- Email: [email protected]
Rapidly progressive glomerulonephritis
Rapidly Progressive Glomerulonephritis A Clinical and Pathologic Study
PETER A. F. MOFMN.
MB.,
F.R.C.P.(C)
Kingston, Ontario, Canade NICOLE HINGLAIS, M.D. B. NABARRA,
D.Sc.
HENRI KREIS, M.D. Paris, France
From the Department of Medicine. Queen’s Unlversity, and the Kingston General Hospital, Kingston, Ontario, Canada; and Clinique Nephrologique, H6pital Necker, Paris and lnserm Unite 25, Paris, France. Requests for reprints should be addressed to Dr. Peter A. F. Morrin, Renal Unit, Kingston General Hospital, Kingston, Ontario, Canada K7L 2V7. Manuscript accepted March 2, 1978.
446
September 1979
Twenty-nine cases of rapldly progressive glomerulonephrltls were reviewed. In all cases there was less than three months between the onset of renal symptoms and renal blopsy. The serum creatlnlne was greater than 2.5 mg/lOO ml at the tl.me of biopsy, and the hlstology showed a 50 per cent or greater Incidence of crescents In the glomerull. lnfectlous or febrlle episodes were present In 21 cases, microscopic hematurla was noted In 15, and protelnurla exceeding 2.5 g/24 hours In elght. Ollgurla less than 500 ml/24 hours was present In 20 cases and dlalysls was required In 22. In 10 cases there was sustalned Improvement; In tlie remainder the disease progressed or the patlent died. The prognosis was related to the number and size of the glomerular crescents. Hlstologlcally cases fell Into two maln groups, one wlth predomlnanily extracapillary prollferatlon and the other with endo- and extracaplllary prollferatlon. In the first group the disease was histologically and clinically more severe, and lmmunofluorescence hlstology was heterogeneous and often nonspecific except for three cases In which there were linear Immunoglobulin deposits. In the second group the leslons were iess severe and lmmunoglobulln deposits were common. Electron mlcroscopy In 14 cases was confirmatory, and also demonstrated capillary rupture and necrosis of podocytes In some loops. Transltlon from group I to group II was observed In serial blopsy specimens In one case. The hlstologlc and lmmunofluorescent heterogenelty suggest that rapidly progressive glomerulonephrltls Is the end result of several dlff erent pathogenetlc mechanisms. It has been recognized for many years that glomerulonephritis can follow a rapidly progressive course terminating in renal failure after a period of several weeks or months [ 11. The terms extracapillary [ 11, rapidly progressive type I [2], malignant [3], acute necrotizing [4], acute anuric [6], proliferative with crescents [6], rapidly progressive nonstreptococcal [7] and endo- and extracapillary type Ill [6] have been employed by different workers to describe this form of the disease. Irrespective of the etiology, the renal biopsy specimens are characterized by massive proliferation of the glomerular extracapillary cells which produces numerous and voluminous crescents [9]; this feature is so prominent that it has sometimes been used as a basis for case selection [6,10-171. In 1972, Sonsino et al. [lo] reviewed the experience at the Necker Hospital with this type of glomerulonephritis. This report extends these earlier observations and includes the more recent experience at this institution with the condition commonly referred to in the English literature as “rapidly progressive glomerulonephritis” and in the French literature as “les giomerulonephrites malignes.”
The Amorlcan Journal of Medlclne
Volume 85
RAPIDLY PROGRESSIVE GLOMERLJLONEPHi?ITIS-MRIN ET AL.
MATERIAL AND METHODS
data. The number of glomeruli containing crescents was expressed as a percentage of the total number of glomeruli in the biopsy specimen excluding obsolete glomeruli. The incidence of segmental crescents, as opposed to circumferential crescents, was recorded as a percentage of all the crescents in the section, i.e., number of segmental crescents to total number of crescents X 100. The histologic abnormalities were graded semiquantitatively on a scale of 0 to 3+. Treatment protocols varied considerably, but prednisone was usually administered in a dose of 2 mg/kg for 15 days and then gradually tapered to a smaller maintenance dose. Azathioprine was employed in a dose of 2 to 3 mg/kg and cyclophosphamide at 3 mg/kg. When anticoagulants were used, heparin was given by continuous intravenous infusion to maintain the clotting time at two to three times normal. In one case, subcutaneous heparin was employed. If treatment extended beyond 15 days, an oral anticoagulant was substituted. Improvement in renal function was defined by survival without dialysis in those who had previously required it, and by a 30 per cent or greater reduction in serum creatinine levels in the others. Cure was definedas a serum creatinine of less than 1.5 mg/lOO ml and the absence of proteinuria
Both clinical and histologic findings were employed in the selection criteria which were as follows: (1) A rapid evolution of renal disease with no more than three months between the first recognized renal symptoms and renal biopsy; (2) a+ vanced impairment of renal function at the time of biopsy as indicated by a serum creatinine >2.5 mgllO0 ml; (3) a histologic picture of severe glomerulonephritis of relatively recent onset with at least 50 per cent of the glomeruli containing crescents. Biopsy specimens without immunofluorescence histology or with less than 9 glomeruli were excluded. Twenty-nine patients were found who met these criteria. A second biopsy specimen was available in nine and a third in two. An autopsy was performed in one. The histologic technics employed have been previously described [ 181. In 21 cases ultrathin sections were stained with either uranyl acetate followed by lead hydroxide or periodic-acid silver methenamine using Movat’s technic [ 191. These sections were examined by light microscopy, and further study was then performed in 14 cases using a Phillips EM 200 electron microscope. lmmunofluorescent histology was performed by Dr. J. Berger. Serum levels of the complement components C3 and C4, and the C3 proactivating factor C3 Pa were measured by radial immunodiffusion [20]; circulating immune complexes were sought by the polyethylene glycol method [21] and circulating antiglomerular basement antibodies by tha technic of Mahieu et al. [ 221. Sections were studied without knowledge of the clinical
TABLE I
and microscopichemeturia. RESULTS The major clinical and laboratory findings are shown in Table I and Figure 1. There were 20 males and nine females. The mean
Clinical Features
case Aas fyr) No. &ldQX
-%I Renal Anl~nts
FMngr
Averaga BF >140
--K Fever mHg
8eNm ovouls
(500 mtl Edema
Creatinlna at Bx (mo/lOO HomaMa
24 hr
ml)
Mac
Mk
bnprovrmsst
1
75,M
Intermittentchest pain d-60
Hernaturia, azotemia
0
0
+
+
D
+
!
+
2
5O.F
Fever d-l 80, sore throat d-90, pneumonia d-15
Hernsturia
+
0
0
+
D
0
0
+
3
44,M
Pleurisy d-30. abdominal pain d-7
Azotemia
+
0
0
+
D
+
I
+
4
68.F
Chronic bronchitis, bronchopneumonia d- 15
Azotemia
0
0
0
0
D
0
+
+
5
51.M
Posttraumatic empyema d-60
Hematuria + azotemia
+
+
+
0
5.7
+
6
70.F
Sore throat d-28
Hematuria + azotemia
+
0
0
+
D
+
7
59,M
Fever + Arthralgia d- 15
Hematuria + anuria
+
0
+
+
D
+
8
74,M
Rhinopharyngitis d-3
Edema
0
+
+
+
D
+
+
I
+
0
I
0
Contitwed September 1978
Ths Amerkan Journal of Medlclne
Volume 85
447
RAPIDLY PROGRESSIVE GLOMERULONEPHRITIS-MORRIN
TABLE I (Cont’d)
Clinical
ET AL.
Features Average BP
Case NO.
Age (yr) and Sex
Presenting Renal Flndlngs
Antecedents
>140
Fever
90 mm Hg
Ollgurla <500 ml/ 24 hr Edema
Serum Creatinine at Bx (mg1100 ml)
Hematuria Mac Mlc
Improvement
9
56,M
Sore throat d-l 4
Azotemia
+
0
0
+
D
0
0
+
10
46,F
Arthralgia d-56, sore throat d-l 4
Oliguria
+
0
+
+
D
+
/
0
11
59,M
Rheumatic heart disease “chills” d-30
Azotemia
0
0
0
+
D
0
0
0
12
61,F
Malaise, nausea, vomiting from d-35
Edema + azotemia
+
0
+
0
6.7
+
I
+
13
69,F
Raynaud’s syndrome years; malaise + arthralaia d-26
Oliguria
0
0
+
+
D
0
+
0
14
21.M
Chronic filiiariasis; malaise -l- vomiting from d-30
Edema + azotemia
0
0
+
+
D
0
0
0
15
70,M
“Grippe”
Proteinuria
+
0
0
+
D
0
0
0
16
42,M
Chronic bilharziasis, penicillin for + W.R. d-14
Oliguria
0
f
+
+
D
+
1
0
17
45,M
Insidious onset
Edema + azotemia
+
+
+
+
D
0
0
0
16
42,M
Insidious onset
Edema
0
0
+
+
D
0
+
t
19
44,F
Insidious onset
Edema
0
0
+
0
3.6
0
0
+
20
63,M
Pulmonary infection d-14
Oliguria
+
0
+
+
D
0
+
0
21
33,M
Sore throat d-6
Hematuria
+
0
0
0
5.1
+
/
+
22
27,F
Dental abscess d-60; sore throat d-30
Edema
0
0
+
0
6.0
0
0
+
23
35,M
Sore throat d-2
Hematuria
0
0
0
+
2.6
+
/
+
24
66.M
Post-traumatic pneumococcal pneumonia d-23
Anuria
+
0
0
+
D
25
50,M
Chronic hypertension, pleural effusion d-26
Hematuria
+
0
0
0
7.9
+
I
+
26
33.M
Sore throat d- 15
Oliguria + azotemia
+
+
+
+
D
+
I
+
27
15.M
Sore throat d-l 4
Oliguria + azotemla
0
+
+
0
D
+
/
+’
26
17,M
Sore throat, purpura, arthralgia d-10
Hematuria ioliguria
+
0
+
0
+
/
0
29
66,F
Azotemla
+
0
0
+
0
0
+
d-7
Arthralgia -f- fever for 6 mo
NOTE: BP = blood pressure, d = days prior to biopsy, D = on dialysis, BX = biopsy, Mac = macroscopic,
448
September
1978
The American
Journal of Medicine
Volume 65
1.0(l) 4.6(2)
D
Anuria
0
Mic = microscopic.
RAPIDLY PROGRESSIVE GLOMERULONEPHRITIS-MORRIN
D BEGUN 6 YRS
AT
33
MTHS
@
21 MTHS
@
I3 MTHS
@
0 BEGUN
AT 16 MTHS
AT 3 ‘/z YEARS 3 lie YEARS
0 08
@
21 MTHS
@
D BEGUN
AT
D BEGUN
ONSET
ET AL.
19 MTHS
AT 22
AT
8 YEARS
AT
3’/r
26
MTHS
MTHS
@
YEARS
@
0 I8
OF
RENAL SYMPTOMATOLOGY I T I 4 8
I
I
I
I
I
12
16
20
24
28
I
I
I
32
36
40
WEEKS D-1 0
t Ccr
= DURATION = SERUM
OF
DIALYSIS
= DEATH 2 CREATININE
PREDNISONE AZATHIOPRINE
CREATININE CLEARANCE
0
CYCLOPHOSPHAMIDE
B
ANTICOAGULANTS
I
Figure 1. The clinical course and evolution of the disease are shown for each patient. The interval between the onset of renal symptoms and the biopsy is indicated by the blank area at the left of the fi ure. The numbers encircled represent the creatinine in milligrams per 100 milliliters. D - f indicates the duration of dialysis. + = death. Ccr = creatinine clearance.
September
1979
The American
Journal
of Mediclne
Volume
65
449
RAPIDLY
PROGRESSIVE
TABLE II
Case No.
1
GLOMERULONEPHRITIS-MORRIN
ET AL.
Morphologic Flndlngs Glom inBx (no.)
Crescents Seg Clrcum Obsol Tubule Ml Crest Crest GlOm (no.) (no.) (no.) Cellul Flbrln Fibros Necrosis Flbrosls Polys Damage
18
2
10
2
2 2ndExlyr 3rd Bx 3 yr
11 25 26
0 12 20
3 2 2
5 0 1
3 2ndBx4mo 3rd Bx 5 yr
13 28 12
1 8 10
6 15 1
3 0 0
4
29
0
22
3
++
+
5
33
2
8
13
++
+
30
0
12
3
++
Num
11 %
35%
5%
7
13
1
3
9
8
23
2
12
4
9 2nd Bx 1 yr
14 40
0 9
11 15
2 1
+++
10
20
1
6
13
+++
11
11
1
4
6
12
23
2
a
4
++
++
13
61
11
0
50
++
++
14
16
13
0
3
15
11
4
3
4
16
20
0
0
20
+++
17
18
5
3
30
+++
18 2nd Bx 4vr
12 34
0 6
7 6
3 6
++ -
-
19 2ndBxlyr
9 19
0 2
2 0
3 3
++ -
-
20
45
13
0
28
+
21
24
0
9
13
+
-
++
-
++
-
++
++
22 2ndBxlmo
12 19
2 9
2 4
6 2
+ -
-
++ +++
-
++ +
-
++ ++
++ +
23
19
2
8
1
+
f
+
+
+
++
24
14
0
6
8
+
f
+
+
++
25
44
4
14
24
+
+
++
+
6 2ndBx2wk Autopsy
+ ++ -_-++
++
+
+
f
++
+
++
+ -
+ f +
f -
++ ++ +++
f
++ -
f ++ -
-
++ ++
+
+
+
-
++
+
t
-
++
f
-
-
+
++
+++
+++
+. -
+ +
f +++
t+
+++
+ ++
+
InlersUllal FlbrosU Edema Cell
-
+++
++
+
++
-
++ -
f
t
-
f
-
++
+
+++
+++ ++
September 1979
The American
Journal of Madlclne
+ f ++
f ++
++ +t+
++ ++
+
++
+
++
++
+
+-t+
+
++
-
++ -
t ++
+ -
++ ++
+ +
++ ++
f
++
+++
++
-
++
+
+
++
+
+
+++
-
+++
f+ + -
+ ++
+++ ++
++
++
++
++
++
++
++
+++
++
-
++
t++
++
-
++ +++
+++
++
+
++
+
++
++
++
++
++
+
++
++
-
++
+++
+++
++
++
-
-
++ -
++ +
+ +
++ +
f+
-
+ f
+ -
++ f
++ -
+ +
-
+
f
+++
Continued
450
++ ++
++
+++
+t
f t+ +++
++
++
+
++ + ++
f
+++
+
-
+t
++
++
+
++
++
Volume 65
++
+
++
+
+++
++
+
++ +++ +++ f
++
+
++
++
++
++
RAPIDLY
TABLE II (Cont’d)
Case No.
Morphologic
GlOfll
Obsol
in 8x (no.1
Glom (no.1
S
PROGRESSIVE GLOMERULONEPHRITIS-MORRIN
Findings Crescents Cl
CrZ (no.1
c:z (no.)
Cellul
Flbrln
Flbros
Necrosis
TuH Fibrosis
0
8
5
++
+
-
f
-
+++
27 2nd Bx 2 yr
24 14
1 10
11 2
11 0
++ -
+ -
++ +++
-
+ -
+++
28 2nd Bx 1 mo
6 26
0 0
0 4
0 17
+t
_ f
t
_ f
_
t+t
29 2nd Bx 2 yr
10 16
1 7
4 8
2 0
+ -
t+ ++
t -
NOTE: Bx = biopsy, Cellul = cellularity, Circum = circumferential, Crew obsolescent, Polys = polymorphonuclear leukocytes, Seg = segmental.
age was 50.1 years (15 to 75 years), but children are not treated in this unit. The group contained only one known patient with systemic disease with vascuiitis (Case 29). No patient with known disseminated lupus erythematosus met the selection criteria, and serologic tests for disseminated lupus erythematosus were negative in 26 and not performed in three. There were no characteristic prodromal features but 21 patients had an infectious or febrile episode in the period prior to admission, and 10 had a history of sore throat. Almost ail the patients with a history of fever had received antibiotics prior to admission which obscured the bacteriologic findings. Antistreptoiysin 0 titers were available for 16. in two (Cases 26 and 27), the values were over 1,000. Two others (Cases 21 and 23) had slight elevations, one of whom had normal antistreptoiysin H and antistreptoiysin K levels (Case 23). Six patients had a history of pleural or pulmonary infection (Cases 2-5, 20 and 24), but pneumococci were only isolated from one (Case 24). Chronic parasitosis was present in two (Cases 14 and 16). The onset was at times very acute, with oiiguria and
Cell
FIbroW Edema
++
++
++
++ +
+t
-
tt
t
tt
t
+ -
-
t +
t
+ +
f
f +
t tt
t t+
= crescents, Glom = glomerulus, Num = numerous, Obsol =
renal failure apparently developing in a few days, whereas at others a more insidious evolution occurred with edema or azotemia as the presenting renal symptom. Renal failure developed rapidly and by the time of biopsy 20 patients had urine outputs of less than 500 ml/24 hours, and 21 had required dialysis. Twelve patients had persistent renal failure (Cases 7, 8, 10, 11, 13-17, 20, 24 and 28) and four others (Cases 2, 12, 22 and 25) had deterioration to end-stage uremia after a temporary improvement. Renal function improved in 13, but three of these (Cases 1,4 and 6) died from causes other than uremia within three months of the biopsy and one (Case 23) was killed in an accident after 32 weeks when his renal function was almost normal. in nine of these 13 (Cases 3,5,9,18, 19,21,26,27 and 29) improvement was maintained over the period of observation, but only two (Cases 15 and 19) met the criteria for cure. The nature and duration of treatment and the subsequent course are shown in Figure 1. Although the more vigorously treated patients appeared to do better, no statistically significant conclusions can be drawn.
lmmunofluorescent Pathology
CamNo.
W
1
-
2
-
3
-
4
-
5
+ Glom
6
Damage
Polys
17
+ -
lnterstltlal
Tubule
26
TABLE lit
ET AL.
w
let
CS
C4
-
-
-
-
+ 1 Glom f2
-
-
others
Clfl
Fibrln ++
ND
ND
t+
-
ND
ND
t
-
ND
ND
t
+ Small Parietal
ND
ND
-
t Mesang
ND
ND
+
Continued
September 1978
The American Journal of Medicine
Volume 85
451
RAPIDLY PROGRESSIVE GLOMERULONEPHRITIS-MORRIN ET AL
TABLE III (Cont’d) Case No.
lmmunofluorescent
W
w + Foe on Glom
7
-
a
-
9
-
10
-
11
f Glom BM
12
-
13
-
-
f Glom BM
+
f Endo
l4-
Pathology
ND
Fibrin ++
+ Foe on Glom
i- Foe on Glom
ND
-
+ Foe on Glom
-
++
+ Small Foe Glom
-
-
+
f
+ Foe & Filaments Glom
-
+
f Glom BM
+ Glom BM
-
+ Glom Foe Fine Endo Some Points
-
+ Foe Glom BM
-
+
-I+
Lin Glom BM
+ Lin Glom BM
-t Glom
+ Glom
++
++
Lin Glom BM
f Glom
f Glom
+ On Crescents
+
Lin Glom BM
+ Foe Glom
-
-I- FocGlom
f
Glom 15
-
-
++
16
-
•t Foe Glom BM
+-t-
+ Gran & Dif in Glom Weak on Tub BM
17
++
+ Foe Glom
+ Glom 8 Mesang
+
ia
-
-
+
+ Endo Glom
+ Foe Endo Glom
ND
19
+-I- Glom Endo & Mesana
+ Glom
i-+
i- Endo Glom
ND
ND
-
20
+ Small Points on Glom BM
-
+ Small Points Glom BM
-t Small Points Glom BM
-
ND
-
21
-
+ lrreg on Glom
-
+ lrreg on Glom
ND
ND
f
22
-
-
-I- Glom Endo & Gran + Tub BM
-I Glom Endo & Gran + Tub BM
-
+ Glom Foe
-
23
-
i- Endo Glom
++
++
f
f
+
24
-
+ Glom Gran 8 Dif
-I- Glom Gran
ND
+
25
-
+ “Humps”
ND
ND
++
26
-
+ Small “Humps”
ND
+ Foe
27
-
+ “Humps” Endo
ND
ND
+
28
++
-I+
+
29
-
lrreg Glom & Mesang
Endo Glom
Endo & Mesang
Endo Glom
+ Glom
++
Endo Glom
Gran 8 Foe Par
f
+ “Humps” Par
& Small
-
+-I- Endo Glom
+
Endo & Gran
September 1979
-
The American Journal ct Yedlclne
& some
+ Endo Glom
Endo Glom
+
NOTE: BM = basement membrane, Dif = diffuse, Endo = endomembranous, irregular, Lin = linear, Mesang = mesangial, Par = parietal, Tub = Tubule.
452
c1q
c4
c3
199
Volume 65
Foe = focal, Glom = glomerulus, Gran = granular, lrreg =
RAPIDLY
MORPHOLOGIC DATA Renal biopsy findings on light microscopy are listed in Table II and the immunohistology in Table Ill. On the basis of light microscopic findings the patients could be divided into two main groups. Group I. Patients with Mainly Extracapillary Prollferation. Light microscopy in 17 initial biopsy specimens (Cases 1- 17) showed no signif icant endocapiltary proliferation (Figure 2) whereas epithelial proliferation resulting in crescent formation was very intense and usually appeared to be of recent origin. The cells were large, basophilic and contiguous to each other. Some fibrosis was present in nearly all specimens, but it was minimal in 11. In 15 instances strands of fibrin were visible between the epithelial cells. All stages of crescent development from segmental to circumferential proliferation which completely filled the urinary space were observed. The extent of epithelial proliferation was variable from one biopsy specimen to another. In three patients (Cases 13, 14 and 16), all the analyzable glomeruli contained circumferential crescents; in the remaining 14, some segmental crescents were in-
PROGRESSIVE C%_OMERlJLONEPHRITIS-MORRlN
variably present (Table II). There negative correlation between the glomeruli containing crescents and segmental crescents (P
ET AL.
was a significant total number of the percentage of = -0.58) (Figure
3). The capillary tufts were either wholly or partly reduced to an amorphous fibrous mass or necrotic. When necrosis was partial the remaining portions of the tuft were relatively normal. There appeared to be a correlation between the amount of tuft necrosis and the size of the crescent; this was clearly seen in several glomeruli which were studied by serial, fine, electron microscopic sections, stained by silver methenamine. In seven patients (Cases 6, 8, 10-12, 16 and 17) the number of intraglomerular polymorphonuclear leukocytes was clearly increased. The results of immunofluorescence were very heterogeneous in this group (Table Ill). Staining with antifibrin/fibrinogen serum was positive in all but three patients (Cases 5, 11 and 15) (Figure 4A). In four pa-
i
0
Pure
extrocap,II3ry
0
Endo
+ extrocap~llory
.m
PERSISTENT RENAL FAILJRE ‘3
0
0
0
0
0
n .
00 l 0
. 8
l
I
. 50
60
70
60
9r)
100
% CRESCENTS
Figure 2. Case 6. Light microscpy. Ultrathin Epon-embe&&d section stained with silver methenamine.In the upper portion of the glomerulus, the capillary tuft is normal; no mesangial proliferation is present and Bowman’s space is open. In the lower portion a dense proliferation of the epithe&l cells ( Ep) has compressed and occludedthe capillaries (arrow) . Several dark plaques of fibrin (F) are no ted. Magnification X 540.
Figure 3. Relationship between the percentage of segmental crescents and the total percentage of crescents. Open symbols indicate patients in whom renal function showed either a temporary or permanent improvement. Closed symbols indicate patients who had no improvement in renal function. It should be noted that some of those who showed initial improvement subsequently showed deterioration or died.
September 1978
The American Journal of Medlclne
Volume 85
453
RAPIDLY PROGRESSIVE GLOMERULONEPtiRITIS-MORRIN
ET AL.
Figure 4. Immunofluorescence. A, anti-fibrin/ fibrinogen serum (Case 7). The serum is fixed by numerous plaques which are probably situated in the urinary space. 6, anti Cl q serum (Case 11). Moderately numerous, irregular arb3granular deposits scattered throughout the glomerulus. C, anti-lgG serum (Case 73). Typical linear fixation delineating the capillary basement membrane. D, anti-/gG serum (Case 23). Significant granular deposits along all the capillary basement membranes.
tients (Cases 1 through 4) there was no fixation of any immunoglobulin or complement and in eight (Cases 5 through 12) there were small focal deposits of doubtful significance (Figure 48). In three patients (Cases 13, 14 and 15), a strong linear fixation of immunoglobulin G (IgG) was observed which was associated with a similar fixation of C3 in two and a focal fixation in one (Figure 4C). Significant granular fixation of immunoglobulin and complement was only found in two instances (Cases 16 and 17). In one (Case 16) the deposits were voluminous and parietal, and contained principally IgG and C3 and more locally Clq which was also present on the tubular basement membranes. In the other (Case 17) the deposits were mainly endocapillary, less abundant and contained principally immunoglobulin A (IgA) and in a more irregular manner some IgG, immunoglobulin M (IgM) and C3 but neither Clq nor C4. Electron microscopy was performed in eight subjects of this first group (Cases l-3,5,6, 10, 16 and 17). The findings confirmed the normal histology of certain parts
454
September 1978
The American Journal of Medlclne
of the tuft and the absence of endothelial or mesangial proliferation. Complete rupture of the glomerular basement membrane was occasionally seen, but much commoner findings were (1) wrinkling of this membrane; (2) extensive necrosis of both endothelial and epithelial cells with preservation of the basement membrane, and (3) partial necrosis of the capillary wall which involved only the endothelial cells in some instances and only visceral epithelial cells in others leaving the endothelial lining apparently normal. These last lesions were generally associated with prominent wrinkling of the basement membrane, but in five biopsy specimens (Cases 1,2,3,10 and 17) they were found in capillary loops which were still being perfused as indicated by plasma or red blood cells in the lumen (Figure 5). In two biopsy specimens (Cases 2 and 3) large amounts of fibrin were observed traversing areas of the basement membrane where isolated epithelial necrosis was present (Figure 6). Degranulated or dying polymorphonuclear cells were sometimes observed in the endocapillary or extracapillary spaces in the ne-
Volume 65
RAPIDLY
PROGRESSIVE Gi_OMERULONEPHRITIS-MORRIN
ET AL,
F&suS. Ektmnmlcms~y(Case2). Several capillary loops and Bowman’s capsule (B) are shown. The capillary lvmens contain n3dcells (MC) andpksms; the 8t&th6&3f C8#S (EN) w RWT&; thetWWment-neislmbrdr8n:ttle vlsceral and p8riet8l epith8lial cells are completely necrosed (err0 w) . Msgnlfication X 18,000, reduced by 20 per cent.
erotic areas. Abnormal deposits were clearly seen in one (Case 16), they were continuous, thick, finely granular and located in the extramembranous region of numerous capillary loops. Occasionally, endomembranous deposits were also noted. In Case 17 abnormal, dense, subendothelial plaques were present but were harder to demonstrate than in the preceding biopsy specimen. Group II. Patients with Extracapillary and Endocapillary Proliferation. By light microscopy 12 biopsy specimens (Cases 18-29) showed endocapillary proliferation (Figure 7A). As in the preceding group, epithelial crescents did not necessarily involve all the glomeruli and could be either circumferential or segmental (Table II). In no biopsy specimen in this group did all the glomeruli contain circumferential crescents. Although, in general, the extent of tuft necrosis was less marked than in the preceding group, there appeared to
be a gradation in severity ranging from crescents which were predominantly segmental, composed of only a few layers of cells, without apparent necrosis of the tuft, and associated with marked endocapillary proliferation, to those which were more hypercellular and associated with definite tuft necrosis and only modest endocapillary proliferation (Figure 7A and 88). In all but two cases (Cases 21 and 22) the fineness of the intercellular membranoid bands indicated recent proliferation. Some fine double contours were visible in the majority of biopsy specimens but particularly in one (Case 18). Deposits were seen by light microscopy of paraffin or Epone sections in all but three (Cases 20, 21 and 29) and isolated extramembranous deposits (“humps”) were observed in three others (Cases 25, 26 and 27). In five biopsy specimens endomembranous deposits were clearly visible but rarely voluminous (Cases 18, 19, 22-24). Three of the five also had segmental ex-
September 1978
The American Journal of Medicine
Volume 85
455
RAPIDLY PROGRESSIVE GLOMERULONEPHRITIS-MORRIN
ET AL.
Figure 6. Electron microscopy (Case 3). Detail of a capillary basement membrane showing intact endothelium (EN) and necrotic epithelium (arrow) . Some clumps of fibrin are seen in the capillary lumen and in the internal portion of the basement membrane. &any/ acetate and lead citrate stain, magnification X 35,000, reduced by 8 per cent.
tramembranous deposits which were small and scanty in two (Cases 22 and 23), and voluminous and confluent in one (Case 24). An increased number of polymorphonuclear leukocytes was present in all and especially in seven (Cases 18, 20, 23, 24,26,27 and 28). Of the three biopsy specimens (Cases 25-27) which showed “humps” two (Cases 26 and 27) fixed anti-IgG serum in a granular pattern and parietal location, and also in small subendothelial deposits. All three fixed anti-& serum in small granular points. The endomembranous deposits found in five cases fixed IgG and C3 in all (Figure 4D). IgA was found in one (Case 19) and IgM in three (Cases 19, 22 and 23). C4 was in three (Cases 18, 23 and 24). Of the three biopsy specimens which showed no deposits on light microscopy, one (Case 20) showed small parietal points of IgA and IgG, and focal deposits of Cat another (Case 21) showed an irregular staining for IgM and Cs but, in view of the advanced fibrous state of the lesions in this case, the specificity of these deposits is doubtful. The third (Case 29) fixed neither immunoglobulin nor complement. Six biopsy specimens (Cases 23,24,26-29) in group II were examined by electron microscopy which confirmed the exact location of the deposits. In Case 24 these were very unusual, abnormally dense, endo- and extramembranous deposits formed by bundles of fine tubular structures 300 A in diameter which were seen in both longitudinal and transverse sections. In this group, rupture of the basement membrane was found in only one instance and wrinkling and cellular necrosis of the capillary wall were found in more limited areas than in the preceding group.
FQure 7. Light microscopy (c;ase A, born mm- and extracapfrtary proliteratron are present. Ine easement memoranes are thickened. The cells in the crescent form loose strands which do not compress the tuft. Trichrome stain, magnification X 485, reduced by 29 per cent. 6, second biopsy specimen. The glomerulus is almost norm/ apart from some discrete mesangial hypertrophy. The capillary lumens are permeable and the basement membranes thin. The urinary space is open, Bowman’s capsule is normal. The surrounding tubules and inferstitium show no abnormality.
456
September 1976
The American Journal of Medicine
Volume 65
RAPIDLY
One patient (Case 28) had a particularly interesting evolution. Two biopsy specimens were available; the first (Figures 8A and 88) unfortunately only contained 6 glomeruli, all of which were identical. There was an endocapillary proliferation and polymorphonuclear infiltration, and numerous capillary loops were obstructed by thrombi composed of an abnormal refringent substance. No extracapillary proliferation was seen. Immunofluorescent staining showed abundant, voluminous deposits of IgA, IgG, Cs, Clq and fibrin. The second biopsy specimen, obtained one month later, contained numerous glomeruli of which 80 per cent contained crescents; 80 per cent of these crescents were circumferential. The adjacent capillary tufts were often fibrous and not analyzable. In those glomeruli which were better preserved there were only slight, irregular mesangial proliferation, a few polymorphonuclear leukocytes and no abnormal deposits. Immunofluorescent staining was negative for both immunoglobulin and complement. Electron microscopy of the first biopsy specimen showed a very large number of polymorphonuclear leukocytes, most of them partially or completely degranulated. Large portions of the basement membrane were abnormally thin and in direct contact with these degranulated cells. In other areas, large abnormal deposits and fibrin bundles were seen against the endocapillary side of the basement membrane. There were no obvious lesions of the epithelial cells apart from some spreading of the podocytes. HISTOLOGIC EVOLUTION Subsequent studies in group I (four cases) showed that necrotic and proliferative lesions evolved to fibrosis. Glomeruli with circumferential crescents became fibrotic whereas segmental crescents were associated
PROGRESSIVE GLOMERULONEPHRITIS-MORRIN
ET AL.
with re-expansion of the tuft. Interstitial lesions subsided but persisted and in Cases 2 and 3, after several years, large cellular crescents with a recent appearance were seen, together with numbers of obsolete glomeruli. In group II (six cases), the evolutionary changes were more variable (Table II). One patient (Case 22) showed slight deterioration and no change in immunofluorescence after one month. In Case 29, diffuse fibrosis developed and in Case 27, after two years there were numerous obsolete and some normal glomeruli and significant tubulointerstitial lesions, and immunofluorescence was negative. In Cases 18 and 19 (Figures 7A and 78) both patients had subendothelial deposits in their initial biopsy specimens. The second biopsy specimens, obtained at one and four years, respectively, showed considerable improvement; rare glomeruli were obsolete whereas the others showed only moderate mesangial hypertrophy, occasional adhesions to Bowman’s capsule and some small fibrous crescents. A few small foci of immunoglobulin and complement persisted on immunofluorescent examination. CLINICOPATHOLOGIC CORRELATION Table IV compares the major, clinical, histologic, immunologic and laboratory findings in the two groups. Cases in group I were clinically and histologically more severe; recovery occurred in only 30 per cent compared with 50 per cent in group II. Proteinuria and immunoglobulin deposits were more marked in group II, but linear deposits were confined to group I. Immunologic parameters were not very helpful. C3 was reduced in five patients, all of whom had immunoglobulin in their biopsy specimens (Cases 14, 16, 22, 23 and 27). No significant abnormality was noted in serum immuno-
Figwe 8. Light microscopy (Case 28). A, marked proliferation of the en&capillary cells with numerous porymorpnonuclear leukocyt8s present. A voluminous &posit is visible. There is no proliferation of the epithelial ceils. MagnificationX 485, reduced by 32 per cent. B, second biopsy specimen. A representative glomerulus in which the urinary space is almost completely OCeluded by a Very dense fibro-cellular epithelial crescent. In the center, the glomerular tuft is compressed and becoming fibrotic. Magnification X 485, reduced by 29 per cent.
September 1978
The American Journal of Medicine
Volume 65
457
RAPIDLY PFQGRESSlVE
TABLE IV
GLOMERULONEPtiFiITIS-MORRIN
ET AL.
Comparison Between Groups 1 and 2
ciroupI (N = 17) Mean Age (yr) Range Symptoms < 30 days Infection or fever Antistreptolysin 0 titer > 300 Oliguria <500 ml/24 hours Dialysis required
56.5 21-75 6117 11117 016 14117 15117
Permanent dialysis or death No remission Proteinuria > 3.5 g/24 hours
12117 9117 0111
Crescents in 100% of glomeruli
All crescents circumferential Necrosis Fibrin Major deposits of complement and/or immunoglobulin Linear deposits Decreased C3 PEG test positive Circulating antiglomerular basement membrane antibodies
6117
3117 2+ 2+ 5117
3117 2/14 415 2/5
GroupW (N = 12) 41.1 15-66 6112 9112 4110 6112 6112 P 0.05 6112 3112 9110 P < 0.01 1112 P-CO.1 > 0.05 o/12 1+ 1+ 9111' P < 0.05 > 0.02 0111 316 O/l O/l
NOTE: PEG = polyethylene glycol precipitation test. One case excluded because of old blopsy. l
globulins (19 cases), Cq (12 cases), Cs Pa (seven cases), cryoglobulins (13 cases) and HB surface antigen (13 cases). Circulating antiglomerular basement membrane antibodies were found in Cases 11 and 14. The morphology in one specimen (Case 18) was more characteristic of membranoproliferative glomerulonephritis than in any of the other biopsy specimens. This patient had one of the best morphologic (Figures 7A and 76) and clinical recoveries. It was of interest that his serum contained a monoclonal IgG with kappa light chains which disappeared on treatment. Similar cases have been reported by others [ 231. COMMENTS
Variable criteria have been used to define rapidly progressive glomerulonephritis [ 1- 11,13- 17,24-321, and similar histologic and clinical findings may occur in poststreptococcal nephritis, Henoch Schonlein purpura, polyarteritis, Wegener’s granulomatosis, disseminated lupus and Goodpasture’s syndrome. Some series have specifically excluded such cases [ 14,17,19,28,28, 30,331, but the present study was not designed to ex-
455
September 1978
The Amerkan Journal of Medlclne
elude these entities if they met the selection criteria. Nevertheless-the great majority of our cases were the so-called “idiopathic” type. When possible, specific etiologies should be identified because it cannot be assumed that prognosis and response to treatment will be the same for all; in the patient with poststreptococcal nephritis it is generally accepted that the outlook is better [28,28,29]. Only two cases in our series had gocd evidence of a streptococcal etiology; both patients recovered, but a streptococcal etiology could have been missed in some of the others. Habib [8] has shown that the prognosis in children is much better if less than 80 per cent of the glomeruli contain crescents. Others have reported similar findings in adults [30]. In our series no patient in whom all glomeruli contained crescents recovered renal function and only seven of 18 patients (39 per cent) with more than an 80 per cent incidence of crescents showed any improvement. Conversely, 10 of 11 (90 per cent) patients with less than an 80 per cent incidence of crescents had some degree of remission (Figure 3). This study also indicates that the percentage of segmental crescents is of prognostic value as reported by Levy and Habib [ 131 in children. Eight of nine patients with less than 35 per cent segmental crescents remained in renal failure and the ninth had a relapse after a temporary remission. Conversely, four patients in whom more than 35 per cent of the crescents were segmental (Cases 9, 21, 25 and 27) regained significant renal function even though 90 per cent of the glomeruli contained crescents. The difference in improvement rates between patients with more than 35 per cent segmental crescents and those with less was significant at the 1 per cent level (X2 = 9.48). We also believed that the morphology of the glomerular lesions was of predictive value. The more severe lesions were associated with predominantly extracapillary proliferation. When endocapillary proliferation was prominent, the glomerular crescents were usually less compact, and necrosis of the tuft was less evident. Similar findings were noted in a previous study from this Department [lo] and also by some other workers [26,29,34,35], but not by all [ 16,171. Early studies showed a very poor prognosis [5,7,21,32,36] which led to the use of multiple therapeutic programs in a statistically uncontrolled fashion [10,15,17,26,29,30,31,37]. Although the efficacy of such programs cannot be unequivocally established, recent reports have shown improvement or cure in a significant percentage of cases [ 10,15,17,25,27, 30,31,37,38]. Unfortunately, most series do not consider all the prognostic factors mentioned herein and this compounds the difficulty in evaluating any specific therapy. Like many others [ 13,15,17,29,33,39,40], we were impressed by the variability of the immunofluorescent
Volume 65
RAPIDLY
findings and we would question the reliability of this technic as an indicator of the immunopathologic process in this type of glomerulonephritis. In the present study, one patient with circulating antiglomerular basement membrane antibodies did not have linear deposits, two patients with a positive polyethylene glycol test showed only focal deposits and, most impressive of all, the deposits disappeared in one (Case 28) in association with the development of widespread crescent formation. This particular patient points out an important time relationship between the immunofluorescent observations and the duration of the disease. The disappearance of immune deposits is poorly understood. Numerous electron microscopic studies have demonstrated holes in glomerular basement membranes which could permit blood products including fibrin/fibrinogen to enter the capillary space in which they appear to stimulate epithelial proliferation [ 10,34,40-441 but the more diffuse necrotic lesions of the capillary wall, which we have previously described [lo], may be of more importance than these holes. In two instances, electron microscopy clearly showed fibrin traversing the basement membrane in these areas of epithelial necrosis. Such increased permeability might permit the passage of immunoglobulins and complement with partial or complete disappearance of immunofluorescent deposits, depending on the duration of the disease and how firmly the deposits were
PROGRESSIVE GLOMERULONEPHRITlS-MORRIN
ET AL.
attached to the basement membrane. (In patients with linear deposits, this attachment involves a different mechanism and intense fluorescence may persist even in advanced cases [45] .) It is apparent from this and other studies, especially that of Levy and Habib [ 131, that rapidly progressive glomerulonephritis is not a homogeneous entity, clinically, histologically or immunologically, but rather a clinical syndrome characterized by rapid development of renal failure and widespread crescent formation. It can be found in a variety of known conditions, and the histology and immunopathology even in the “idiopathic” form are extremely heterogeneous. It is no longer appropriate to describe therapeutic programs and recovery rates for rapidly progressive glomerulonephritis without previously defining the nature and extent of the renal lesions by immunofluorescence and, if necessary, electron microscopy in addition to routine histology. Any further understanding of this condition will require a careful search for all possible etiologic factors and pathogenetic mechanisms correlated with precise histologic and immunopathologic study of each case. ACKNOWLEDGMENT
We are indebted to Dr. J. Berger for performing the immunofluorescent studies, to Madamoiselle Monique Lillie and Madame lngrid Muller for the preparation of the photographs, and to Mrs. Lorraine Dale and Mrs. Shirley Friend for the typing of the manuscript.
REFERENCES 1. 2.
3.
7.
6.
9. 10.
11.
Volhard F, Fahr T: Die Brightshe Nierenkrankheit, Berlin, Springer Verlag, 1914. Ellis A: Natural history of Bright’s disease: clinical, histological and experimental observation. Lancet 1: I, 34, 72, 1942. Hamburger J: Les Glorn&ulo-Nephrites Malignes. Entretiens de Bfchat. Paris, Expansion Scientlfique, France, 1956, p 231. Bialestock D, Tange JD: Acute necrotizing glomerulitis: the clinical features and pathology in 9 cases. Aust Ann Med 6: 281, 1959. Berylene Gfvf,Baker SB deC: Acute anuric glomerulonephrlitis. QJ Med 33: 105, 1964. Proesmans W: Proliferative Glomerulonephritis with Crescents. Proceedings of the Second International Symposium on Paediatrlc Nephrology, Paris, 1971, p 91. Bacani RA, Velasquez F, Kanter A, et al.: Bapkfly progressive (nonstreptococcal) glomerulonephritis. Ann Intern Med 69: 463, 1968. Habib R: Classification Anatomique des Nephropathies Glorn&ulaires. Extrait de P&flat. Fortbildungskurse 28: 61, 1970. Heptlnstall RH: Pathology of the Kidney, Boston, Little. Brown, 8 Co., 1966. Sonsino E, Nabarra B, Kazatchkine M, et al.: Extracapillary proliferative glomerulonephrltis so-called malignant glomerulonephrltls. Advances in Nephrology, from the Necker Hospital (Hamburger J, Crosnier J. Maxwell MH. eds.), Chicago, Year Book Medical Publishers, 2, 1972. p 12 1. CameronJS, Ogg CS: Rapidly progressive gknnerukxqhriiis with extensive crescents. Glomerulonephrltls, Morphology,
12.
13.
14.
15.
Natural History and Treatment, (Kincaid-Smith P, Mathew TH, Becker, EL, eds), New York, John Wiley & Sons, Inc.. 1973, p 735. Churg J, Morii T, Suzuki Y: Glomsrulonephrltis with fibrin and crescent formation. Glomerulonephritis, Morphology. Natural History and Treatment, (Kincaid-Smith P, Mathew TH, Becker EL, eds). New York. John Wiley & Sons, Inc., 1973, p 677. Levy M, Habib R: lmmunopathologie des Glom&rulon&phrites a Croissants Epitheliaux Diffus Chez L’Enfant. Estratto da Minerva Nefrologlca 20: 184, 1973. Mathew TH. Kincaid-Smith P: Severe fibrin and crescent glomerulonephritis. Glornerulonephritis, Morphology, Natural History and Treatment, (Kincaid-Smith P, Mathew TH, Becker EL, eds). New York. John Wiley & Sons, Inc., 1973. Bernard D. Bariety J, Oruet P, et al.: Les Glomerulonephrites Proliferatives Extracapillaires. Sem Hop Paris 50: 539, 1974.
16.
Olsen S: Extracapillary glomerulonephritis. Acta Pathol Microbiol Stand [A] 82 (suppl 249): 7. 1974.
17.
Whitworth, JA, et al.: The significance of extracapillary proliferation. Nephron 16: 1, 1976. Hinglais N, Garcia-Tones R, Kleinknecht 0: Long-term prognosis in acute glomerulonephritis. Am J Med 56: 52, 1974.
16.
19.
Movat HZ, Steiner JW, Huhn D: The fine structure of the glomerulus in acute glomerulonephrltfs. Lab Invest 11: 117. 1962.
20.
Mancini S, Carbonara AO. Heremans GF: lmmunochemical
Soptembet 1978
The American Journal of MerJlclno
Volume 85
459
RAPIDLY PROGFtESSIVEGLOMERULONEPHRITIS-MORRIN ET AL.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
460
quantitation of antigens by single radial immunodiffusion. Immunochemistry 2: 235. 1985. Creighton WD, Lambert PH. Miescer PA: Detection of antibodies aiid soluble antigen-antibody complexes by precipitation with polyethylene glycol. J lmmunol 111: 1219, 1973. Mahieu PO, Dardenne M, Bach JF: Detection of humoral and cell-mediated immunity to kidney basement membranes in human renal diseases. Am J Med 53: 185, 1972. Verroust P, Mery JP, Morel-Maroger L, et al.: Glomerular lesions in monoclonal gammopathies and mixed essential cryoglobulinemia IgGlgM. Advances in Nephrology from the Necker Hospital, (Hambtrger J, Crosnier J, Maxwell MH, eds), Chjcago, Year Book Medical Publishers, 197 1. Slama R, Maurat JP, de Montera H: Les glom&ulonbphritis maliznes, Actualit& Nbphrologiques de I’Hbpital Necker, Paris, Flammarion, 1961. p 85. Harrison CV. Loughridge LW, Milne MD: Acute oliguric renal failure in acute glomerulonepfriils and poiyarteritis nodosa. QJ Med 33: 39,1964. Leonard CD, Nagle RB, Striker GE, et al.: Acute glornerule nephritis with prolonged oliguria. An analysis of 29 cases. Ann Intern Med 73: 703, 1970. Arieff Al, Plngerra WF: Rapidly progressive glomerulonephriiis treated with anticoagulants. Arch Intern Med 129: 77, 1972. Schreiner ff, Rakowski TA, Argy WP Jr, et al.: Natual history of oliguric glomerulonephritis. Glomerulonephritis Morphology, Natural History and Treatment, (Kincaid-Smith P, Mathew TH, Becker EL. eds), New York, John Wiley & Sons, Inc., 1973. p 711. Striker GE, Cutler RE, Huang TW, et al.: Renal failure glomerulonephritis and glomerular epithelial cell hyperplasia. Glomerulonephritis, Morphology, Natural History and Treatment, (Kincaid-Smith P, Mathew TH. Becker EL, eds), New York, John Wiley 8. Sons Inc., 1973, p 857. Lawrence JR: Glomerolonephritis with Fibrin and Crescent Formation in Glomerulonephritis, Morphology, Natural History and Treatment, (Kincaid-Smith P, Mathew TH, Becker EL, eds), New York, John Wiley & Sons, Inc., 1973. p 739. Brown CB, Wilson D, Turner D. et al.: Combined immunosuppression and anticoagulation in rapidly progressive
September 1978
The Amerkan
Journal ol Medlclne
32.
33.
34. 35.
36.
37. 38.
39.
40.
41.
42.
43.
44.
45.
Volume 65
glomerulonephritis. Lancet II: 1168, 1974. Brun C, Gormsen H, Hilden T, et al.: Kidney biopsy in acute glomerulonephritis. 13 cases. Acta Med Stand 160: 155, 1958. Lewis EJ, Cavallo T, Harrington JT, et al.: An immunologic study of rapaly progre+ve glomerulonephritis in the adult. Hum Patho12: 185, 1971. Morita T, Suzuki Y, Churg J: Structure and development of the glomerular crescent. Am J Patho172: 349, 1973. Churg J: Glornerulonephritis, Morphology. Natural History and Treatment, (Kincaid-Smith P, Mathew TH, Becker EL, eds), New York, John Wiley 8 Sons, Inc., 1973, p 793. Forland M, Jones RE, Easterling RE, et al.: Clinical and renal biopsy observations in oliguric glomerulonephritis. J Chron Dis 19: 163, 1968. Kincaid-Smith P, Saker BM, Fairley KF: Anticoagulants in “irreversible” acute renal failure. Lancet 2: 1360, 1968. Jensen H, Faarup P, Hess T, et al.: Immunosuppressive treatment of rapidly progressive glomerulonephritis (letter). Lancet 2: 1572, 1974. Olsen S, Posborg Petersen V, Sommer Hansen E: Immunofluorescence Studies of Extracapillary Glomerulonephritis. Acta Pathol Microbial Stand [A] 82 (suppl 249): 20, 1974. Burkholder PM: Ultrastructural demonstration of injury and perforation of glomerular capillary basement membrane in acute proliferative glomerulonephritis. Am J Pathol 57: 251, 1969. Min KW, Gybrkey F, Yium JJ, et al.: The morphogenesis of glomerular crescents in rapidly progressive glomerulonephritis. Kidney Int 5: 47, 1974. Stejskal J, Pirani CL, Okada M, et al.: Discontinuities (gaps) of the glomerular capillary wall and basement membrane in renal disease. Lab Invest 28: 149, 1973. Berger J, Yaneva H, Hinglais N: lmmunohistochemistry of Glomerulonephritis. Advances in Nephrology, from the Necker Hospital (Hamburger J, Crosnier J, Maxwell MH, eds.). Chicago VI, Year Book Medical Publishers, 1971, p 11. Bohman S, Olsen S, Posborg Petersen V: Glomerular ultrastructure in extracapillary glomerulonephritis. Acta Pathol Microbial Stand [A] 82: (suppl 249): 29, 1974. Beiger J: Personal communication.
PETER A. F. MOFMN.
MB.,
F.R.C.P.(C)
Kingston, Ontario, Canade NICOLE HINGLAIS, M.D. B. NABARRA,
D.Sc.
HENRI KREIS, M.D. Paris, France
From the Department of Medicine. Queen’s Unlversity, and the Kingston General Hospital, Kingston, Ontario, Canada; and Clinique Nephrologique, H6pital Necker, Paris and lnserm Unite 25, Paris, France. Requests for reprints should be addressed to Dr. Peter A. F. Morrin, Renal Unit, Kingston General Hospital, Kingston, Ontario, Canada K7L 2V7. Manuscript accepted March 2, 1978.
446
September 1979
Twenty-nine cases of rapldly progressive glomerulonephrltls were reviewed. In all cases there was less than three months between the onset of renal symptoms and renal blopsy. The serum creatlnlne was greater than 2.5 mg/lOO ml at the tl.me of biopsy, and the hlstology showed a 50 per cent or greater Incidence of crescents In the glomerull. lnfectlous or febrlle episodes were present In 21 cases, microscopic hematurla was noted In 15, and protelnurla exceeding 2.5 g/24 hours In elght. Ollgurla less than 500 ml/24 hours was present In 20 cases and dlalysls was required In 22. In 10 cases there was sustalned Improvement; In tlie remainder the disease progressed or the patlent died. The prognosis was related to the number and size of the glomerular crescents. Hlstologlcally cases fell Into two maln groups, one wlth predomlnanily extracapillary prollferatlon and the other with endo- and extracaplllary prollferatlon. In the first group the disease was histologically and clinically more severe, and lmmunofluorescence hlstology was heterogeneous and often nonspecific except for three cases In which there were linear Immunoglobulin deposits. In the second group the leslons were iess severe and lmmunoglobulln deposits were common. Electron mlcroscopy In 14 cases was confirmatory, and also demonstrated capillary rupture and necrosis of podocytes In some loops. Transltlon from group I to group II was observed In serial blopsy specimens In one case. The hlstologlc and lmmunofluorescent heterogenelty suggest that rapidly progressive glomerulonephrltls Is the end result of several dlff erent pathogenetlc mechanisms. It has been recognized for many years that glomerulonephritis can follow a rapidly progressive course terminating in renal failure after a period of several weeks or months [ 11. The terms extracapillary [ 11, rapidly progressive type I [2], malignant [3], acute necrotizing [4], acute anuric [6], proliferative with crescents [6], rapidly progressive nonstreptococcal [7] and endo- and extracapillary type Ill [6] have been employed by different workers to describe this form of the disease. Irrespective of the etiology, the renal biopsy specimens are characterized by massive proliferation of the glomerular extracapillary cells which produces numerous and voluminous crescents [9]; this feature is so prominent that it has sometimes been used as a basis for case selection [6,10-171. In 1972, Sonsino et al. [lo] reviewed the experience at the Necker Hospital with this type of glomerulonephritis. This report extends these earlier observations and includes the more recent experience at this institution with the condition commonly referred to in the English literature as “rapidly progressive glomerulonephritis” and in the French literature as “les giomerulonephrites malignes.”
The Amorlcan Journal of Medlclne
Volume 85
RAPIDLY PROGRESSIVE GLOMERLJLONEPHi?ITIS-MRIN ET AL.
MATERIAL AND METHODS
data. The number of glomeruli containing crescents was expressed as a percentage of the total number of glomeruli in the biopsy specimen excluding obsolete glomeruli. The incidence of segmental crescents, as opposed to circumferential crescents, was recorded as a percentage of all the crescents in the section, i.e., number of segmental crescents to total number of crescents X 100. The histologic abnormalities were graded semiquantitatively on a scale of 0 to 3+. Treatment protocols varied considerably, but prednisone was usually administered in a dose of 2 mg/kg for 15 days and then gradually tapered to a smaller maintenance dose. Azathioprine was employed in a dose of 2 to 3 mg/kg and cyclophosphamide at 3 mg/kg. When anticoagulants were used, heparin was given by continuous intravenous infusion to maintain the clotting time at two to three times normal. In one case, subcutaneous heparin was employed. If treatment extended beyond 15 days, an oral anticoagulant was substituted. Improvement in renal function was defined by survival without dialysis in those who had previously required it, and by a 30 per cent or greater reduction in serum creatinine levels in the others. Cure was definedas a serum creatinine of less than 1.5 mg/lOO ml and the absence of proteinuria
Both clinical and histologic findings were employed in the selection criteria which were as follows: (1) A rapid evolution of renal disease with no more than three months between the first recognized renal symptoms and renal biopsy; (2) a+ vanced impairment of renal function at the time of biopsy as indicated by a serum creatinine >2.5 mgllO0 ml; (3) a histologic picture of severe glomerulonephritis of relatively recent onset with at least 50 per cent of the glomeruli containing crescents. Biopsy specimens without immunofluorescence histology or with less than 9 glomeruli were excluded. Twenty-nine patients were found who met these criteria. A second biopsy specimen was available in nine and a third in two. An autopsy was performed in one. The histologic technics employed have been previously described [ 181. In 21 cases ultrathin sections were stained with either uranyl acetate followed by lead hydroxide or periodic-acid silver methenamine using Movat’s technic [ 191. These sections were examined by light microscopy, and further study was then performed in 14 cases using a Phillips EM 200 electron microscope. lmmunofluorescent histology was performed by Dr. J. Berger. Serum levels of the complement components C3 and C4, and the C3 proactivating factor C3 Pa were measured by radial immunodiffusion [20]; circulating immune complexes were sought by the polyethylene glycol method [21] and circulating antiglomerular basement antibodies by tha technic of Mahieu et al. [ 221. Sections were studied without knowledge of the clinical
TABLE I
and microscopichemeturia. RESULTS The major clinical and laboratory findings are shown in Table I and Figure 1. There were 20 males and nine females. The mean
Clinical Features
case Aas fyr) No. &ldQX
-%I Renal Anl~nts
FMngr
Averaga BF >140
--K Fever mHg
8eNm ovouls
(500 mtl Edema
Creatinlna at Bx (mo/lOO HomaMa
24 hr
ml)
Mac
Mk
bnprovrmsst
1
75,M
Intermittentchest pain d-60
Hernaturia, azotemia
0
0
+
+
D
+
!
+
2
5O.F
Fever d-l 80, sore throat d-90, pneumonia d-15
Hernsturia
+
0
0
+
D
0
0
+
3
44,M
Pleurisy d-30. abdominal pain d-7
Azotemia
+
0
0
+
D
+
I
+
4
68.F
Chronic bronchitis, bronchopneumonia d- 15
Azotemia
0
0
0
0
D
0
+
+
5
51.M
Posttraumatic empyema d-60
Hematuria + azotemia
+
+
+
0
5.7
+
6
70.F
Sore throat d-28
Hematuria + azotemia
+
0
0
+
D
+
7
59,M
Fever + Arthralgia d- 15
Hematuria + anuria
+
0
+
+
D
+
8
74,M
Rhinopharyngitis d-3
Edema
0
+
+
+
D
+
+
I
+
0
I
0
Contitwed September 1978
Ths Amerkan Journal of Medlclne
Volume 85
447
RAPIDLY PROGRESSIVE GLOMERULONEPHRITIS-MORRIN
TABLE I (Cont’d)
Clinical
ET AL.
Features Average BP
Case NO.
Age (yr) and Sex
Presenting Renal Flndlngs
Antecedents
>140
Fever
90 mm Hg
Ollgurla <500 ml/ 24 hr Edema
Serum Creatinine at Bx (mg1100 ml)
Hematuria Mac Mlc
Improvement
9
56,M
Sore throat d-l 4
Azotemia
+
0
0
+
D
0
0
+
10
46,F
Arthralgia d-56, sore throat d-l 4
Oliguria
+
0
+
+
D
+
/
0
11
59,M
Rheumatic heart disease “chills” d-30
Azotemia
0
0
0
+
D
0
0
0
12
61,F
Malaise, nausea, vomiting from d-35
Edema + azotemia
+
0
+
0
6.7
+
I
+
13
69,F
Raynaud’s syndrome years; malaise + arthralaia d-26
Oliguria
0
0
+
+
D
0
+
0
14
21.M
Chronic filiiariasis; malaise -l- vomiting from d-30
Edema + azotemia
0
0
+
+
D
0
0
0
15
70,M
“Grippe”
Proteinuria
+
0
0
+
D
0
0
0
16
42,M
Chronic bilharziasis, penicillin for + W.R. d-14
Oliguria
0
f
+
+
D
+
1
0
17
45,M
Insidious onset
Edema + azotemia
+
+
+
+
D
0
0
0
16
42,M
Insidious onset
Edema
0
0
+
+
D
0
+
t
19
44,F
Insidious onset
Edema
0
0
+
0
3.6
0
0
+
20
63,M
Pulmonary infection d-14
Oliguria
+
0
+
+
D
0
+
0
21
33,M
Sore throat d-6
Hematuria
+
0
0
0
5.1
+
/
+
22
27,F
Dental abscess d-60; sore throat d-30
Edema
0
0
+
0
6.0
0
0
+
23
35,M
Sore throat d-2
Hematuria
0
0
0
+
2.6
+
/
+
24
66.M
Post-traumatic pneumococcal pneumonia d-23
Anuria
+
0
0
+
D
25
50,M
Chronic hypertension, pleural effusion d-26
Hematuria
+
0
0
0
7.9
+
I
+
26
33.M
Sore throat d- 15
Oliguria + azotemia
+
+
+
+
D
+
I
+
27
15.M
Sore throat d-l 4
Oliguria + azotemla
0
+
+
0
D
+
/
+’
26
17,M
Sore throat, purpura, arthralgia d-10
Hematuria ioliguria
+
0
+
0
+
/
0
29
66,F
Azotemla
+
0
0
+
0
0
+
d-7
Arthralgia -f- fever for 6 mo
NOTE: BP = blood pressure, d = days prior to biopsy, D = on dialysis, BX = biopsy, Mac = macroscopic,
448
September
1978
The American
Journal of Medicine
Volume 65
1.0(l) 4.6(2)
D
Anuria
0
Mic = microscopic.
RAPIDLY PROGRESSIVE GLOMERULONEPHRITIS-MORRIN
D BEGUN 6 YRS
AT
33
MTHS
@
21 MTHS
@
I3 MTHS
@
0 BEGUN
AT 16 MTHS
AT 3 ‘/z YEARS 3 lie YEARS
0 08
@
21 MTHS
@
D BEGUN
AT
D BEGUN
ONSET
ET AL.
19 MTHS
AT 22
AT
8 YEARS
AT
3’/r
26
MTHS
MTHS
@
YEARS
@
0 I8
OF
RENAL SYMPTOMATOLOGY I T I 4 8
I
I
I
I
I
12
16
20
24
28
I
I
I
32
36
40
WEEKS D-1 0
t Ccr
= DURATION = SERUM
OF
DIALYSIS
= DEATH 2 CREATININE
PREDNISONE AZATHIOPRINE
CREATININE CLEARANCE
0
CYCLOPHOSPHAMIDE
B
ANTICOAGULANTS
I
Figure 1. The clinical course and evolution of the disease are shown for each patient. The interval between the onset of renal symptoms and the biopsy is indicated by the blank area at the left of the fi ure. The numbers encircled represent the creatinine in milligrams per 100 milliliters. D - f indicates the duration of dialysis. + = death. Ccr = creatinine clearance.
September
1979
The American
Journal
of Mediclne
Volume
65
449
RAPIDLY
PROGRESSIVE
TABLE II
Case No.
1
GLOMERULONEPHRITIS-MORRIN
ET AL.
Morphologic Flndlngs Glom inBx (no.)
Crescents Seg Clrcum Obsol Tubule Ml Crest Crest GlOm (no.) (no.) (no.) Cellul Flbrln Fibros Necrosis Flbrosls Polys Damage
18
2
10
2
2 2ndExlyr 3rd Bx 3 yr
11 25 26
0 12 20
3 2 2
5 0 1
3 2ndBx4mo 3rd Bx 5 yr
13 28 12
1 8 10
6 15 1
3 0 0
4
29
0
22
3
++
+
5
33
2
8
13
++
+
30
0
12
3
++
Num
11 %
35%
5%
7
13
1
3
9
8
23
2
12
4
9 2nd Bx 1 yr
14 40
0 9
11 15
2 1
+++
10
20
1
6
13
+++
11
11
1
4
6
12
23
2
a
4
++
++
13
61
11
0
50
++
++
14
16
13
0
3
15
11
4
3
4
16
20
0
0
20
+++
17
18
5
3
30
+++
18 2nd Bx 4vr
12 34
0 6
7 6
3 6
++ -
-
19 2ndBxlyr
9 19
0 2
2 0
3 3
++ -
-
20
45
13
0
28
+
21
24
0
9
13
+
-
++
-
++
-
++
++
22 2ndBxlmo
12 19
2 9
2 4
6 2
+ -
-
++ +++
-
++ +
-
++ ++
++ +
23
19
2
8
1
+
f
+
+
+
++
24
14
0
6
8
+
f
+
+
++
25
44
4
14
24
+
+
++
+
6 2ndBx2wk Autopsy
+ ++ -_-++
++
+
+
f
++
+
++
+ -
+ f +
f -
++ ++ +++
f
++ -
f ++ -
-
++ ++
+
+
+
-
++
+
t
-
++
f
-
-
+
++
+++
+++
+. -
+ +
f +++
t+
+++
+ ++
+
InlersUllal FlbrosU Edema Cell
-
+++
++
+
++
-
++ -
f
t
-
f
-
++
+
+++
+++ ++
September 1979
The American
Journal of Madlclne
+ f ++
f ++
++ +t+
++ ++
+
++
+
++
++
+
+-t+
+
++
-
++ -
t ++
+ -
++ ++
+ +
++ ++
f
++
+++
++
-
++
+
+
++
+
+
+++
-
+++
f+ + -
+ ++
+++ ++
++
++
++
++
++
++
++
+++
++
-
++
t++
++
-
++ +++
+++
++
+
++
+
++
++
++
++
++
+
++
++
-
++
+++
+++
++
++
-
-
++ -
++ +
+ +
++ +
f+
-
+ f
+ -
++ f
++ -
+ +
-
+
f
+++
Continued
450
++ ++
++
+++
+t
f t+ +++
++
++
+
++ + ++
f
+++
+
-
+t
++
++
+
++
++
Volume 65
++
+
++
+
+++
++
+
++ +++ +++ f
++
+
++
++
++
++
RAPIDLY
TABLE II (Cont’d)
Case No.
Morphologic
GlOfll
Obsol
in 8x (no.1
Glom (no.1
S
PROGRESSIVE GLOMERULONEPHRITIS-MORRIN
Findings Crescents Cl
CrZ (no.1
c:z (no.)
Cellul
Flbrln
Flbros
Necrosis
TuH Fibrosis
0
8
5
++
+
-
f
-
+++
27 2nd Bx 2 yr
24 14
1 10
11 2
11 0
++ -
+ -
++ +++
-
+ -
+++
28 2nd Bx 1 mo
6 26
0 0
0 4
0 17
+t
_ f
t
_ f
_
t+t
29 2nd Bx 2 yr
10 16
1 7
4 8
2 0
+ -
t+ ++
t -
NOTE: Bx = biopsy, Cellul = cellularity, Circum = circumferential, Crew obsolescent, Polys = polymorphonuclear leukocytes, Seg = segmental.
age was 50.1 years (15 to 75 years), but children are not treated in this unit. The group contained only one known patient with systemic disease with vascuiitis (Case 29). No patient with known disseminated lupus erythematosus met the selection criteria, and serologic tests for disseminated lupus erythematosus were negative in 26 and not performed in three. There were no characteristic prodromal features but 21 patients had an infectious or febrile episode in the period prior to admission, and 10 had a history of sore throat. Almost ail the patients with a history of fever had received antibiotics prior to admission which obscured the bacteriologic findings. Antistreptoiysin 0 titers were available for 16. in two (Cases 26 and 27), the values were over 1,000. Two others (Cases 21 and 23) had slight elevations, one of whom had normal antistreptoiysin H and antistreptoiysin K levels (Case 23). Six patients had a history of pleural or pulmonary infection (Cases 2-5, 20 and 24), but pneumococci were only isolated from one (Case 24). Chronic parasitosis was present in two (Cases 14 and 16). The onset was at times very acute, with oiiguria and
Cell
FIbroW Edema
++
++
++
++ +
+t
-
tt
t
tt
t
+ -
-
t +
t
+ +
f
f +
t tt
t t+
= crescents, Glom = glomerulus, Num = numerous, Obsol =
renal failure apparently developing in a few days, whereas at others a more insidious evolution occurred with edema or azotemia as the presenting renal symptom. Renal failure developed rapidly and by the time of biopsy 20 patients had urine outputs of less than 500 ml/24 hours, and 21 had required dialysis. Twelve patients had persistent renal failure (Cases 7, 8, 10, 11, 13-17, 20, 24 and 28) and four others (Cases 2, 12, 22 and 25) had deterioration to end-stage uremia after a temporary improvement. Renal function improved in 13, but three of these (Cases 1,4 and 6) died from causes other than uremia within three months of the biopsy and one (Case 23) was killed in an accident after 32 weeks when his renal function was almost normal. in nine of these 13 (Cases 3,5,9,18, 19,21,26,27 and 29) improvement was maintained over the period of observation, but only two (Cases 15 and 19) met the criteria for cure. The nature and duration of treatment and the subsequent course are shown in Figure 1. Although the more vigorously treated patients appeared to do better, no statistically significant conclusions can be drawn.
lmmunofluorescent Pathology
CamNo.
W
1
-
2
-
3
-
4
-
5
+ Glom
6
Damage
Polys
17
+ -
lnterstltlal
Tubule
26
TABLE lit
ET AL.
w
let
CS
C4
-
-
-
-
+ 1 Glom f2
-
-
others
Clfl
Fibrln ++
ND
ND
t+
-
ND
ND
t
-
ND
ND
t
+ Small Parietal
ND
ND
-
t Mesang
ND
ND
+
Continued
September 1978
The American Journal of Medicine
Volume 85
451
RAPIDLY PROGRESSIVE GLOMERULONEPHRITIS-MORRIN ET AL
TABLE III (Cont’d) Case No.
lmmunofluorescent
W
w + Foe on Glom
7
-
a
-
9
-
10
-
11
f Glom BM
12
-
13
-
-
f Glom BM
+
f Endo
l4-
Pathology
ND
Fibrin ++
+ Foe on Glom
i- Foe on Glom
ND
-
+ Foe on Glom
-
++
+ Small Foe Glom
-
-
+
f
+ Foe & Filaments Glom
-
+
f Glom BM
+ Glom BM
-
+ Glom Foe Fine Endo Some Points
-
+ Foe Glom BM
-
+
-I+
Lin Glom BM
+ Lin Glom BM
-t Glom
+ Glom
++
++
Lin Glom BM
f Glom
f Glom
+ On Crescents
+
Lin Glom BM
+ Foe Glom
-
-I- FocGlom
f
Glom 15
-
-
++
16
-
•t Foe Glom BM
+-t-
+ Gran & Dif in Glom Weak on Tub BM
17
++
+ Foe Glom
+ Glom 8 Mesang
+
ia
-
-
+
+ Endo Glom
+ Foe Endo Glom
ND
19
+-I- Glom Endo & Mesana
+ Glom
i-+
i- Endo Glom
ND
ND
-
20
+ Small Points on Glom BM
-
+ Small Points Glom BM
-t Small Points Glom BM
-
ND
-
21
-
+ lrreg on Glom
-
+ lrreg on Glom
ND
ND
f
22
-
-
-I- Glom Endo & Gran + Tub BM
-I Glom Endo & Gran + Tub BM
-
+ Glom Foe
-
23
-
i- Endo Glom
++
++
f
f
+
24
-
+ Glom Gran 8 Dif
-I- Glom Gran
ND
+
25
-
+ “Humps”
ND
ND
++
26
-
+ Small “Humps”
ND
+ Foe
27
-
+ “Humps” Endo
ND
ND
+
28
++
-I+
+
29
-
lrreg Glom & Mesang
Endo Glom
Endo & Mesang
Endo Glom
+ Glom
++
Endo Glom
Gran 8 Foe Par
f
+ “Humps” Par
& Small
-
+-I- Endo Glom
+
Endo & Gran
September 1979
-
The American Journal ct Yedlclne
& some
+ Endo Glom
Endo Glom
+
NOTE: BM = basement membrane, Dif = diffuse, Endo = endomembranous, irregular, Lin = linear, Mesang = mesangial, Par = parietal, Tub = Tubule.
452
c1q
c4
c3
199
Volume 65
Foe = focal, Glom = glomerulus, Gran = granular, lrreg =
RAPIDLY
MORPHOLOGIC DATA Renal biopsy findings on light microscopy are listed in Table II and the immunohistology in Table Ill. On the basis of light microscopic findings the patients could be divided into two main groups. Group I. Patients with Mainly Extracapillary Prollferation. Light microscopy in 17 initial biopsy specimens (Cases 1- 17) showed no signif icant endocapiltary proliferation (Figure 2) whereas epithelial proliferation resulting in crescent formation was very intense and usually appeared to be of recent origin. The cells were large, basophilic and contiguous to each other. Some fibrosis was present in nearly all specimens, but it was minimal in 11. In 15 instances strands of fibrin were visible between the epithelial cells. All stages of crescent development from segmental to circumferential proliferation which completely filled the urinary space were observed. The extent of epithelial proliferation was variable from one biopsy specimen to another. In three patients (Cases 13, 14 and 16), all the analyzable glomeruli contained circumferential crescents; in the remaining 14, some segmental crescents were in-
PROGRESSIVE C%_OMERlJLONEPHRITIS-MORRlN
variably present (Table II). There negative correlation between the glomeruli containing crescents and segmental crescents (P
ET AL.
was a significant total number of the percentage of = -0.58) (Figure
3). The capillary tufts were either wholly or partly reduced to an amorphous fibrous mass or necrotic. When necrosis was partial the remaining portions of the tuft were relatively normal. There appeared to be a correlation between the amount of tuft necrosis and the size of the crescent; this was clearly seen in several glomeruli which were studied by serial, fine, electron microscopic sections, stained by silver methenamine. In seven patients (Cases 6, 8, 10-12, 16 and 17) the number of intraglomerular polymorphonuclear leukocytes was clearly increased. The results of immunofluorescence were very heterogeneous in this group (Table Ill). Staining with antifibrin/fibrinogen serum was positive in all but three patients (Cases 5, 11 and 15) (Figure 4A). In four pa-
i
0
Pure
extrocap,II3ry
0
Endo
+ extrocap~llory
.m
PERSISTENT RENAL FAILJRE ‘3
0
0
0
0
0
n .
00 l 0
. 8
l
I
. 50
60
70
60
9r)
100
% CRESCENTS
Figure 2. Case 6. Light microscpy. Ultrathin Epon-embe&&d section stained with silver methenamine.In the upper portion of the glomerulus, the capillary tuft is normal; no mesangial proliferation is present and Bowman’s space is open. In the lower portion a dense proliferation of the epithe&l cells ( Ep) has compressed and occludedthe capillaries (arrow) . Several dark plaques of fibrin (F) are no ted. Magnification X 540.
Figure 3. Relationship between the percentage of segmental crescents and the total percentage of crescents. Open symbols indicate patients in whom renal function showed either a temporary or permanent improvement. Closed symbols indicate patients who had no improvement in renal function. It should be noted that some of those who showed initial improvement subsequently showed deterioration or died.
September 1978
The American Journal of Medlclne
Volume 85
453
RAPIDLY PROGRESSIVE GLOMERULONEPtiRITIS-MORRIN
ET AL.
Figure 4. Immunofluorescence. A, anti-fibrin/ fibrinogen serum (Case 7). The serum is fixed by numerous plaques which are probably situated in the urinary space. 6, anti Cl q serum (Case 11). Moderately numerous, irregular arb3granular deposits scattered throughout the glomerulus. C, anti-lgG serum (Case 73). Typical linear fixation delineating the capillary basement membrane. D, anti-/gG serum (Case 23). Significant granular deposits along all the capillary basement membranes.
tients (Cases 1 through 4) there was no fixation of any immunoglobulin or complement and in eight (Cases 5 through 12) there were small focal deposits of doubtful significance (Figure 48). In three patients (Cases 13, 14 and 15), a strong linear fixation of immunoglobulin G (IgG) was observed which was associated with a similar fixation of C3 in two and a focal fixation in one (Figure 4C). Significant granular fixation of immunoglobulin and complement was only found in two instances (Cases 16 and 17). In one (Case 16) the deposits were voluminous and parietal, and contained principally IgG and C3 and more locally Clq which was also present on the tubular basement membranes. In the other (Case 17) the deposits were mainly endocapillary, less abundant and contained principally immunoglobulin A (IgA) and in a more irregular manner some IgG, immunoglobulin M (IgM) and C3 but neither Clq nor C4. Electron microscopy was performed in eight subjects of this first group (Cases l-3,5,6, 10, 16 and 17). The findings confirmed the normal histology of certain parts
454
September 1978
The American Journal of Medlclne
of the tuft and the absence of endothelial or mesangial proliferation. Complete rupture of the glomerular basement membrane was occasionally seen, but much commoner findings were (1) wrinkling of this membrane; (2) extensive necrosis of both endothelial and epithelial cells with preservation of the basement membrane, and (3) partial necrosis of the capillary wall which involved only the endothelial cells in some instances and only visceral epithelial cells in others leaving the endothelial lining apparently normal. These last lesions were generally associated with prominent wrinkling of the basement membrane, but in five biopsy specimens (Cases 1,2,3,10 and 17) they were found in capillary loops which were still being perfused as indicated by plasma or red blood cells in the lumen (Figure 5). In two biopsy specimens (Cases 2 and 3) large amounts of fibrin were observed traversing areas of the basement membrane where isolated epithelial necrosis was present (Figure 6). Degranulated or dying polymorphonuclear cells were sometimes observed in the endocapillary or extracapillary spaces in the ne-
Volume 65
RAPIDLY
PROGRESSIVE Gi_OMERULONEPHRITIS-MORRIN
ET AL,
F&suS. Ektmnmlcms~y(Case2). Several capillary loops and Bowman’s capsule (B) are shown. The capillary lvmens contain n3dcells (MC) andpksms; the 8t&th6&3f C8#S (EN) w RWT&; thetWWment-neislmbrdr8n:ttle vlsceral and p8riet8l epith8lial cells are completely necrosed (err0 w) . Msgnlfication X 18,000, reduced by 20 per cent.
erotic areas. Abnormal deposits were clearly seen in one (Case 16), they were continuous, thick, finely granular and located in the extramembranous region of numerous capillary loops. Occasionally, endomembranous deposits were also noted. In Case 17 abnormal, dense, subendothelial plaques were present but were harder to demonstrate than in the preceding biopsy specimen. Group II. Patients with Extracapillary and Endocapillary Proliferation. By light microscopy 12 biopsy specimens (Cases 18-29) showed endocapillary proliferation (Figure 7A). As in the preceding group, epithelial crescents did not necessarily involve all the glomeruli and could be either circumferential or segmental (Table II). In no biopsy specimen in this group did all the glomeruli contain circumferential crescents. Although, in general, the extent of tuft necrosis was less marked than in the preceding group, there appeared to
be a gradation in severity ranging from crescents which were predominantly segmental, composed of only a few layers of cells, without apparent necrosis of the tuft, and associated with marked endocapillary proliferation, to those which were more hypercellular and associated with definite tuft necrosis and only modest endocapillary proliferation (Figure 7A and 88). In all but two cases (Cases 21 and 22) the fineness of the intercellular membranoid bands indicated recent proliferation. Some fine double contours were visible in the majority of biopsy specimens but particularly in one (Case 18). Deposits were seen by light microscopy of paraffin or Epone sections in all but three (Cases 20, 21 and 29) and isolated extramembranous deposits (“humps”) were observed in three others (Cases 25, 26 and 27). In five biopsy specimens endomembranous deposits were clearly visible but rarely voluminous (Cases 18, 19, 22-24). Three of the five also had segmental ex-
September 1978
The American Journal of Medicine
Volume 85
455
RAPIDLY PROGRESSIVE GLOMERULONEPHRITIS-MORRIN
ET AL.
Figure 6. Electron microscopy (Case 3). Detail of a capillary basement membrane showing intact endothelium (EN) and necrotic epithelium (arrow) . Some clumps of fibrin are seen in the capillary lumen and in the internal portion of the basement membrane. &any/ acetate and lead citrate stain, magnification X 35,000, reduced by 8 per cent.
tramembranous deposits which were small and scanty in two (Cases 22 and 23), and voluminous and confluent in one (Case 24). An increased number of polymorphonuclear leukocytes was present in all and especially in seven (Cases 18, 20, 23, 24,26,27 and 28). Of the three biopsy specimens (Cases 25-27) which showed “humps” two (Cases 26 and 27) fixed anti-IgG serum in a granular pattern and parietal location, and also in small subendothelial deposits. All three fixed anti-& serum in small granular points. The endomembranous deposits found in five cases fixed IgG and C3 in all (Figure 4D). IgA was found in one (Case 19) and IgM in three (Cases 19, 22 and 23). C4 was in three (Cases 18, 23 and 24). Of the three biopsy specimens which showed no deposits on light microscopy, one (Case 20) showed small parietal points of IgA and IgG, and focal deposits of Cat another (Case 21) showed an irregular staining for IgM and Cs but, in view of the advanced fibrous state of the lesions in this case, the specificity of these deposits is doubtful. The third (Case 29) fixed neither immunoglobulin nor complement. Six biopsy specimens (Cases 23,24,26-29) in group II were examined by electron microscopy which confirmed the exact location of the deposits. In Case 24 these were very unusual, abnormally dense, endo- and extramembranous deposits formed by bundles of fine tubular structures 300 A in diameter which were seen in both longitudinal and transverse sections. In this group, rupture of the basement membrane was found in only one instance and wrinkling and cellular necrosis of the capillary wall were found in more limited areas than in the preceding group.
FQure 7. Light microscopy (c;ase A, born mm- and extracapfrtary proliteratron are present. Ine easement memoranes are thickened. The cells in the crescent form loose strands which do not compress the tuft. Trichrome stain, magnification X 485, reduced by 29 per cent. 6, second biopsy specimen. The glomerulus is almost norm/ apart from some discrete mesangial hypertrophy. The capillary lumens are permeable and the basement membranes thin. The urinary space is open, Bowman’s capsule is normal. The surrounding tubules and inferstitium show no abnormality.
456
September 1976
The American Journal of Medicine
Volume 65
RAPIDLY
One patient (Case 28) had a particularly interesting evolution. Two biopsy specimens were available; the first (Figures 8A and 88) unfortunately only contained 6 glomeruli, all of which were identical. There was an endocapillary proliferation and polymorphonuclear infiltration, and numerous capillary loops were obstructed by thrombi composed of an abnormal refringent substance. No extracapillary proliferation was seen. Immunofluorescent staining showed abundant, voluminous deposits of IgA, IgG, Cs, Clq and fibrin. The second biopsy specimen, obtained one month later, contained numerous glomeruli of which 80 per cent contained crescents; 80 per cent of these crescents were circumferential. The adjacent capillary tufts were often fibrous and not analyzable. In those glomeruli which were better preserved there were only slight, irregular mesangial proliferation, a few polymorphonuclear leukocytes and no abnormal deposits. Immunofluorescent staining was negative for both immunoglobulin and complement. Electron microscopy of the first biopsy specimen showed a very large number of polymorphonuclear leukocytes, most of them partially or completely degranulated. Large portions of the basement membrane were abnormally thin and in direct contact with these degranulated cells. In other areas, large abnormal deposits and fibrin bundles were seen against the endocapillary side of the basement membrane. There were no obvious lesions of the epithelial cells apart from some spreading of the podocytes. HISTOLOGIC EVOLUTION Subsequent studies in group I (four cases) showed that necrotic and proliferative lesions evolved to fibrosis. Glomeruli with circumferential crescents became fibrotic whereas segmental crescents were associated
PROGRESSIVE GLOMERULONEPHRITIS-MORRIN
ET AL.
with re-expansion of the tuft. Interstitial lesions subsided but persisted and in Cases 2 and 3, after several years, large cellular crescents with a recent appearance were seen, together with numbers of obsolete glomeruli. In group II (six cases), the evolutionary changes were more variable (Table II). One patient (Case 22) showed slight deterioration and no change in immunofluorescence after one month. In Case 29, diffuse fibrosis developed and in Case 27, after two years there were numerous obsolete and some normal glomeruli and significant tubulointerstitial lesions, and immunofluorescence was negative. In Cases 18 and 19 (Figures 7A and 78) both patients had subendothelial deposits in their initial biopsy specimens. The second biopsy specimens, obtained at one and four years, respectively, showed considerable improvement; rare glomeruli were obsolete whereas the others showed only moderate mesangial hypertrophy, occasional adhesions to Bowman’s capsule and some small fibrous crescents. A few small foci of immunoglobulin and complement persisted on immunofluorescent examination. CLINICOPATHOLOGIC CORRELATION Table IV compares the major, clinical, histologic, immunologic and laboratory findings in the two groups. Cases in group I were clinically and histologically more severe; recovery occurred in only 30 per cent compared with 50 per cent in group II. Proteinuria and immunoglobulin deposits were more marked in group II, but linear deposits were confined to group I. Immunologic parameters were not very helpful. C3 was reduced in five patients, all of whom had immunoglobulin in their biopsy specimens (Cases 14, 16, 22, 23 and 27). No significant abnormality was noted in serum immuno-
Figwe 8. Light microscopy (Case 28). A, marked proliferation of the en&capillary cells with numerous porymorpnonuclear leukocyt8s present. A voluminous &posit is visible. There is no proliferation of the epithelial ceils. MagnificationX 485, reduced by 32 per cent. B, second biopsy specimen. A representative glomerulus in which the urinary space is almost completely OCeluded by a Very dense fibro-cellular epithelial crescent. In the center, the glomerular tuft is compressed and becoming fibrotic. Magnification X 485, reduced by 29 per cent.
September 1978
The American Journal of Medicine
Volume 65
457
RAPIDLY PFQGRESSlVE
TABLE IV
GLOMERULONEPtiFiITIS-MORRIN
ET AL.
Comparison Between Groups 1 and 2
ciroupI (N = 17) Mean Age (yr) Range Symptoms < 30 days Infection or fever Antistreptolysin 0 titer > 300 Oliguria <500 ml/24 hours Dialysis required
56.5 21-75 6117 11117 016 14117 15117
Permanent dialysis or death No remission Proteinuria > 3.5 g/24 hours
12117 9117 0111
Crescents in 100% of glomeruli
All crescents circumferential Necrosis Fibrin Major deposits of complement and/or immunoglobulin Linear deposits Decreased C3 PEG test positive Circulating antiglomerular basement membrane antibodies
6117
3117 2+ 2+ 5117
3117 2/14 415 2/5
GroupW (N = 12) 41.1 15-66 6112 9112 4110 6112 6112 P
NOTE: PEG = polyethylene glycol precipitation test. One case excluded because of old blopsy. l
globulins (19 cases), Cq (12 cases), Cs Pa (seven cases), cryoglobulins (13 cases) and HB surface antigen (13 cases). Circulating antiglomerular basement membrane antibodies were found in Cases 11 and 14. The morphology in one specimen (Case 18) was more characteristic of membranoproliferative glomerulonephritis than in any of the other biopsy specimens. This patient had one of the best morphologic (Figures 7A and 76) and clinical recoveries. It was of interest that his serum contained a monoclonal IgG with kappa light chains which disappeared on treatment. Similar cases have been reported by others [ 231. COMMENTS
Variable criteria have been used to define rapidly progressive glomerulonephritis [ 1- 11,13- 17,24-321, and similar histologic and clinical findings may occur in poststreptococcal nephritis, Henoch Schonlein purpura, polyarteritis, Wegener’s granulomatosis, disseminated lupus and Goodpasture’s syndrome. Some series have specifically excluded such cases [ 14,17,19,28,28, 30,331, but the present study was not designed to ex-
455
September 1978
The Amerkan Journal of Medlclne
elude these entities if they met the selection criteria. Nevertheless-the great majority of our cases were the so-called “idiopathic” type. When possible, specific etiologies should be identified because it cannot be assumed that prognosis and response to treatment will be the same for all; in the patient with poststreptococcal nephritis it is generally accepted that the outlook is better [28,28,29]. Only two cases in our series had gocd evidence of a streptococcal etiology; both patients recovered, but a streptococcal etiology could have been missed in some of the others. Habib [8] has shown that the prognosis in children is much better if less than 80 per cent of the glomeruli contain crescents. Others have reported similar findings in adults [30]. In our series no patient in whom all glomeruli contained crescents recovered renal function and only seven of 18 patients (39 per cent) with more than an 80 per cent incidence of crescents showed any improvement. Conversely, 10 of 11 (90 per cent) patients with less than an 80 per cent incidence of crescents had some degree of remission (Figure 3). This study also indicates that the percentage of segmental crescents is of prognostic value as reported by Levy and Habib [ 131 in children. Eight of nine patients with less than 35 per cent segmental crescents remained in renal failure and the ninth had a relapse after a temporary remission. Conversely, four patients in whom more than 35 per cent of the crescents were segmental (Cases 9, 21, 25 and 27) regained significant renal function even though 90 per cent of the glomeruli contained crescents. The difference in improvement rates between patients with more than 35 per cent segmental crescents and those with less was significant at the 1 per cent level (X2 = 9.48). We also believed that the morphology of the glomerular lesions was of predictive value. The more severe lesions were associated with predominantly extracapillary proliferation. When endocapillary proliferation was prominent, the glomerular crescents were usually less compact, and necrosis of the tuft was less evident. Similar findings were noted in a previous study from this Department [lo] and also by some other workers [26,29,34,35], but not by all [ 16,171. Early studies showed a very poor prognosis [5,7,21,32,36] which led to the use of multiple therapeutic programs in a statistically uncontrolled fashion [10,15,17,26,29,30,31,37]. Although the efficacy of such programs cannot be unequivocally established, recent reports have shown improvement or cure in a significant percentage of cases [ 10,15,17,25,27, 30,31,37,38]. Unfortunately, most series do not consider all the prognostic factors mentioned herein and this compounds the difficulty in evaluating any specific therapy. Like many others [ 13,15,17,29,33,39,40], we were impressed by the variability of the immunofluorescent
Volume 65
RAPIDLY
findings and we would question the reliability of this technic as an indicator of the immunopathologic process in this type of glomerulonephritis. In the present study, one patient with circulating antiglomerular basement membrane antibodies did not have linear deposits, two patients with a positive polyethylene glycol test showed only focal deposits and, most impressive of all, the deposits disappeared in one (Case 28) in association with the development of widespread crescent formation. This particular patient points out an important time relationship between the immunofluorescent observations and the duration of the disease. The disappearance of immune deposits is poorly understood. Numerous electron microscopic studies have demonstrated holes in glomerular basement membranes which could permit blood products including fibrin/fibrinogen to enter the capillary space in which they appear to stimulate epithelial proliferation [ 10,34,40-441 but the more diffuse necrotic lesions of the capillary wall, which we have previously described [lo], may be of more importance than these holes. In two instances, electron microscopy clearly showed fibrin traversing the basement membrane in these areas of epithelial necrosis. Such increased permeability might permit the passage of immunoglobulins and complement with partial or complete disappearance of immunofluorescent deposits, depending on the duration of the disease and how firmly the deposits were
PROGRESSIVE GLOMERULONEPHRITlS-MORRIN
ET AL.
attached to the basement membrane. (In patients with linear deposits, this attachment involves a different mechanism and intense fluorescence may persist even in advanced cases [45] .) It is apparent from this and other studies, especially that of Levy and Habib [ 131, that rapidly progressive glomerulonephritis is not a homogeneous entity, clinically, histologically or immunologically, but rather a clinical syndrome characterized by rapid development of renal failure and widespread crescent formation. It can be found in a variety of known conditions, and the histology and immunopathology even in the “idiopathic” form are extremely heterogeneous. It is no longer appropriate to describe therapeutic programs and recovery rates for rapidly progressive glomerulonephritis without previously defining the nature and extent of the renal lesions by immunofluorescence and, if necessary, electron microscopy in addition to routine histology. Any further understanding of this condition will require a careful search for all possible etiologic factors and pathogenetic mechanisms correlated with precise histologic and immunopathologic study of each case. ACKNOWLEDGMENT
We are indebted to Dr. J. Berger for performing the immunofluorescent studies, to Madamoiselle Monique Lillie and Madame lngrid Muller for the preparation of the photographs, and to Mrs. Lorraine Dale and Mrs. Shirley Friend for the typing of the manuscript.
REFERENCES 1. 2.
3.
7.
6.
9. 10.
11.
Volhard F, Fahr T: Die Brightshe Nierenkrankheit, Berlin, Springer Verlag, 1914. Ellis A: Natural history of Bright’s disease: clinical, histological and experimental observation. Lancet 1: I, 34, 72, 1942. Hamburger J: Les Glorn&ulo-Nephrites Malignes. Entretiens de Bfchat. Paris, Expansion Scientlfique, France, 1956, p 231. Bialestock D, Tange JD: Acute necrotizing glomerulitis: the clinical features and pathology in 9 cases. Aust Ann Med 6: 281, 1959. Berylene Gfvf,Baker SB deC: Acute anuric glomerulonephrlitis. QJ Med 33: 105, 1964. Proesmans W: Proliferative Glomerulonephritis with Crescents. Proceedings of the Second International Symposium on Paediatrlc Nephrology, Paris, 1971, p 91. Bacani RA, Velasquez F, Kanter A, et al.: Bapkfly progressive (nonstreptococcal) glomerulonephritis. Ann Intern Med 69: 463, 1968. Habib R: Classification Anatomique des Nephropathies Glorn&ulaires. Extrait de P&flat. Fortbildungskurse 28: 61, 1970. Heptlnstall RH: Pathology of the Kidney, Boston, Little. Brown, 8 Co., 1966. Sonsino E, Nabarra B, Kazatchkine M, et al.: Extracapillary proliferative glomerulonephrltis so-called malignant glomerulonephrltls. Advances in Nephrology, from the Necker Hospital (Hamburger J, Crosnier J. Maxwell MH. eds.), Chicago, Year Book Medical Publishers, 2, 1972. p 12 1. CameronJS, Ogg CS: Rapidly progressive gknnerukxqhriiis with extensive crescents. Glomerulonephrltls, Morphology,
12.
13.
14.
15.
Natural History and Treatment, (Kincaid-Smith P, Mathew TH, Becker, EL, eds), New York, John Wiley & Sons, Inc.. 1973, p 735. Churg J, Morii T, Suzuki Y: Glomsrulonephrltis with fibrin and crescent formation. Glomerulonephritis, Morphology. Natural History and Treatment, (Kincaid-Smith P, Mathew TH, Becker EL, eds). New York. John Wiley & Sons, Inc., 1973, p 677. Levy M, Habib R: lmmunopathologie des Glom&rulon&phrites a Croissants Epitheliaux Diffus Chez L’Enfant. Estratto da Minerva Nefrologlca 20: 184, 1973. Mathew TH. Kincaid-Smith P: Severe fibrin and crescent glomerulonephritis. Glornerulonephritis, Morphology, Natural History and Treatment, (Kincaid-Smith P, Mathew TH, Becker EL, eds). New York. John Wiley & Sons, Inc., 1973. Bernard D. Bariety J, Oruet P, et al.: Les Glomerulonephrites Proliferatives Extracapillaires. Sem Hop Paris 50: 539, 1974.
16.
Olsen S: Extracapillary glomerulonephritis. Acta Pathol Microbiol Stand [A] 82 (suppl 249): 7. 1974.
17.
Whitworth, JA, et al.: The significance of extracapillary proliferation. Nephron 16: 1, 1976. Hinglais N, Garcia-Tones R, Kleinknecht 0: Long-term prognosis in acute glomerulonephritis. Am J Med 56: 52, 1974.
16.
19.
Movat HZ, Steiner JW, Huhn D: The fine structure of the glomerulus in acute glomerulonephrltfs. Lab Invest 11: 117. 1962.
20.
Mancini S, Carbonara AO. Heremans GF: lmmunochemical
Soptembet 1978
The American Journal of MerJlclno
Volume 85
459
RAPIDLY PROGFtESSIVEGLOMERULONEPHRITIS-MORRIN ET AL.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
460
quantitation of antigens by single radial immunodiffusion. Immunochemistry 2: 235. 1985. Creighton WD, Lambert PH. Miescer PA: Detection of antibodies aiid soluble antigen-antibody complexes by precipitation with polyethylene glycol. J lmmunol 111: 1219, 1973. Mahieu PO, Dardenne M, Bach JF: Detection of humoral and cell-mediated immunity to kidney basement membranes in human renal diseases. Am J Med 53: 185, 1972. Verroust P, Mery JP, Morel-Maroger L, et al.: Glomerular lesions in monoclonal gammopathies and mixed essential cryoglobulinemia IgGlgM. Advances in Nephrology from the Necker Hospital, (Hambtrger J, Crosnier J, Maxwell MH, eds), Chjcago, Year Book Medical Publishers, 197 1. Slama R, Maurat JP, de Montera H: Les glom&ulonbphritis maliznes, Actualit& Nbphrologiques de I’Hbpital Necker, Paris, Flammarion, 1961. p 85. Harrison CV. Loughridge LW, Milne MD: Acute oliguric renal failure in acute glomerulonepfriils and poiyarteritis nodosa. QJ Med 33: 39,1964. Leonard CD, Nagle RB, Striker GE, et al.: Acute glornerule nephritis with prolonged oliguria. An analysis of 29 cases. Ann Intern Med 73: 703, 1970. Arieff Al, Plngerra WF: Rapidly progressive glomerulonephriiis treated with anticoagulants. Arch Intern Med 129: 77, 1972. Schreiner ff, Rakowski TA, Argy WP Jr, et al.: Natual history of oliguric glomerulonephritis. Glomerulonephritis Morphology, Natural History and Treatment, (Kincaid-Smith P, Mathew TH, Becker EL. eds), New York, John Wiley & Sons, Inc., 1973. p 711. Striker GE, Cutler RE, Huang TW, et al.: Renal failure glomerulonephritis and glomerular epithelial cell hyperplasia. Glomerulonephritis, Morphology, Natural History and Treatment, (Kincaid-Smith P, Mathew TH. Becker EL, eds), New York, John Wiley 8. Sons Inc., 1973, p 857. Lawrence JR: Glomerolonephritis with Fibrin and Crescent Formation in Glomerulonephritis, Morphology, Natural History and Treatment, (Kincaid-Smith P, Mathew TH, Becker EL, eds), New York, John Wiley & Sons, Inc., 1973. p 739. Brown CB, Wilson D, Turner D. et al.: Combined immunosuppression and anticoagulation in rapidly progressive
September 1978
The Amerkan
Journal ol Medlclne
32.
33.
34. 35.
36.
37. 38.
39.
40.
41.
42.
43.
44.
45.
Volume 65
glomerulonephritis. Lancet II: 1168, 1974. Brun C, Gormsen H, Hilden T, et al.: Kidney biopsy in acute glomerulonephritis. 13 cases. Acta Med Stand 160: 155, 1958. Lewis EJ, Cavallo T, Harrington JT, et al.: An immunologic study of rapaly progre+ve glomerulonephritis in the adult. Hum Patho12: 185, 1971. Morita T, Suzuki Y, Churg J: Structure and development of the glomerular crescent. Am J Patho172: 349, 1973. Churg J: Glornerulonephritis, Morphology. Natural History and Treatment, (Kincaid-Smith P, Mathew TH, Becker EL, eds), New York, John Wiley 8 Sons, Inc., 1973, p 793. Forland M, Jones RE, Easterling RE, et al.: Clinical and renal biopsy observations in oliguric glomerulonephritis. J Chron Dis 19: 163, 1968. Kincaid-Smith P, Saker BM, Fairley KF: Anticoagulants in “irreversible” acute renal failure. Lancet 2: 1360, 1968. Jensen H, Faarup P, Hess T, et al.: Immunosuppressive treatment of rapidly progressive glomerulonephritis (letter). Lancet 2: 1572, 1974. Olsen S, Posborg Petersen V, Sommer Hansen E: Immunofluorescence Studies of Extracapillary Glomerulonephritis. Acta Pathol Microbial Stand [A] 82 (suppl 249): 20, 1974. Burkholder PM: Ultrastructural demonstration of injury and perforation of glomerular capillary basement membrane in acute proliferative glomerulonephritis. Am J Pathol 57: 251, 1969. Min KW, Gybrkey F, Yium JJ, et al.: The morphogenesis of glomerular crescents in rapidly progressive glomerulonephritis. Kidney Int 5: 47, 1974. Stejskal J, Pirani CL, Okada M, et al.: Discontinuities (gaps) of the glomerular capillary wall and basement membrane in renal disease. Lab Invest 28: 149, 1973. Berger J, Yaneva H, Hinglais N: lmmunohistochemistry of Glomerulonephritis. Advances in Nephrology, from the Necker Hospital (Hamburger J, Crosnier J, Maxwell MH, eds.). Chicago VI, Year Book Medical Publishers, 1971, p 11. Bohman S, Olsen S, Posborg Petersen V: Glomerular ultrastructure in extracapillary glomerulonephritis. Acta Pathol Microbial Stand [A] 82: (suppl 249): 29, 1974. Beiger J: Personal communication.