IgA Nephropathy with crescents - PowerPoint PPT Presentation


PPT – IgA Nephropathy with crescents PowerPoint presentation | free to view - id: 446f95-NGQyO


The Adobe Flash plugin is needed to view this content

Get the plugin now

View by Category
About This Presentation

IgA Nephropathy with crescents


Most common form of primary glomerulonephritis around the world. Berger et al. J Urol Nephrol, 74:p694, 1968. – PowerPoint PPT presentation

Number of Views:536
Avg rating:3.0/5.0
Slides: 65
Provided by: Tina218


Write a Comment
User Comments (0)
Transcript and Presenter's Notes

Title: IgA Nephropathy with crescents

IgA Nephropathy with crescents
  • Nephrology Grand Rounds
  • March 16th, 2010
  • Aditya Mattoo

  • Background
  • 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, 74p694, 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 21 in Japan to as high as
    61 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

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
  • 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

Donadio et al. NEJM, 347p738, 2002. Shouno et
al. Acta Pathol Jpn, 43p723, 1993.
Clinical Presentation
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 20-25
    of these patients.

Clinical Presentation
  • Of the patients with gross hematuria secondary to
    IgAN, up to 40 will develop transient renal
  • Less than 10 present with either nephrotic
    syndrome or RPGN (characterized by edema,
    hypertension, and renal dysfunction).

Clinical Presentation Crescentic vs
  Crescentic IgAN Noncrescentic IgAN P value
Number of patients 35 229  
Sex male/female 26/9 147/82 NS
Mean age years 33 12.5 32 13 NS
Serum creatinine mg/dL 1.3 0.5 1.2 0.4 NS
Proteinuria g/day 2.3 2.1 1.1 1.2 lt 0.003
History of recurrent macroscopic Hematuria of patients 20 31.2 NS
Arterial hypertension of patients 37 41 NS
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 gt1g/d, HTN, and serum Cr 1.4 mg/d
    developed in 33, 26, and 7, respectively.

Hotta et al. AJKD, 39p493, 2002. Szeto et al. Am
J Med. 110434, 2001.
  • Approximately 25-30 of patients will reach ESRD
    at 10 years.
  • Clinical risk factors associated with progressive
    disease are
  • HTN
  • gt 1g/d proteinuria
  • Male gender
  • Persistent microscopic hematuria
  • Histologic risk factors include cellular
    crescents and endocapillary proliferation.

Donadio et al. NEJM, 347p738, 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 gt 1g proteinuria).
  • 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 24p256, 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
  • IgA1 is found in serum and made by bone marrow B
  • 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
  • Glycosylation is restricted to the hinge region
    of IgA1.
  • N-acetyl galactosamine (GalNAc) is O-linked to
    Ser or Thr residues.
  • GalNAc is linked to Gal through the action of the
    enzyme ß1,3-galactosyl transferase.
  • Sialic acid is linked to Gal through an a2,3 link
    and to GalNac through an a2,6 link.

Donadio et al. NEJM, 347p738, 2002.
Pathogenesis Mesangial Deposition
  • Although the pathogenesis of IgAN is not
    completely clear, it is well accepted that
    aberrant glycosylation pattern of IgA is
  • This is supported by the fact that in IgAN,
    mesangial deposits of IgA contain high
    concentrations of abnormally under-galactosylated
  • 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, 17p50, 2002.
Pathogenesis Mesangial Deposition
  • Leukocyte ß1,3-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 62p465, 2006. Allen et al. NDT.
12p701, 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 galactosylation).
  • 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, 11p2395, 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 24p197,
2004. Taniguchi et al. Scand J of Urol Nephrol.
33p243, 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 cells.
  • Systemically, low-grade complement activation
    through the alternative pathway can be seen in
    patients with IgAN as well.

Zwriner at al. KI, 51p1257, 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 IgA-immune
    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. 119p1668, 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. 119p1668, 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 lt 0.0001) and disease
    controls (P lt 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 Gal-deficient
    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
    Gal-deficient IgA1 correlated with urine Pr/Cr
    ratio as well as with urinary IgA-IgG immune

Susuki at al J Clin Invest. 119p1668, 2009
  • The major finding on light microscopy is
    mesangial proliferation and matrix expansion
    (arrows) that can be focal, but more often seen

  • Light microscopy of a glomerulus from a patient
    with IgAN showing increased mesangial matrix and

  1. HE demonstrating mesangial hypercellularity and
    matrix expansion.
  2. HE with mesangial cell hypercellularity and
    focal area of endocapillary proliferation (bold
  3. HE demonstrating diffuse endocapillary
    proliferation and mesangial hypercellularity.
  4. HE -silver demonstrating cellular crescent with
    partial collapse of glomerular tuft.
  5. HE demonstrating diffuse endocapillary
    proliferation and fibrinoid necrosis.
  6. Silver stain demonstrating crescent and focal
    glomerular tuft adhesion to Bowmans capsule.

Tumlin et al. CJASN. 2p1054, 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
  • 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 proteinuria).

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 microscopy.

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 (arrow).

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 lt 4 mesangial cells are present per mesangial
  • 1 4-5 mesangial cells are present per mesangial
  • 2 6-7 mesangial cells are present per mesangial
  • 3 gt8 mesangial cells are present per mesangial
  • 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
  • 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 gt50 percent, respectively.

Histology Haas Classification
  • Based on the histological features of 244 cases
    of IgAN over a 14 year period at one institution
  • 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 gt 40
    globally sclerotic glomeruli and/or gt 40
    estimated cortical tubular atrophy or loss.

Haas et al. AJKD, 29p829, 1997.
Histology Haas Classification
Haas et al. AJKD, 29p829, 1997.
Histology Haas Classification
  • Haas showed a statistically significant
    correlation between histologic subclass and renal
    survival, with an order I, II (greatest survival)
    gt Ill gt IV, V.

Histology Haas Classification with Crescents
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 lt50 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

Praga et al. JASN, 14p1578, 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
  • The effect of ACE/ARB was not assessed.

Pozzi et al. Lancet, 353p883, 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 alone.
  • Similarly, the studies were primarily performed
    prior to the widespread use of aggressive ACE/ARB

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
  • A lower degree of proteinuria was also observed
    in treatment group compared to controls.

Ballardie et al. JASN, 13p142 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
    gt40 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, 10p2054, 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

Tumlin et al. NDT, 18p1321, 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
    lt130/70 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

Tumlin et al. NDT, 18p1321, 2003.
Igan in Transplants
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, 38p588, 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 year.

Kowalewska et al. AJKD, 45p167, 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. 30p611, 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 grafts.
  • 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

Mousson et al. Transplantation Proceedings,
39p2595, 2007.
Thank you
  • The End
About PowerShow.com