day).
Repeat biopsy at six months revealed the absence of cellular
crescents and endocapillary proliferation in all patients.
Throughout a three-year follow-up, all patients continued
prednisone (0.15 mg/kg per day), and the blood pressure was
controlled to a goal of <130/70 mmHg with ACE inhibitors and
other agents as needed.
Compared with 12 untreated historic controls (matched for age,
gender, baseline serum Cr and histologic severity), the incidence
of ESRD at three years was significantly lower in the treated
group (1 of 12 = 8% versus 5 of 12 = 42%).
Tumlin et al. NDT, 18:p1321, 2003.
Transplant IgAN Recurrence
In 1975, only 7 years after his initial description
of the entity of IgAN, Berger et al reported the
first case of recurrent IgA in a renal allograft.
 The recurrence of IgA in transplants among
patients with IgAN in their native kidneys
occurred in 40-60% of cases when protocol
biopsies were performed.
 In one study of 240 recipients, after a mean
follow up of 5 years, 13% of exhibited
recurrence related graft dysfunction with 5%
losing the graft secondary to recurrent IgAN.
Wang et al. AJKD, 38:p588, 2001.
CIgAN in Transplants – Kowalewska et al
A study reviewed 2959 renal biopsies over a period
of 14 years and found 33 cases of
glomerulonephritis with crescents (1.1%).
Of these 33 cases, 8 had the diagnosis of IgAN
(0.2% of total).
6 of the 8 cases were the result of recurrent IgAN,
and 2 cases were presumptive de novo IgAN.
6 patients had 10-30% crescents in the glomeruli,
the 2 remaining cases about 7%.
Despite intensified therapy, 4 patients developed
renal failure and returned to hemodialysis within 1
Kowalewska et al. AJKD, 45:p167, 2005.
CIgAN in Transplants – Tang et al
Another retrospective study reviewed 1742
allograft biopsies over a period of 9 years at
a Chinese University hospital and found 18
cases with crescent formation, of which 10
patients (0.5% of total) were diagnosed with
recurrent or de novo IgAN.
9 cases progressed to ESRD and returned to
dialysis after 6 to 36 months.
Tang et al. Renal Failure. 30:p611, 2008.
CIgAN in Transplants – Mousson et al
Over a 15 year period, 42 patients with biopsy proven
IgAN received kidney transplants, they were followed for a
mean 9 year period and had sequential allograft biopsies.
In their native kidneys, 5 patients (12%) had more then
20% crescents, and only 2 (5%) had more than 50% of the
glomeruli involved.
52.4% of recipients showed recurrent IgA deposits in their
The 2 patients with diffuse crescentic IgAN in their native
kidneys, experienced acute graft dysfunction at 15 and 47
months post transplant.
No crescentic proliferation was observed during follow up
in any other case.
The authors suggest that only diffuse crescentic IgAN in
the native kidneys was associated with occurrence of
crescents in the kidney transplants.
Mousson et al. Transplantation Proceedings, 39:p2595, 2007.
The End