IgA Nephropathy with crescents

1
IgA Nephropathy with crescents

• Nephrology Grand Rounds
• March 16th, 2010
• Aditya Mattoo

2
Outline

• Background
• Epidemiology
• Clinical Presentation
• Prognosis
• Pathogenesis
• Histology
• Treatment
• Recurrence in Transplant

3
Background

• 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.
4
Epidemiology
5
Demographics

• 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.

6
Demographics

• 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.

7
IgAN Nationwide
8
Epidemiology

• 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, 347p738, 2002. Shouno et
al. Acta Pathol Jpn, 43p723, 1993.
9
Clinical Presentation
10
Clinical Presentation

• IgAN is highly variable, both clinically and
  pathologically.
• 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.)

11
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.

12
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).

13
Clinical PresentationCrescentic vs
Non-crescentic
  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.
14
Prognosis
15
Prognosis

• Between 5-30 of patients with mild proteinuria,
  hematuria or mild renal dysfunction undergo
  spontaneous remission of abnormal laboratory
  findings.
• 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.
16
Prognosis

• 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.
17
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.
18
pathogenesis
19
Pathogenesis

• 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
  secretions.
• 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

20
Pathogenesis

• 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 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.
21
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 under-galactosylated
  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, 17p50, 2002.
22
Pathogenesis Mesangial Deposition

• Leukocyte ß1,3-galactosyl transferase activity is
  decreased in patients with IgAN which may be
  responsible for deficient galactosylation of
  IgA1.
• 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.
23
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).

24
Pathogenesis - Summary
Floege et al. JASN, 11p2395, 2000.
25
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.
26
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.
27
Diagnosis
28
Diagnosis

• 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.)

29
Diagnosis

• 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
  diagnosis.
• 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.
30
Diagnosis

• 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.
31
Diagnosis

• (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
  complexes.

Susuki at al J Clin Invest. 119p1668, 2009
32
Histology
33
Histology

• The major finding on light microscopy is
  mesangial proliferation and matrix expansion
  (arrows) that can be focal, but more often seen
  diffusely.

34
Histology

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

35
Histology

1. HE demonstrating mesangial hypercellularity and
   matrix expansion.
2. HE with mesangial cell hypercellularity and
   focal area of endocapillary proliferation (bold
   arrow).
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.
36
Histology

• 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 proteinuria).

37
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.

38
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.

39
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.

40
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.

41
Histology - EM

• Higher power EM with significant expansion of
  mesangial matrix and presence of large mesangial
  dense deposits (arrow).

42
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
  area
• 1 4-5 mesangial cells are present per mesangial
  area
• 2 6-7 mesangial cells are present per mesangial
  area
• 3 gt8 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 gt50 percent, respectively.

43
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
  proliferation
• 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.
44
Histology Haas Classification
Haas et al. AJKD, 29p829, 1997.
45
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.

46
Histology Haas Classification with Crescents
Haas also reported the probability of renal
survival when crescents were present in Haas
subclass III and IV.
47
treatment
48
Treatment

• 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.

49
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
  groups.

Praga et al. JASN, 14p1578, 2003.
50
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.

51
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.

52
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, 353p883, 1999.
53
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
  therapy.

54
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 controls.

Ballardie et al. JASN, 13p142 2002.
55
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
  prednisone,
• IV or PO cyclophosphamide,
• and/or plasmapheresis.

56
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.
57
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, 18p1321, 2003.
58
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
  42).

Tumlin et al. NDT, 18p1321, 2003.
59
Igan in Transplants
60
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.
61
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.
62
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.
63
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
  transplants.

Mousson et al. Transplantation Proceedings,
39p2595, 2007.
64
Thank you

• The End