Nephron 16: 1-19(1976)
The Significance of Extracapillary Proliferation Clinicopathological Review of 60 Patients1
J u d ith A. W h it w o r t h 2, L. M orel -M a ro g er , F. M ig n o n and G. R ich et Unité de Recherches de Néphrologie normale et pathologique de PInserm, U 64, Hôpital Tenon, Paris
Key Words. Extracapillary proliferation • Crescents • Rapidly progressive glomerulo nephritis • Renal biopsy • Immunofluorescence Abstract. Renal biopsy and clinical data from 60 patients with extracapillary proliferation (crescent formation) in >50% of glomeruli were correlated. Nephropathy was related to infection (15 cases) malignancy (4 cases) and trichlorethylene exposure (2 cases). Isolated proteinuria was found 0.5-20 years before biopsy in 16 patients. Outcome was significantly related to percentage of crescentic involvement. Oligoanuria and impaired function at presentation were bad prognostic signs but preceding infection was favourable. Diverse histological and immunofluorescent findings indicate that extracapillary glomerulo nephritis is not a single entity. The clinical course is not always rapidly progressive.
There is an extensive if somewhat confused literature concerning a clinical entity of rapidly progressive glomerulonephritis [1-3] characterized by rapidly progressive renal failure usually in association with extensive epithelial cell proliferation. The term ‘extracapillary’ glomerulonephritis was used by V o lh a r d and F a h r [4] in 1914 and a clinicopathological entity has been variously described as a rapidly progressive course in type 1 glomerulo nephritis [5], malignant glomerulonephritis [6,7], acute necrotizing glomerulo nephritis [8], acute anuric glomerulonephritis [9], proliferative glomerulo nephritis with crescents [10], and endo- and extracapillary glomerulonephritis
Received: December 3, 1974; accepted: December 17, 1974.
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1 A part of this work was presented at the Xlth Congress of the European Society for Dialysis and Transplantation in Tel Aviv, Israel, November 1974. 2 1973 Royal Australasian College of Physicians Winthrop Travelling Fellow and Rési dent Etranger du Collège de Médecine des Hôpitaux de Paris.
2
W hitworth
type 3 [11]. P o lla k and M en d o za [3] clearly distinguished rapidly progressive (non-streptococcal) glomerulonephritis of unknown aetiology from the numerous other conditions which can produce a similar clinical picture. The mechanism of crescent formation has been studied by several workers [12,13] and focal crescent formation can occur in a wide variety of histological entities [14]. This study attempts to analyze the clinicopathological significance of ex tensive (>50% ) crescent formation in adults, the extracapillary glomerulo nephritis of V o lh a r d and F a h r [4], using morphological criteria as the determinant of inclusion in the study. Methods Over 3,000 renal biopsies, nephrectomy and autopsy specimens have been examined in the Service de Néphrologie, Hôpital Tenon, over the period 1965-1973. 80 specimens with 8 or more glomeruli from 60 patients were classed as having 50% or more glomeruli with extracapillary proliferation (crescents) on their initial biopsy. Patients with definite poly arteritis nodosa, systemic lupus erythematosus and Henoch-Schônlein purpura were ex cluded. Renal biopsy specimens were obtained by percutaneous puncture using a Vim-Silverman needle modified by Franklin, fixed in Dubosq-Brazil fixative (alcoholic Bouin), embedded in paraffin, and cut at 2 p.m. The following stains were used: HE, Masson trichrome, PAS, Wilder’s reticulin and Weigert’s fuchsin. Immunofluorescence studies were performed on 54 biopsies from 44 patients. Biopsies were snap-frozen in liquid nitrogen, cut in a cryostat at -2 5 °C , and stained with antisera specific for IgG, IgM, IgA, [31C and fibrinogen, as previously described [15]. 31 biopsies having >80% glomeruli involved by crescent forma tion (group I) were analyzed separately from 29 with 50-80% involvement (group II) as >80% involvement has been regarded as the morphological equivalent of rapidly pro gressive glomerulonephritis, indicating a particularly poor prognosis [11,13]. All specimens of renal tissue were examined independently by two observers (L. M. M. and J. W.). In each specimen at least 8 glomeruli were examined by light microscopy and 5 on immunofluorescence. The percentage of glomeruli with crescent formation was calculated from the number of crescentic plus obsolescent glomeruli over total glomeruli x 100 and histological features were graded from 0 to + + + . Retrospective analysis of all available clinical and laboratory data was performed independently of the biopsy findings. Cryo globulins were sought in 28 patients according to the method of A dam et al. [16], Statistical analysis was performed using a x2 test.
Results
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Biopsy Findings on Light Microscopy Renal tissue was obtained by biopsy in 60 patients. The number of glom
3
eruli available for analysis ranged from 8 to 52, mean 19. The findings on the initial biopsy specimen are shown in table I. Individual crescent size was significantly related to percentage of glomerular crescentic involvement (p 80%) was more common in the women (13/21 cases, 62%) than the men (18/39 cases, 46%), but this difference was not significant. Antecedents (tables II, III). In 16 patients (27%) isolated proteinuria (plus microscopic haematuria in 4 cases) was discovered 6 months to 20 years be fore biopsy (mean 4 years); 15 patients (25%) presented after an infection. In 4 patients presentation with extracapillary glomerulonephritis coincided with the diagnosis of malignancy; 2 patients had a history of occupational ex posure to trichlorethylene but information about prior exposure was not always available; 4 patients (7%) presented with ill-defined multi-system
Significance of Extracapillary Proliferation
7
disease, suggestive of systemic lupus erythematosus in 1 and polyarteritis nodosa in the other 3. However, diagnostic confirmation was not forthcoming in these patients despite extensive investigation and continuing observation. The paucity of necrotizing vascular lesions on biopsy supported the diagnosis of primary glomerular disease in this series of 60 patients. Presenting features. The presenting renal symptoms and signs are shown in figure 2 and tables II and III. 26 patients had an apparently acute onset with symptoms for less than 1 month prior to presentation and were equally divided between groups I and II. 30 patients had a chronic onset with symptoms or signs for over 3 months prior to presentation, 17 in group I and 13 in group II. All patients had microscopic haematuria (>5,000 RBC/min) at presenta tion and in 7 (12%) the haematuria was macroscopic. All except one patient had proteinuria in excess of 0.5 g/day, frequently heavy. 18 patients (30%) had a nephrotic syndrome at presentation (proteinuria > 5 g/day, serum albumin < 3 g/100 ml) and in 7 it was the principal presenting feature. Nephrotic syndrome developed subsequently in 4 other patients. Oliguria (urine output < 600 ml/day) was present in 21 patients (35%) (13/31 group I ; 8/29 group II). Oliguria was also a common pre-terminal event in those patients presenting with an adequate diuresis. 47 patients (78%) had impaired renal function on admission (creatinine clearance < 60 ml/min, creatinine >1.5 mg%, urea >40 mg%). Hypertension (blood pressure >150/90 mm Hg on admission) was present in 28 patients (47%) and the majority of the remainder subse quently became hypertensive. 2 patients (3%) presented with a nephritic syndrome (hypertension, haematuria, proteinuria, oliguria and oedema). Fever was present in 11 cases, 2 of those with infection, 4 with a probable
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Fig. 1. Age and sex distribution (open, males; shaded, females) in 60 patients with extra capillary glomerulonephritis (>50% glomeruli involved by crescents).
8
Whitworth Tabic II. Clinical features in group I (>80% crescents)
Patient
Antecedents
M.B. M.D. J.S. S.H. D.D. H.F. P.D.
sore throat proteinuria (6 months) proteinuria (1 year) bronchial carcinoma sore throat
IV
C.R. A.L. L.H. L.C.
bacterial endocarditis proteinuria (2 years) sore throat proteinuria (10 years)
11 III III II
+
+
+
M. da C. R.P. N.C. D.C. L.C.
proteinuria (2 years) known renal disease (3 years) sinusitis, fever, purpura proteinuria (20 years) proteinuria (18 years) tonsillitis pulmonary abscess proteinuria (6 months)
IV IV IV II II
— +
-
+ + + +
III IV II I I I I I IV II
+ -
+ + +
+ + + + -
III -
—
+ + + +
+ + +
G.D. R.S. J.M. M.R. N. leN. S.L. J.L. G.D. H.Z. S.P. J.C. D.D. N.L. L.R. E.C.
basal cell carcinoma -
Immuno- Presentation Evolution and fluo-------------------------------- follow-up oliguria hyperrescence nephrotic tension syndrome
_ 1
+ + + +
+ + + +
—
+ + + +
+
lost to follow-up RPGN, dialysis (3 days)t 1 yeart RPGN (4 days)! dialysis (2 years) RPGN (3 weeks) t creatinine 3.6 mg% (4 years) normal function (3 years) RPGN (3 months) t RPGN, dialysis (1 month) creatinine 2.7 mg% (4 years) RPGN, dialysis (2 days)t dialysis (2 years) dialysis (3 years) t 6 years t dialysis (2 years) f urea 100 mg% (3 years) RPGN, dialysis (4 days) RPGN, dialysis (2 weeks) urea 80 mg% (2 years) dialysis (6 months) dialysis (20 months) dialysis (9 months), graft RPGN (1 month) t dialysis (3 years) f RPGN (5 days) f creatinine clearance 54 ml/min (6 months) RPGN, dialysis (2 days) RPGN (1 week)t RPGN (3 days) t urea 60 mg% (1 year)
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RPGN = Rapidly progressive glomerulonephritis, t = Death.
Significance of Extracapillary Proliferation
9
Table 111. Clinical features in group II (50-80% crescents) Patients
Antecedents
C.G.
proteinuria (10 years) sore throat proteinuria (1 year) trichlorethylene sub-phrenic abscess polyneuritis —
B.D.-L. P.T. J.B. G.L. J.F. L.M. E. L. A.D. V.L. J.W. C.P. M.G. J.V. E.B. M.M.
pulmonary abscess -
G.D. M.R. P.T. A.L. M.T. G.R. C.M.
proteinuria (2 years) proteinuria (1 year) proteinuria (6 months) disseminated breast carcinoma proteinuria (2 years) ‘lupus-like’ syndrome proteinuria (8 months) trichlorethylene sore throat proteinuria (1 year)
P.B. G.M. A.C. C.C. C. de B.
sore throat pulmonary abscess disseminated carcinoma dental abscess pulmonary abscess
R.G.
appendix abscess
Evolution and Immuno- Presentation follow-up fluo oliguria hyperrescence ncphrotic tension syndrome -
+
+
+
-
-
-
II Ill
-
+ -
+ +
-
-
+ +
+ + +
+ -
+ + + -
-
I II II 0 I -
I II II
+ + + + +
normal function (10 years) normal function (1 year) RPGN, dialysis (days) RPGN (5 months) t 18 months t normal function (2 years) lost to follow-up RPGN, dialysis (days) t creatinine clearance 55 ml/min (4 years) normal function (1 year) lost to follow-up lost to follow-up dialysis (10 years) dialysis (3 years) normal function (1 year) 1 yeart
"
II II
-
-
+
II
+
-
-
III I II II
+
-
-
+
-
—
-
-
+
I
+
-
-
1
-
+
-
+
-
-
-
+
-
+
+
II I I -
dialysis (5 years) normal function (3 years) dialysis (6 months) f normal function (2 years) lost to follow-up dialysis (18 months) RPGN, dialysis (4 months), graft normal function (2 years) dialysis (1 year) 1 year t creatinine 4 mg% (1 year) creatinine clearance 40 ml/min (6 months) creatinine 4 mg% (1 year)
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RPGN = Rapidly progressive glomerulonephritis, t = Death.
10
Whitworth
Fig. 2. Clinical features at presentation in 60 patients with cxtracapillary glomerulo nephritis.
systemic disease or malignancy and in 5 as an isolated feature. In the latter group, it was frequently associated with muscle or joint pains. 5 of 40 patients tested (12%) had an antistreptolysin titre >300. Serum complement was de pressed in only 2 of 29 patients tested (both of whom had normal anti streptolysin titre) in accord with other published series [17,18]. Cryoglobulins were found in 13 of 28 patients tested (46%) confirming our experience that cryoglobulinaemia in glomerulonephritis correlates with proliferation [16]. They were identified in 9 cases (IgM 1, IgG 2, IgG/IgM 2, IgG/IgM/IgA 2, IgG/IgM/piC 2). There were no clinical or histological differences between patients with positive or negative cryoglobulins. Treatment All patients received supportive treatment (hypotensive and antibiotic therapy, drainage of surgical infection, dietary, fluid and electrolyte regulation and peritoneal or haemodialysis according to clinical indications). Therapy specifically directed against the glomerular lesion included corticosteroids (13 patients), indomethacin (4 patients), immunosuppressives (20 patients), heparin (with or without oral anticoagulant) (13 patients), streptokinase (1 patient) and dipyridamole (1 patient). Varying therapeutic regimes using one or many of these drugs were administered. Dosage and length of adminis tration varied from case to case.
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Evolution (tables II, III) Five patients have been lost to follow-up. Of the remaining 55, 21 have
Significance of Extracapillary Proliferation
11
Survival time, years
Fig. 3. Cumulative 5-year survival (23 ± 8 % ), calculated from the life table method of C utler and E derer [19]. 60 patients were available for initial analysis, 32 at 1 year, 19 at 2 years, 17 at 3 years, 12 at 4 years, and 8 at 5 years.
Linear and Granular Deposits Six patients had demonstrable linear immunoglobulin deposits. On light microscopy, this group was characterized by little or no tuft proliferation and the absence of polymorphs. Antecedent features included previous proteinuria, infection and malignancy. Clinical findings at presentation were variable. Three patients, all in group I, ran a rapidly progressive course to haemo-
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died (from malignancy, infection or complications of dialysis and transplan tation), and 15 others are alive on recurrent haemodialysis (13 patients) or with a functioning renal allograft (2 patients). Thus, 36/55 patients (65%) progressed to terminal renal failure, over a period varying from the day of presentation to 10 years, mean 15 months (from biopsy to commencement of dialysis or death). 14 of these patients required immediate institution of main tenance dialysis (less than 1 month after presentation). Cumulative 5-year survival was 23 ±8% using a life table method [19], as shown in figure 3. The remaining 19 patients are alive after 6 months to 10 years of follow-up; 9 are in remission with normal renal function after a mean follow-up period of 42 months, range 1-10 years; 10 patients have renal insufficiency. In all 10, renal insufficiency was present at presentation and in 7 of them was associated with oliguria but subsequently improved coincident with diuresis. These patients have a mild to moderate degree of renal impairment 6 months to 4 years later (mean follow-up 22 months).
12
W hitworth
dialysis or death within days or months. One patient in group I is well with impaired function and the 2 patients in group II are well with normal function 2 years later. No particular histologic, clinical or evolutive pattern could be distin guished among the patients with granular deposits. Preceding Proteinuria In 16 patients, proteinuria was first discovered at least 6 months prior to diagnosis and may reflect the frequency of routine urine testing in France. Patients were evenly divided between groups I and II and included two patients with linear fluorescence. No specific histological features were appar ent, apart from the absence of polymorphs. In view of the known proteinuria, the biopsy finding of extensive crescent formation in these patients was un expected. In one case presentation coincided with a sore throat followed by a nephritic/nephrotic episode and in another with carcinoma of the lung, sug gesting that crescent formation may have been superimposed on an underlying quiescent glomerular lesion by these additional insults. Alternatively, ex tensive crescent formation might represent an exacerbation of a primitive nephropathy. Clinical features and evolution in this group were quite in constant.
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Malignancy The nephropathy was closely associated in time with malignancy in 4 cases (7%): carcinoma of the lung and of the breast with secondary involvement, widely disseminated secondary carcinoma of unknown origin, and a localized basal cell carcinoma of the face. Large extramembranous deposits on light and immunofluorescence microscopy were found in one patient with dis seminated carcinoma of the breast, suggesting the deposition of tumourspecific immune deposits in glomeruli [20], but in the three other patients with malignancy, the loops were too collapsed for proper assessment. One had granular and another linear deposits on immunofluorescence. The patient with linear deposits presented with oliguria and a basal cell carcinoma of the face and ran a rapidly progressive course. He is now well on recurrent haemo dialysis. The other three patients all presented with nephrotic syndrome. One patient had had a mastectomy for carcinoma of the breast 2 years previously with biopsy evidence of extramembranous nephropathy and presentation coincided with the appearance of métastasés. In the two other patients, malignancy was first diagnosed at presentation. One died shortly afterwards
Significance of Extracapillary Proliferation
13
in anuria and the others died 12 months later from malignancy and terminal renal failure.
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Infection In all, 15 patients (25%) presented after an infection. The preceding in fection was a sore throat in 7, only one of which was unequivocally due to streptococcal infection (isolation of the organism and a rise in antistreptolysin titre). The other 8 had subacute bacterial endocarditis (1), pulmonary abscess (3), dental abscess (1), sub-phrenic abscess (1), appendical abscess (1), and sinusitis (1). Endomesangial proliferation was common but not invariable in this group and no significant relationship could be demonstrated. However, the presence of polymorphonuclear leucocytes on renal biopsy correlated significantly with evidence of preceding infection (8 of 15 patients with a definite preceding in fection had polymorphs on biopsy compared with only 7 of the remaining 45 patients, p80% crescents on the initial biopsy could be regarded as ‘rapidly progressive glomerulonephritis’ on clinical criteria and it seems likely that ‘rapidly pro gressive glomerulonephritis’ is one end of the clinical spectrum of extra capillary glomerulonephritis (and other forms of glomerulonephritis) rather than a specific disease entity. In our series, the striking finding was the diversity of histological, immunofluorescence, clinical and evolutive features. No common clinical pattern emerged. Extracapillary glomerulonephritis is not synonymous with rapidly progressive glomerulonephritis. The extreme vari ability of immunofluorescence patterns suggests that extensive extracapillary proliferation does not constitute a distinct morphological entity.
16
W hitworth
Aetiological Features Preceding proteinuria has not been a feature of previous descriptions of extracapillary glomerulonephritis. Possibly the presence of an underlying glo merular lesion predisposes to crescent formation in response to an additional insult or immunological challenge (infection, malignancy). Alternatively, lowgrade crescent formation may occur, subject to unpredictable exacerbation. The nephrotic syndrome in association with cancer has been widely reported [25,26] and the lesions described include minimal lesion [25] extra
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Crescent size in this series of 60 patients was related (p
The Significance of Extracapillary Proliferation Clinicopathological Review of 60 Patients1
J u d ith A. W h it w o r t h 2, L. M orel -M a ro g er , F. M ig n o n and G. R ich et Unité de Recherches de Néphrologie normale et pathologique de PInserm, U 64, Hôpital Tenon, Paris
Key Words. Extracapillary proliferation • Crescents • Rapidly progressive glomerulo nephritis • Renal biopsy • Immunofluorescence Abstract. Renal biopsy and clinical data from 60 patients with extracapillary proliferation (crescent formation) in >50% of glomeruli were correlated. Nephropathy was related to infection (15 cases) malignancy (4 cases) and trichlorethylene exposure (2 cases). Isolated proteinuria was found 0.5-20 years before biopsy in 16 patients. Outcome was significantly related to percentage of crescentic involvement. Oligoanuria and impaired function at presentation were bad prognostic signs but preceding infection was favourable. Diverse histological and immunofluorescent findings indicate that extracapillary glomerulo nephritis is not a single entity. The clinical course is not always rapidly progressive.
There is an extensive if somewhat confused literature concerning a clinical entity of rapidly progressive glomerulonephritis [1-3] characterized by rapidly progressive renal failure usually in association with extensive epithelial cell proliferation. The term ‘extracapillary’ glomerulonephritis was used by V o lh a r d and F a h r [4] in 1914 and a clinicopathological entity has been variously described as a rapidly progressive course in type 1 glomerulo nephritis [5], malignant glomerulonephritis [6,7], acute necrotizing glomerulo nephritis [8], acute anuric glomerulonephritis [9], proliferative glomerulo nephritis with crescents [10], and endo- and extracapillary glomerulonephritis
Received: December 3, 1974; accepted: December 17, 1974.
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1 A part of this work was presented at the Xlth Congress of the European Society for Dialysis and Transplantation in Tel Aviv, Israel, November 1974. 2 1973 Royal Australasian College of Physicians Winthrop Travelling Fellow and Rési dent Etranger du Collège de Médecine des Hôpitaux de Paris.
2
W hitworth
type 3 [11]. P o lla k and M en d o za [3] clearly distinguished rapidly progressive (non-streptococcal) glomerulonephritis of unknown aetiology from the numerous other conditions which can produce a similar clinical picture. The mechanism of crescent formation has been studied by several workers [12,13] and focal crescent formation can occur in a wide variety of histological entities [14]. This study attempts to analyze the clinicopathological significance of ex tensive (>50% ) crescent formation in adults, the extracapillary glomerulo nephritis of V o lh a r d and F a h r [4], using morphological criteria as the determinant of inclusion in the study. Methods Over 3,000 renal biopsies, nephrectomy and autopsy specimens have been examined in the Service de Néphrologie, Hôpital Tenon, over the period 1965-1973. 80 specimens with 8 or more glomeruli from 60 patients were classed as having 50% or more glomeruli with extracapillary proliferation (crescents) on their initial biopsy. Patients with definite poly arteritis nodosa, systemic lupus erythematosus and Henoch-Schônlein purpura were ex cluded. Renal biopsy specimens were obtained by percutaneous puncture using a Vim-Silverman needle modified by Franklin, fixed in Dubosq-Brazil fixative (alcoholic Bouin), embedded in paraffin, and cut at 2 p.m. The following stains were used: HE, Masson trichrome, PAS, Wilder’s reticulin and Weigert’s fuchsin. Immunofluorescence studies were performed on 54 biopsies from 44 patients. Biopsies were snap-frozen in liquid nitrogen, cut in a cryostat at -2 5 °C , and stained with antisera specific for IgG, IgM, IgA, [31C and fibrinogen, as previously described [15]. 31 biopsies having >80% glomeruli involved by crescent forma tion (group I) were analyzed separately from 29 with 50-80% involvement (group II) as >80% involvement has been regarded as the morphological equivalent of rapidly pro gressive glomerulonephritis, indicating a particularly poor prognosis [11,13]. All specimens of renal tissue were examined independently by two observers (L. M. M. and J. W.). In each specimen at least 8 glomeruli were examined by light microscopy and 5 on immunofluorescence. The percentage of glomeruli with crescent formation was calculated from the number of crescentic plus obsolescent glomeruli over total glomeruli x 100 and histological features were graded from 0 to + + + . Retrospective analysis of all available clinical and laboratory data was performed independently of the biopsy findings. Cryo globulins were sought in 28 patients according to the method of A dam et al. [16], Statistical analysis was performed using a x2 test.
Results
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Biopsy Findings on Light Microscopy Renal tissue was obtained by biopsy in 60 patients. The number of glom
3
eruli available for analysis ranged from 8 to 52, mean 19. The findings on the initial biopsy specimen are shown in table I. Individual crescent size was significantly related to percentage of glomerular crescentic involvement (p 80%) was more common in the women (13/21 cases, 62%) than the men (18/39 cases, 46%), but this difference was not significant. Antecedents (tables II, III). In 16 patients (27%) isolated proteinuria (plus microscopic haematuria in 4 cases) was discovered 6 months to 20 years be fore biopsy (mean 4 years); 15 patients (25%) presented after an infection. In 4 patients presentation with extracapillary glomerulonephritis coincided with the diagnosis of malignancy; 2 patients had a history of occupational ex posure to trichlorethylene but information about prior exposure was not always available; 4 patients (7%) presented with ill-defined multi-system
Significance of Extracapillary Proliferation
7
disease, suggestive of systemic lupus erythematosus in 1 and polyarteritis nodosa in the other 3. However, diagnostic confirmation was not forthcoming in these patients despite extensive investigation and continuing observation. The paucity of necrotizing vascular lesions on biopsy supported the diagnosis of primary glomerular disease in this series of 60 patients. Presenting features. The presenting renal symptoms and signs are shown in figure 2 and tables II and III. 26 patients had an apparently acute onset with symptoms for less than 1 month prior to presentation and were equally divided between groups I and II. 30 patients had a chronic onset with symptoms or signs for over 3 months prior to presentation, 17 in group I and 13 in group II. All patients had microscopic haematuria (>5,000 RBC/min) at presenta tion and in 7 (12%) the haematuria was macroscopic. All except one patient had proteinuria in excess of 0.5 g/day, frequently heavy. 18 patients (30%) had a nephrotic syndrome at presentation (proteinuria > 5 g/day, serum albumin < 3 g/100 ml) and in 7 it was the principal presenting feature. Nephrotic syndrome developed subsequently in 4 other patients. Oliguria (urine output < 600 ml/day) was present in 21 patients (35%) (13/31 group I ; 8/29 group II). Oliguria was also a common pre-terminal event in those patients presenting with an adequate diuresis. 47 patients (78%) had impaired renal function on admission (creatinine clearance < 60 ml/min, creatinine >1.5 mg%, urea >40 mg%). Hypertension (blood pressure >150/90 mm Hg on admission) was present in 28 patients (47%) and the majority of the remainder subse quently became hypertensive. 2 patients (3%) presented with a nephritic syndrome (hypertension, haematuria, proteinuria, oliguria and oedema). Fever was present in 11 cases, 2 of those with infection, 4 with a probable
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Fig. 1. Age and sex distribution (open, males; shaded, females) in 60 patients with extra capillary glomerulonephritis (>50% glomeruli involved by crescents).
8
Whitworth Tabic II. Clinical features in group I (>80% crescents)
Patient
Antecedents
M.B. M.D. J.S. S.H. D.D. H.F. P.D.
sore throat proteinuria (6 months) proteinuria (1 year) bronchial carcinoma sore throat
IV
C.R. A.L. L.H. L.C.
bacterial endocarditis proteinuria (2 years) sore throat proteinuria (10 years)
11 III III II
+
+
+
M. da C. R.P. N.C. D.C. L.C.
proteinuria (2 years) known renal disease (3 years) sinusitis, fever, purpura proteinuria (20 years) proteinuria (18 years) tonsillitis pulmonary abscess proteinuria (6 months)
IV IV IV II II
— +
-
+ + + +
III IV II I I I I I IV II
+ -
+ + +
+ + + + -
III -
—
+ + + +
+ + +
G.D. R.S. J.M. M.R. N. leN. S.L. J.L. G.D. H.Z. S.P. J.C. D.D. N.L. L.R. E.C.
basal cell carcinoma -
Immuno- Presentation Evolution and fluo-------------------------------- follow-up oliguria hyperrescence nephrotic tension syndrome
_ 1
+ + + +
+ + + +
—
+ + + +
+
lost to follow-up RPGN, dialysis (3 days)t 1 yeart RPGN (4 days)! dialysis (2 years) RPGN (3 weeks) t creatinine 3.6 mg% (4 years) normal function (3 years) RPGN (3 months) t RPGN, dialysis (1 month) creatinine 2.7 mg% (4 years) RPGN, dialysis (2 days)t dialysis (2 years) dialysis (3 years) t 6 years t dialysis (2 years) f urea 100 mg% (3 years) RPGN, dialysis (4 days) RPGN, dialysis (2 weeks) urea 80 mg% (2 years) dialysis (6 months) dialysis (20 months) dialysis (9 months), graft RPGN (1 month) t dialysis (3 years) f RPGN (5 days) f creatinine clearance 54 ml/min (6 months) RPGN, dialysis (2 days) RPGN (1 week)t RPGN (3 days) t urea 60 mg% (1 year)
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RPGN = Rapidly progressive glomerulonephritis, t = Death.
Significance of Extracapillary Proliferation
9
Table 111. Clinical features in group II (50-80% crescents) Patients
Antecedents
C.G.
proteinuria (10 years) sore throat proteinuria (1 year) trichlorethylene sub-phrenic abscess polyneuritis —
B.D.-L. P.T. J.B. G.L. J.F. L.M. E. L. A.D. V.L. J.W. C.P. M.G. J.V. E.B. M.M.
pulmonary abscess -
G.D. M.R. P.T. A.L. M.T. G.R. C.M.
proteinuria (2 years) proteinuria (1 year) proteinuria (6 months) disseminated breast carcinoma proteinuria (2 years) ‘lupus-like’ syndrome proteinuria (8 months) trichlorethylene sore throat proteinuria (1 year)
P.B. G.M. A.C. C.C. C. de B.
sore throat pulmonary abscess disseminated carcinoma dental abscess pulmonary abscess
R.G.
appendix abscess
Evolution and Immuno- Presentation follow-up fluo oliguria hyperrescence ncphrotic tension syndrome -
+
+
+
-
-
-
II Ill
-
+ -
+ +
-
-
+ +
+ + +
+ -
+ + + -
-
I II II 0 I -
I II II
+ + + + +
normal function (10 years) normal function (1 year) RPGN, dialysis (days) RPGN (5 months) t 18 months t normal function (2 years) lost to follow-up RPGN, dialysis (days) t creatinine clearance 55 ml/min (4 years) normal function (1 year) lost to follow-up lost to follow-up dialysis (10 years) dialysis (3 years) normal function (1 year) 1 yeart
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II II
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II
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III I II II
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—
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I
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1
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II I I -
dialysis (5 years) normal function (3 years) dialysis (6 months) f normal function (2 years) lost to follow-up dialysis (18 months) RPGN, dialysis (4 months), graft normal function (2 years) dialysis (1 year) 1 year t creatinine 4 mg% (1 year) creatinine clearance 40 ml/min (6 months) creatinine 4 mg% (1 year)
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RPGN = Rapidly progressive glomerulonephritis, t = Death.
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Fig. 2. Clinical features at presentation in 60 patients with cxtracapillary glomerulo nephritis.
systemic disease or malignancy and in 5 as an isolated feature. In the latter group, it was frequently associated with muscle or joint pains. 5 of 40 patients tested (12%) had an antistreptolysin titre >300. Serum complement was de pressed in only 2 of 29 patients tested (both of whom had normal anti streptolysin titre) in accord with other published series [17,18]. Cryoglobulins were found in 13 of 28 patients tested (46%) confirming our experience that cryoglobulinaemia in glomerulonephritis correlates with proliferation [16]. They were identified in 9 cases (IgM 1, IgG 2, IgG/IgM 2, IgG/IgM/IgA 2, IgG/IgM/piC 2). There were no clinical or histological differences between patients with positive or negative cryoglobulins. Treatment All patients received supportive treatment (hypotensive and antibiotic therapy, drainage of surgical infection, dietary, fluid and electrolyte regulation and peritoneal or haemodialysis according to clinical indications). Therapy specifically directed against the glomerular lesion included corticosteroids (13 patients), indomethacin (4 patients), immunosuppressives (20 patients), heparin (with or without oral anticoagulant) (13 patients), streptokinase (1 patient) and dipyridamole (1 patient). Varying therapeutic regimes using one or many of these drugs were administered. Dosage and length of adminis tration varied from case to case.
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Evolution (tables II, III) Five patients have been lost to follow-up. Of the remaining 55, 21 have
Significance of Extracapillary Proliferation
11
Survival time, years
Fig. 3. Cumulative 5-year survival (23 ± 8 % ), calculated from the life table method of C utler and E derer [19]. 60 patients were available for initial analysis, 32 at 1 year, 19 at 2 years, 17 at 3 years, 12 at 4 years, and 8 at 5 years.
Linear and Granular Deposits Six patients had demonstrable linear immunoglobulin deposits. On light microscopy, this group was characterized by little or no tuft proliferation and the absence of polymorphs. Antecedent features included previous proteinuria, infection and malignancy. Clinical findings at presentation were variable. Three patients, all in group I, ran a rapidly progressive course to haemo-
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died (from malignancy, infection or complications of dialysis and transplan tation), and 15 others are alive on recurrent haemodialysis (13 patients) or with a functioning renal allograft (2 patients). Thus, 36/55 patients (65%) progressed to terminal renal failure, over a period varying from the day of presentation to 10 years, mean 15 months (from biopsy to commencement of dialysis or death). 14 of these patients required immediate institution of main tenance dialysis (less than 1 month after presentation). Cumulative 5-year survival was 23 ±8% using a life table method [19], as shown in figure 3. The remaining 19 patients are alive after 6 months to 10 years of follow-up; 9 are in remission with normal renal function after a mean follow-up period of 42 months, range 1-10 years; 10 patients have renal insufficiency. In all 10, renal insufficiency was present at presentation and in 7 of them was associated with oliguria but subsequently improved coincident with diuresis. These patients have a mild to moderate degree of renal impairment 6 months to 4 years later (mean follow-up 22 months).
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dialysis or death within days or months. One patient in group I is well with impaired function and the 2 patients in group II are well with normal function 2 years later. No particular histologic, clinical or evolutive pattern could be distin guished among the patients with granular deposits. Preceding Proteinuria In 16 patients, proteinuria was first discovered at least 6 months prior to diagnosis and may reflect the frequency of routine urine testing in France. Patients were evenly divided between groups I and II and included two patients with linear fluorescence. No specific histological features were appar ent, apart from the absence of polymorphs. In view of the known proteinuria, the biopsy finding of extensive crescent formation in these patients was un expected. In one case presentation coincided with a sore throat followed by a nephritic/nephrotic episode and in another with carcinoma of the lung, sug gesting that crescent formation may have been superimposed on an underlying quiescent glomerular lesion by these additional insults. Alternatively, ex tensive crescent formation might represent an exacerbation of a primitive nephropathy. Clinical features and evolution in this group were quite in constant.
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Malignancy The nephropathy was closely associated in time with malignancy in 4 cases (7%): carcinoma of the lung and of the breast with secondary involvement, widely disseminated secondary carcinoma of unknown origin, and a localized basal cell carcinoma of the face. Large extramembranous deposits on light and immunofluorescence microscopy were found in one patient with dis seminated carcinoma of the breast, suggesting the deposition of tumourspecific immune deposits in glomeruli [20], but in the three other patients with malignancy, the loops were too collapsed for proper assessment. One had granular and another linear deposits on immunofluorescence. The patient with linear deposits presented with oliguria and a basal cell carcinoma of the face and ran a rapidly progressive course. He is now well on recurrent haemo dialysis. The other three patients all presented with nephrotic syndrome. One patient had had a mastectomy for carcinoma of the breast 2 years previously with biopsy evidence of extramembranous nephropathy and presentation coincided with the appearance of métastasés. In the two other patients, malignancy was first diagnosed at presentation. One died shortly afterwards
Significance of Extracapillary Proliferation
13
in anuria and the others died 12 months later from malignancy and terminal renal failure.
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Infection In all, 15 patients (25%) presented after an infection. The preceding in fection was a sore throat in 7, only one of which was unequivocally due to streptococcal infection (isolation of the organism and a rise in antistreptolysin titre). The other 8 had subacute bacterial endocarditis (1), pulmonary abscess (3), dental abscess (1), sub-phrenic abscess (1), appendical abscess (1), and sinusitis (1). Endomesangial proliferation was common but not invariable in this group and no significant relationship could be demonstrated. However, the presence of polymorphonuclear leucocytes on renal biopsy correlated significantly with evidence of preceding infection (8 of 15 patients with a definite preceding in fection had polymorphs on biopsy compared with only 7 of the remaining 45 patients, p80% crescents on the initial biopsy could be regarded as ‘rapidly progressive glomerulonephritis’ on clinical criteria and it seems likely that ‘rapidly pro gressive glomerulonephritis’ is one end of the clinical spectrum of extra capillary glomerulonephritis (and other forms of glomerulonephritis) rather than a specific disease entity. In our series, the striking finding was the diversity of histological, immunofluorescence, clinical and evolutive features. No common clinical pattern emerged. Extracapillary glomerulonephritis is not synonymous with rapidly progressive glomerulonephritis. The extreme vari ability of immunofluorescence patterns suggests that extensive extracapillary proliferation does not constitute a distinct morphological entity.
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Aetiological Features Preceding proteinuria has not been a feature of previous descriptions of extracapillary glomerulonephritis. Possibly the presence of an underlying glo merular lesion predisposes to crescent formation in response to an additional insult or immunological challenge (infection, malignancy). Alternatively, lowgrade crescent formation may occur, subject to unpredictable exacerbation. The nephrotic syndrome in association with cancer has been widely reported [25,26] and the lesions described include minimal lesion [25] extra
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Crescent size in this series of 60 patients was related (p
