RAPIDLY PROGRESSIVE

GLOMERULONEPHRITIS
Bancha Satirapoj, MD
Renal Division
Department of Medicine
Phramongkutklao hospital
 Clinical Syndrome of Glomerular Diseases
Acute glomerulonephritis (AGN) An abrupt onset of glomerular hematuria (RBC cast and/or dysmorphic
RBCs) together with two or more of the following proteinuria, azotemia,
edema, oliguria, and recent onset hypertension

Nephrotic syndrome (NS) A syndrome of massive proteinuria (>3.5 g/day), with variable edema,
hypoalbuminuria, hyperlipidemia, and lipiduria

Rapidly progressive Any glomerular disease characterized by extensive crescents (usually >50%),
glomerulonephritis (RPGN) as the primary histologic finding and a rapid loss of renal function (usually a
50% decline in GFR within 3 months)

Asymptomatic urinary Isolated proteinuria (usually <2.0 g/day) or hematuria (with or without
abnormalities proteinuria)

Chronic glomerulonephritis Slowing developing renal failure accompanied by proteinuria, hematuria, and
hypertension
Rapidly progressive glomerulonephritis

Clinical syndrome:
Rapid loss of renal function

Often accompanied by oliguria or anuria

Glomerulonephritis

Aggressive glomerulonephritis:
extensive crescentric GN
Breaks in the glomerular basement membrane
 Immunopathologic categories

Type I: Anti- GBM crescentic glomerulonephritis

Type 2: Immune-complex crescentic GN

Type 3: Pauci-immune crescentic glomerulonephritis

Type 4: Double-antibody positive disease: types 1+3

 Antibody mediated GN

Linear glomerular IgG IF Immune complex,granular IF Pauci-immune IF,

anti GBM AntiDNA, complement, ANCA
antiHBC, anti-HBV, C3Nf, cryos,
ant-strep, IgA

ANCA GN
lung hemorrhage no lung hemorrhage Microscopic polyangiitis
IgA nephropathy Wegener Granulomatosis
H-S Purpura Churg-Struss Syndrome
Lupus nephritis
Post-infectious GN
Goodpasture Syndrome
Type 1 MPGN
Type 2 MPGN
Anti GBM GN Membranous GN
Frillary GN

Brenner BM,The Kidney 7th ed.,W.B.Saunders Company, Philadelphia, 2008

 Frequency of different types of
crescentic glomerulonephritis evaluated by the University of
North Carolina Nephropathology Laboratory

Charles J, Kidney International, Vol. 63 (2003), pp. 11641177

Frequency of glomerular crescents, necrosis, and endocapillary
hypercellularity in different types of glomerular disease

Charles J, Kidney International, Vol. 63 (2003), pp. 11641177

CLINICAL PRESENTATION

Acute onset of hematuria, decreased urine output, and edema.

Insidious onset with the initial symptoms being fatigue or
edema
Renal insufficiency is present at diagnosis in almost all cases,
with the plasma creatinine concentration > 3 mg/dL
Urinalysis typically reveals dysmorphic hematuria, red cell and
other casts, and a variable degree of proteinuria.
Marked reduction in GFR usually limits the rate of protein filtration
Nephrotic syndrome is unusual : Less severe renal insufficiency
 CLINICAL PRESENTATION
Systemic complaints, including extrarenal organ involvement,
are common in patients with pauci-immune RPGN

Patients with anti-GBM antibody disease

Pulmonary hemorrhage and hemoptysis due to antibodies

directed against the alveolar basement membranes.
Prolonged bleeding period, leading to anemia and iron
deficiency
Lung hemorrhage and nephritis
Pulmonary renal syndrome
%
60
54.55
50

40
30.68
30

20

10 6.82 7.95

0
ANCA Anti GBM ANCA+antiGBM Not specific

Niles JL, et al. Arch Intern Med 1996; 26;156(4):440-5.

Evaluation
Serologic tests
ANCA antibodies
Anti-GBM antibodies
Immune complex
Complement component assays
Antinuclear antibodies
Cryoglobulinemia
ASO titiers
HBSAg, anti-HCV

Skin biopsy: leukocytoclastic vasculitis and IgA deposition: Henoch-Schnlein

purpura
Renal biopsy
Type 3: Pauci-immune RPGN
Necrotizing glomerulonephritis
Few or no immune deposits by immunofluorescence or
electron microscopy.
Renal-limited vasculitis: 75 to 80 percent having
myeloperoxidase (MPO)-ANCA
Systemic vasculitis
Wegener's granulomatosis
Microscopic polyangiitis
Classification of ANCA-associated vasculitis
European League Against Rheumatism (EULAR)

Localized Upper and/or lower respiratory tract disease without any

other systemic involvement or constitutional symptoms.
Early systemic Any, without organ-threatening or life-threatening
disease.
Generalized Renal or other organ-threatening disease, serum
creatinine 5.6 mg/dL (500 micromol/L).
Severe Renal or other vital organ failure, serum creatinine 5.7 mg/dL
(500 micromol/L)
Refractory Progressive disease unresponsive to glucocorticoids and
cyclophosphamide.

Mukhtyar, C, et al. . Ann Rheum Dis 2008

Wegener's granulomatosis
In 1990, American College of Rheumatology proposed clinical
criteria

1. Nasal or oral inflammation (painful or painless oral ulcers or purulent

or bloody nasal discharge)
2. Abnormal chest radiograph showing nodules, fixed infiltrates, or
cavities
3. Abnormal urinary sediment (microscopic hematuria with or without
red cell casts)
4. Granulomatous inflammation on biopsy of an artery or perivascular
area
>2 criteria: a sensitivity of 88 % and a specificity of 92 %

Leavitt RY, et al. Arthritis Rheum 1990;33(8):1101-7.

ACR 1990 criteria of Churg-Strauss syndrome (4/6)
Criteria Remarks
1.Asthma History of expiratory rales

2.Eosinophilia More than 10 %

3.Mononeuropathy or polyneuropathy Caused by systemic vasculitis

4.Pulmonary infiltrate, non-fixed Migratory/ transitory infiltrate

5.Paranasal sinus abnormality Clinical evidence of acute or chronic

paranasal sinusitis
6.Extravascular eosinophils accumulation

>4 criteria had a sensitivity of 85 % and a specificity of 99.7 %

Renal-limited vasculitis
Pauci-immune vasculitis limited to the kidney is characterized
by necrotizing glomerulonephritis with little or no deposition
of IgG, IgM, IgA, and complement components.
75 to 80 percent having MPO-ANCA.
Antibodies directed against another ANCA subtype, lysosome associated
membrane protein-2 (LAMP-2), are pathogenetically important in this
setting
LAMP-2 antibodies frequently coexist with anti-PR3 and anti-MPO
antibodies
Antibodies to LAMP-2 cause pauci-immune FNGN when injected into
rats, and induces apoptosis of human microvascular endothelium in vitro.

Kain R; et al. Nat Med. 200814(10):1088-96. 2008

Salama AD. Kidney Int. 2009 Jul;76(1):15-7. 2009.
 Pauciimmune GN

Systemic vasculitis

Yes No

No asthma Granulomas Eosinophilia

Or granulomas and no asthma asthma and
granulomas

MPA WG CSS PI-CGN

 ANCA associated vasculitis
Indirect immunofluorescence assay

Antibodies directed against PR3 Antibodies directed against MPO

Wegener's granulomatosis 80-90% Microscopic polyangiitis 70%
Renal limited vasculitis 70-85%
Churg-Strauss syndrome 70%

Indirect immunofluorescence assay : more sensitive

Enzyme-linked immunosorbent assay (ELISA): more specific.
Frequency of ANCA reactivity
100 p-ANCA
c-ANCA
80

60

40

20

0
WG MPA idiopathic CSS
RPGN
ANCA negative
up to 40 % of patients with limited WG (10 percent of those
with severe disease)
30 % of all MPA patients
50 % of all CSS patients
 Positive ANCA serology
Clinical presentation of RPGN
PPV at least 98 %.
Adults with hematuria, proteinuria, and a serum creatinine of
less than 1.5 mg/dL
PPV was only 47 %

Clinical presentation Prevalence of Positive predictive Negative

pauci-immune GN value predictive value
(%) (%) (%)
Rapidly progressive glomerulonephritis 47 98 80
Hematuria, proteinuria, and creatinine >3 mg/dL 21 92 93
Hematuria, proteinuria, and creatinine 1.5-3 mg/dL 7 77 98
Hematuria, proteinuria, and creatinine <1.5 mg/dL 2 47 99

Jennette, JC, et al. . Kidney Int 1998; 53:796.

Does a rise in ANCA titers predict a disease
flare?
Unable to conclude that following serial ANCA titers
has clinical utility
Closely follow patients with rising ANCA titers but not to alter their
therapy unless there are clearcut clinical signs of active disease.

Birck R; et al. Am J Kidney Dis. 2006;47(1):15-23.

Monitoring
We suggest not changing immunosuppression based on
changes in ANCA titer alone. (2D)
KDIGO. Kidney International Supplements (2012) 2, 143153
Histopathologic Classification of ANCA-Associated GN

Yes
50% globally Sclerotic Class Inclusion criteria
sclerotic glomeruli class

Focal 50% normal glomeruli

Yes
50% normal Focal Crescentic 50% glomeruli with cellular crescents
glomeruli class

Mixed < 50% normal, < 50% crescentic,

< 50% globally sclerotic glomeruli
50% cellular Yes Crescentic
crescent class Sclerotic 50% globally sclerotic glomeruli

No
Mixed
class

Berden AE, et al. J Am Soc Nephrol 21: 16281636, 2010

Renal survival is depicted according to the four
histologic categories
1

Focal
0.8
Renal survival

Crescentic
0.6
Mixed
0.4

Sclerotic
0.2

0
0 2 4 6 8 10 12
Month

Berden AE, et al. J Am Soc Nephrol 21: 16281636, 2010

INDUCTION OF REMISSION
Glucocorticoids alone
Glucocorticoid monotherapy is NOT generally
considered for remission induction
Remission rate is much lower than in combination with
cyclophosphamide (56 versus 85 percent)
Rate of relapse much higher

Nachman PH, et al. J Am Soc Nephrol 1996 Jan;7(1):33-9.

Choice of cyclophosphamide regimen
Oral cyclophosphamide and glucocorticoids induces remission
in 85-90 %
Cyclophosphamide 1.5-2 mg/kg/day + Prednisolone 1 MKD
Usually achieved within 3-6 months.
WBC should remain above 3000/microL and the absolute
neutrophil count above 1500/microL

de Groot K; et al. Ann Intern Med. 2009;150(10):670-80.

Adu D; et al. QJM 1997;90(6):401-9.
Guillevin L; et al. Arthritis Rheum 1997;40(12): 2187-98.
Haubitz M, et al. Arthritis Rheum 1998;41(10):1835-44.
RANDOMIZEDTRIAL COMPARING STEROIDS AND PULSE CYCLOPHOSPHAMIDE
VERSUS STEROIDS AND ORAL CYCLOPHOSPHAMIDE IN THE TREATMENT OF
GENERALIZEDWEGENER'S GRANULOMATOSIS

Renal relapse
1 Daily oral
Fifty patients were included in the
Pulse
study: 0.8

Remission: At 6 months, 24 IV 0.6

CYC patients (88.9%) were in
remission, vs 18 Oral CYC patients 0.4
(78.3%)
0.2
Infectious side effects were
significantly more frequent in Oral 0
0 2.0 4.0 6.0
CYC (69.6%) than in IV CYC month
(40.7%) (P < 0.05).
Relapses were significantly more frequent in IV
CYC (59.2%) than Oral CYC(13%) (P = 0.02).

Guillevin L; et al. Arthritis Rheum 1997;40(12): 2187-98.

 IV PULSE ADMINISTRATION OF CYCLOPHOSPHAMIDEVERSUS DAILY ORAL
TREATMENT IN PATIENTS WITH ANCA-ASSOCIATEDVASCULITIS AND RENAL
INVOLVEMENT

Patient survival, remission rate, time of remission, relapse rate, and outcome of
renal function were not different between the 2 treatment groups (N= 22 and 25)

Probability of toxic even-free interval (no death, severe infection, leukopenia, or

thrombocytopenia)
1

0.8 IV pulse CYC

Patients %

0.6 P<0.01

0.4
Daily oral CYC
0.2

0
0 2 4 6 8 10 12
month

Haubitz M, et al. Arthritis Rheum 1998;41(10):1835-44.

Pulse Versus Daily Oral Cyclophosphamide for Induction of Remission
in ANCAAssociatedVasculitis: A Randomized Trial
42 centers in 12 European countries.
149 patients who had newly diagnosed generalized
1
ANCA-associated vasculitis with renal involvement

Patients With Remission, % 0.8

0.6

0.4
Daily oral
Pulse

0.2

0
2.0 4.0 0 6.0 8.0 10.0
Time to Remission , mo
No difference in the time to remission or the percentage of remission by nine months (88
% in both groups)
de Groot K; et al. Ann Intern Med. 2009;150(10):670-80.
Pulse Versus Daily Oral Cyclophosphamide for Induction of Remission
in ANCAAssociatedVasculitis: A Randomized Trial

The mean estimated GFR improved by a similar amount in both groups

from about 30 at study entry to 45 mL/min per 1.73 m2 at study end.

Pulse cyclophosphamide
Lower cumulative cyclophosphamide dose (8.2 versus 15.8 g)
Lower rate of leukopenia (26 versus 45 percent)

More relapses in IV pulse cyclophosphamide group (13 vs 6) (not statistically

significant )

de Groot K; et al. Ann Intern Med. 2009;150(10):670-80.

Rituximab versus Cyclophosphamide in
ANCA-Associated Renal Vasculitis
Rituximab-based regimen was not
superior to standard intravenous
cyclophosphamide for severe
ANCA-associated vasculitis.

Sustained-remission rates were

high in both groups

Rituximab-based regimen was not

associated with reductions in
early severe adverse events.

N Engl J Med 2010; 363:211-220

Plasma exchange in focal necrotizing
glomerulonephritis without anti-GBM antibodies

Improvement in renal function at one month

Treatment (25) Control (23)

Creatinine <500 smol/liter 9/9 7/8

Creatinine >500 smol/liter 5/5 7/7

Dialysis dependenta 10/11 3/8

a P = 0.041, Fisher's exact test

Treatment: plasma exchange, prednisolone, cyclophosphamide and azathioprine
Control: drug alone

Pusey CD, et al. Kidney Int 1991;40(4):757-63.

RandomizedTrial of Plasma Exchange or High-Dosage
Methylprednisolone as AdjunctiveTherapy for Severe Renal
Vasculitis (serum creatinine >5.8 mg/dl)
1

PE

Proportion of patients without ESRD

MP
0.8

Plasma exchange was associated

0.6
with a reduction in risk for
progression to ESRD of 24% (95%
CI 6.1 to 41%), from 43 to 19%, at
0.4
12 mo.

0.2

0
0 2 4 6 8 10 12
Months from entry

Jayne DR, et al. J Am Soc Nephrol. 2007;18(7):2180-8

Plasma exchange
Severe renal disease/dialysis dependent
Concurrent anti-glomerular basement membrane (GBM)
antibody disease
Severe pulmonary hemorrhage

Pusey CD, et al. Kidney Int 1991;40(4):757-63.

Jayne DR, et al. J Am Soc Nephrol. 2007;18(7):2180-8.
Levy Jb, et al. Kidney Int 2004;66(4):1535-40.
Klemmer PJ, et al. Am J Kidney Dis 2003;42(6):1149-53.
GENERAL PRINCIPLES
Long-term cyclophosphamide has significant
treatment-related toxicity

Almost all patients with WG or MPA are switched to

a less toxic non-cyclophosphamide maintenance
regimen

Azathioprine or methotrexate, to reduce the risk of relapse.

 CYCAZAREM trial
1.0

Proportion surviving without replapse

Severe adverse events occurred Cyclophosphamide group 86.3%
in 8 patients in the azathioprine
group during the remission 0.9
phase (11 percent), and in 7
patients in the
cyclophosphamide group during 0.8
the remission phase (10 Azathioprine group 84.5%
percent, P=0.94).
0.7

0.6
Generalized vasculitis, the withdrawal of cyclophosphamide and the
substitution of azathioprine after remission did not increase the
0.0
rate of relapse. 3 6 9 12 15 18
Months from entry

Jayne D; et al. N Engl J Med 2003;349(1):36-44.

Azathioprine or methotrexate maintenance for ANCA-
associated vasculitis.
Time to First Relapse Adverse events occurred in 29 azathioprine recipients
1 and 35 methotrexate recipients (P = 0.29)
0.9
Relapse free Survival (%)

0.8 Methotrexate
0.7

0.6

0.5
Azathioprine
0.4

0.3

0.2

0.1

0
0 6 12 18 24 30 36
Months since randomization
Pagnoux C; et al. N Engl J Med. 2008; 359(26):2790-803.
Induction of remission in active ANCA-
associated vasculitis with MMF in patients who
cannot be treated with cyclophosphamide.

Complete or partial remissions were obtained in 78 and 19 percent,

respectively. Relapse during follow-up occurred in 19 of 25 patients (76
percent) who attained complete remission and in all six who attained partial
remission.

MMF appears to have efficacy both for induction of remission in patients

who are resistant to or cannot take cyclophosphamide, and for remission
maintenance.

Stassen PM; et al. Ann Rheum Dis. 2007;66(6):798-802.

 MMF versus cyclophosphamide for inducing
remission of ANCA vasculitis with moderate renal
involvement

18 in the MMF group and 17 in the CTX group.

4
Serum creatinine (mg/dL)
77.8% treated with 3.5
MMF CTX
MMF 3
47.1% treated with 2.5
CTX 2
Complete remission 1.5
with an absolute 1
difference of 30.7%. 0.5
0
0 3 mo 6 mo

Hu W, et al. Nephrol Dial Transplant 2008; 23(4): 1307-12.

Initial treatment of pauci-immune focal and segmental
necrotizing GN
Induction

Cyclophosphamide and corticosteroids be used as initial

treatment. (1A)
Rituximab and corticosteroids: alternative initial treatment in
patients without severe disease or in whom cyclophosphamide
is contraindicated. (1B)

Discontinuing cyclophosphamide therapy after 3 months in

patients who remain dialysis-dependent and who do not have
any extrarenal manifestations of disease (2C)

KDIGO. Kidney International Supplements (2012) 2, 143153

Initial treatment of pauci-immune focal and segmental
necrotizing GN

Addition of plasmapheresis

Patients requiring dialysis or with rapidly increasing SCr (1C)

Diffuse pulmonary hemorrhage (2C)

Overlap syndrome of ANCA vasculitis and anti-GBM GN

(2D)

KDIGO. Kidney International Supplements (2012) 2, 143153

Maintenance therapy
Continuing maintenance therapy for at least 18 months (2D)

Azathioprine 1-2 mg/kg/d orally (1B)

MMF, up to 1 g twice daily, in patients who are allergic to, or

intolerant of, azathioprine (2C)

Trimethoprim-sulfamethoxazole as an adjunct in patients with upper

respiratory tract disease (2B)

Methotrexate (initially 0.3mg/kg/wk, maximum 25mg/wk) for

maintenance therapy in patients intolerant of azathioprine and MMF,
but not if GFR is o60 ml/min per 1.73m2 (1C)

KDIGO. Kidney International Supplements (2012) 2, 143153

ANTI GBM DISEASE
Pathogenesis
Main target of these autoantibodies is the
noncollagenous domain (NC1) of the 3 chain of
type IV collagen [ 3(IV)NC1]

Frequency of T cells specific for 3(IV)NC1 is higher in

patients than in controls

Hellmark T, et al:Kidney Int 55:936944, 1999

Localization of 3(IV)NC1 in the GBM
Clinical features
Bimodal age, with peak incidence in the third and sixth decades

Most patients present with the combination of rapidly

progressive glomerulonephritis and lung hemorrhage

30% to 40% present with isolated renal involvement

Malaise, fatigue, and weight loss, and anemia from pulmonary

hemorrhage or to the effects of uremia

Renal disease progresses rapidly and rarely resolves

spontaneously
Laboratory features
Pulmonary tissue can disclose alveoli containing red cells
with hemosiderin-laden macrophages.

Immunofluorescence of lung tissue technically difficult

but can reveal intermittent linear deposits of IgG along
the alveolar basement membrane.
Renal Biopsy
Focal and segmental glomerulonephritis with infiltration by
leukocytes accompanied by segmental necrosis with prominent
breaks in the GBM.
Later, glomeruli develop extensive crescent formation composed
of parietal epithelial cells and macrophages in association with
destruction of the GBM.
Crescents are usually at the same stage of evolutionagain
emphasizing the explosive nature of the disease.
Renal Biopsy
Glomeruli show diffuse inflammation with segmental or total
necrosis and extensive crescent formation, which eventually leads
to scarring and the appearance of an end-stage kidney

IF : Linear binding of IgG and C3

Linear deposition of IgG along the basement membrane
Results of studies assessing the effect of treatment
on mortality and renal survival

KLUTH DC and ANDREWJR. JASN 10: 24462453, 1999

KLUTH DC and ANDREWJR. JASN 10: 24462453, 1999
Treatment
Plasma exchange rapidly removes the pathogenic
autoantibodies,
Cyclophosphamide prevents further antibody
synthesis,
Steroids act as a powerful anti-inflammatory agent
Treatment of anti-GBM disease

Plasma exchange: 4 L exchanges daily with human albumin as

replacement solution. Risk of hemorrhage, FFP should be given.

Corticosteroids: 1 mg/kg/day for first week then reduce at

weekly intervals to 45, 30, 25, 20, 15, 10 and 5 mg

Cyclophosphamide: 3 mg/kg (age > 55 yr use 2 mg/kg)

Outcome of patients with Goodpastures disease

Pusey CD,Kidney International, Vol. 64 (2003), pp. 15351550

Summary treatment
All patients should be offered treatment with plasma
exchange and immunosuppression.

Patients on dialysis and serum creatinine >6.6 mg/dL

Low probability of recovery and risks of immunosuppression
Younger patients with evidence of recent crescents on biopsy, and no
anuric, aggressive therapy still could be considered.

Lung hemorrhage, which resolved in 90%, provides a

separate indication for intensive treatment, regardless of the
severity of renal disease.
Pusey CD, Kidney International, Vol. 64 (2003), pp. 15351550
Treatment of anti-GBM GN
Cyclophosphamide
Corticosteroids
Plasmapheresis

in all patients with anti-GBM GN

Except those who are dialysis-dependent at presentation and

have 100% crescents in an adequate biopsy sample, and do not
have pulmonary hemorrhage (1B)

KDIGO. Kidney International Supplements (2012) 2, 143153

Treatment of anti-GBM GN
No maintenance immunosuppressive therapy for anti-
GBM GN (1D)

Defer kidney transplantation after anti-GBMGN until

anti-GBM antibodies have been undetectable for a
minimum of 6 months

KDIGO. Kidney International Supplements (2012) 2, 143153

 Immunopathologic categories

Type I: Anti- GBM crescentic glomerulonephritis

Type 2: Immune-complex crescentic GN

Type 3: Pauci-immune crescentic glomerulonephritis

Type 4: Double-antibody positive disease: types 1+3

Both anti-GBM antibodies and ANCA
Patients with both anti-GBM antibodies and ANCA

Receive the same initial treatment as those with pure anti-GBM disease

Receive maintenance immunosuppression, as used in ANCA-positive

systemic vasculitis

Levy JB et al, J Am Soc Nephrol 12:113A, 2001

Prognosis
Factors Poorer prognosis Better prognosis

Urine output at Oliguric Non-oliguric

presentation
Extent of crescent >80% 50-80%
formation
Glomerulus Fibrinoid necrosis Endocapillary cell
proliferation
Glomerular immune Linear deposition (anti-GBM) Granular deposition
deposits (immune complex) or no
immune reactants

Interstitium Interstitial fibrosis and

tubular atrophy
GRADE AND QUALITY OF EVIDENCE
Thank you for your attention

Phramongkutklao Hospital
and College of Medicine