Idiopathic mesangiocapillary glomerulonephritis

CLINICAL STUDIES

Idiopathic Mesangiocapillary Glomerulonephritis Comparison of Types I and II in Children and Adults and Long-Term Prognosis

J. STEWART CAMERON, M.D., F.R.C.P. DAVID R. TURNER, Ph.D., M.R.C.Path. JULIET HEATON, M.D., M.R.C.Path. D. GWYN WILLIAMS, M.D., F.R.C.P. CHISHOLM S. OGG, M.D., F.R.C.P. CYRIL CHANTLER, M.D., F.R.C.P. GEORGE B. HAYCOCK, M.D., F.R.C.P. JACKIE HICKS London, England

Fromthe Deparbnents of f&di&W, PathokJ9y.and Paediatrics. Guy’s Hospital, London. England. Requestsfor reprints should be addressed to Professor J. Stewart Cameron, Clinical Science Laboratories, 17th Floor, Guy’s Tower, London SE 1 9RT. England. Manuscript accepted MY 12, 1982.

Dl 104 patients with idiopathic mesangiocapillary gkmeruknephritk studied for at least two years, 69 patients had type I disease and 35 had type II. Forty-five patients were children, and 59 were adults. Type II mesangiocapillary glomerulonephritis was more common in children than in adults, but no other clfnkal feature distinguished the two types at onset. Complement studies revealed that patients with type II had lower serum C3 concentrations and more frequently showed CB-splitting activity (C3 nephritk factor) in the serum. Children had hypertension or a lowered gkmerular filtratton rate less frequently at onset than did adults, but children had a higher incidence of a hematuric onset; C3 nephritic factor was also more frequent in the children. During a follow-up perlod of two to 21 years (mean eight years), only seven patients (five with type I and two with type II) showed clinical remission, whereas 38 percent of patients with type I and 49 percent of patients with type II died or required dialysis; a further 23 percent of patients with type I and 16 percent of patients with type II had continuing disease and reduced glomerular fiftration rate. Only the presence and persistence of a nephrotic syndrome in type I predicted renal failure. In both types, the presence of sclerosis or crescents in the initial renal biopsy specimen was associated with a poorer prognosis, but no other feature was of major prognostic value. Mesangiocapillary glomerulonephritis (also called membranoproliferative glomerulonephritis) is a well-defined histopathologic entity [l-19] that, although it may be found in a variety of clinical settings [ 13- 151, is usually idiopathic. Two main types have been distinguished histologically [8,13-X]: type I (or subendothelial deposit variety) with electron-dense material presumed to be immune deposits situated mainly at subendothelial sites in the glomerular capillaries; and type II (or linear dense deposit disease) in which a refractile, electron-dense material almost completely replaces the lamina densa of the glomerular capillary basement membranes [ 9- 11,16- 191. The main clinical associations of mesangiocapillary glomerulonephritis have been with abnormalities of the complement system. The most prominent of these is persistent depression of the serum concentration of C3 and, through this, of total hemolytic complement [ 1,20,25] together with the presence of a CSsplitting activity in the

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IDIOPATHIC MESANGIOCAPILLARYGLOMERULONEPHRITIS-CAMERONET AL

Figure 1. Top left, mesangiocapillary glomerulonephritis on haematoxylin and eosin staining of an affected glomervlus. This is increased in size and more solid and hyperceliutar than normal, and the lobulation of the tuft is accentuated. The capillary lumens are narrowed, to the point where many are not visible in this preparation. Top right, glomerulus from another patient with type I mesangiocapillary glomerulonephritis. In this silver methenamine-stained preparation, the increase in silver staining mesangial matrix (h4) can be seen. In some of the capillary loops, the fine silver-stained basement membrane can be seen outlining the capillary, with new basement membrane deposited near the lumen to give a “double contour” appearance to the glomenrlar capillary wall (arrows). This can be seen better in the inset (arrow). MhWfe left, 1 pm section embedded in plastic and stained with toluidine blue. In this preparation, the relationship of deposited material to the capillary wall can be seen, with large darkly staining deposits in the peripheral capillary walls; some stain less strongly (arrows). Middle right, electron microscopic view of a peripheral glomerular capillary wall to demonstrate the subendothelial site of the masses of deposited material (0) on the capillary side of the basement membrane (bm). The complicated thickening of the capillary wall in addition to this deposited material is seen. The capillary lumen (CL) is much reduced, and between the deposit (D) at an immediately subendothelial site under the true basement membrane bm is a complex mass of mesangial cytoplasmic processes (mc) and new basement membrane (bm) giving the “‘double contour” appearance. US is the urinary space. Bottom, corresponding immunofluorescent appearance on staining with anti-C3 reagent. The masses of material in the peripheral capillary walls are stained brightly in an irregular fashion; the mesangium is relatively spared.

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IDIOPATHIC

serum, usually called C3 nephritic

factor

neither the low C3 or the presence

of C3 nephritic

is invariable or entirely specific glomerulonephritis [ 2,2 l-251.

MESANGIOCAPILLARY

GLOMERULONEPHRITIS-CAMERON

ET AL

[21], although factor

for mesangiocapillary

Only three studies have compared the features of type I and type II mesangiocapillary glomerulonephritis, one in adults [8] and two in children [10,14,26]; one report has compared type I mesangiocapillary glomerulonephritis in children and adults [27]. No study has surveyed

the whole spectrum

of both types of dis-

ease in both adults and children from a single series, and this is the purpose of the present report. In addition, published information on prognosis beyond five years of follow-up study is scanty, being dependent on only a handful of patients beyond 10 years. We present data in this paper on 104 patients, both adults and children with types I and II mesangiocapillary glomerulonephritis, who have been followed up for two to 21 years (mean eight years); 35 patients had been followed up for more than 10 years. PATIENTS AND METHODS Patients.

In 104 patients, biopsy findings satisfied strict diagnosis of mesangiocapillary glomerulonephritis between 1964 and 1977 inclusive; these 104 patients are the subject of this report. The histologic [l-19], and only a brief decriteria are well-documented scription is necessary here. As the name implies, both the mesangial areas and the peripheral glomerular capillary walls are involved in the disease process. In both types of mesangiocapillary glomerulonephritis, the overall appearance of the glomeruli may vary, but they are commonly increased in size, with some accentuation of the lobularity of the glomerular tuft (Figure 1). This increase in size is the result of accumulation of both ceils and mesangial matrix within the glomerulus. The degree of lobularity does not appear to correlate with any clinical feature [2], and Mandalenakis et ai [ 51, in careful study confirmed this. Thus, a division into “lobular” and “nonlobular” forms no longer seems to have any justification. Particularly in type II glomerulonephritis, the increase in the size of the glomerular tuft may be very slight. Crescents may be observed, both segmental and circumferential, and the correlations of this finding are discussed later in this report. Ultrastructural studies reveal that, in type I mesangiocapillary glomerulonephritis, the glomerular capillary watt thickening is the result of several features (Figure 1). The first are large-sometimes very large-subendothelial collections of electrondense material, presumed to be immune deposits from the fact that they contain almost invariably IgG and C3, and variably Clq, C4, IgM, and IgA on immunofluorescent study. Second, processes of mesangial cell cytoplasm invade the peripheral capillary wall, again in a subendothelial site. Third, new mesangial matrix is laid down on the endothelial side of this material and mesangial processes and, together with the true basement membrane at the outside of the

criteria for the histologic

The dense deposit or type II variety of mesanFrgUre 2. giocapiliary glomerulonephritis Top, appearance on electron microscopy of a glomerular lobule. As in type I, the mesangial matrix (mm) is expanded, the mesangium is hypercellular, but the distinctive appearance is the almost continuous replacement of the lamina densa of the capillary basement membrane by a material that is very electron-dense when prepared by osmium and lead citrate (DO). Note that at the arrow there is a discontinuity in the “deposit. ” The capillary lumen contains two red cells (RBC). Bottom, appearances on immunofluorescent microscopy of a glomerulus in type II mesangiocapillary glomerulonephritis stained with anti43 reagent. Although no staining at all may be seen, in many patients the peripheral material in the capillary wall is associated with a rather continuous faint staining with the reagent. In the mesangium, much brighter large masses of C3 are seen. Staining for immunoglobulins is nearly always absent, except for some IgM on occasion.

capillary wall, gives the ‘double-contour” appearance, best seen in silver-stained preparations [ 1,6,8]. In contrast, the distinguishing findings in type II mesangiocapillary glomerulonephritis is the replacement of the lamina densa of the glomerular basement membrane with a very electron-dense material, which is present in long strips, although interrupted here and there so that it is not entirely continuous (Figure 2). This material takes conventional stains such as eosin, lissamine green, periodic acid-Schiff,

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GLOMERULONEPHRITIS-CAMERON

15 i Adults

Children

Type I

Type ll

II 0 5

I

15

I

I,

I

a5 35 45 55 Years of age at onset

I

65

1 75

Age at onset in type I and type II mesangiocapMary glomerulonephritis. The arrows indicate the median age of onset for the two types, which is younger in patients with type I/, Figure 3.

thloflavine T, and Martius scarlet very avidly [ 191, and appears slightly birefringent on oil-immersion of optical preparations so stained. It is present not only in the basement membranes of the glomeruli but also in Bowman’s capsule and in tubular basement membranes. In either case, subepithelial deposits or “humps” may be found, occasionally in large numbers. Using silver-impregnated preparations viewed under low-power electron microscopy, Anders et al [28,29] and Strife et al [30] have suggested that a third type of mesangiocapillary glomerulonephritis, designated type Ill, be separated by the frequent presence of such extracapillary deposits and the finding of deposit-like material irregularly distributed ‘through the TABLE I

Distribution ol Types I and II Mesanglocaplllary Glomerulonephritis in Patients Older and Younger than 15 Years at Onset

Type I (subendothelial) Type II (intramembranous) Total x* = 6.07; p = 0.004.

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Adulls

children

46 13 59

23 22 45

69 35 104

ET AL

basement membrane. This variety appears to us to be a variety of type I and has not been distinguished in this paper. The 104 patients were selected from a total of 132 patients in whom biopsy showed a mesangiocapillary pattern because the others: (1) had (or were later shown to have) systemic infections such as subacute bacterial endocarditis (three cases), hepatitis (one case), infected juguloatrial shunts (two cases), systemic lupus erythematosus (four cases) or Schdnlein-Henoch purpura (two cases); (2) had not undergone biopsy in our institution, and therefore the biopsy findings could not be reviewed with such rigor as in our own cases (nine cases); or (3) had been followed up less than two years by January 1, 1980, or have been lost to follow-up study (seven cases). In addition, further examination of all the biopsy specimens by two of us (DRT and JH) resulted in a change from type I to type II designation in five patients. All 28 patients excluded for reason 1 to 3 (just listed) were from the group of patients with type I disease. These changes account for minor differences in detailed figures given in this paper and those given in a preliminary analysis of the data presented at the Fifth Annual Conference in Pediatric Nephrology, on the nephrotic syndrome, held in Miami, January 1978 [ 131. Methods: All patients underwent needle biopsy. In patients with type II, 80 percent of the specimens were obtained within six months of apparent onset; in type I, 56 percent of the biopsy specimens were obtained within one year, and 80 percent within three years of apparent onset. From 1963 to 1968, biopsy specimens were fixed in buffered formalin; from 1968 to 1977, they were fixed in alcoholic picrate (Bouin’s solution). The cores were dehydrated, embedded in paraffin, and cut at approximately 3 pm for optical microscopy using hematoxylin and eosin, periodic acid-Schiff, methenamine silver, Martius scarlet blue, and trichrome stains. Crescents were defined as a layer of cells at least three thick, occupying at least half the circumference of the glomerulus in the plane of the section. Percentages of crescents were counted using unsclerosed glomeruli as a base. In type II, six specimens and in type I, seven biopsy specimens contained less than 10 unsclerosed glorneruli in the paraffin-embedded material. The remainder contained 10 to 82 glomeruli (mean 32); additional glomeruli were available for inspection in the plastic-embedded material. From 1970 (34 patients with type I and 19 with type II), material was also fixed in cacodylate-buffered 2.5 percent glutaraldehyde, post-fixed in osmium tetroxide, embedded in araldite, and cut at 1 pm for optical and 50 nm for electron microscopy using either an RCA EMU or Hitachi 12A electron microscope. Since 1972, material from 29 patients with type I and 18 with type II was snap-frozen in liquid nitrogen, cut in a cryostat at approximately 5 pm, and stained with a variety of fluorescent and peroxidase-conjugated reagents. Antiserum directed against IgG, IgA, Igfvl, Clq, C4, C3 and fibrin(ogen) was used regularly (Turner et al, 1976). Thus, in 35 of 69 patients with type I and 15 of 35 with type II the designation of type I or II was made on the basis of optical microscopy alone. Complement Studles. Only data regarding serum C3, C4, and C3 nephritic factor are given in this paper; more detailed studies of complement profiles are to be found elsewhere

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TABLE II

Features at Onset in Types I and II Mesanglocaplllary Glomerulonephrltls: Data from Patients of All Ages at Onset

VW Femalemale ratio Age (yr) at onset (mean f SD) Microscopic hematuria Macroscopic hematuria Glomerular filtration rate <80 mUmin71.73 m2 Blood pressure 95 mm Hg or more Serum C3 % normal Serum C3 <60% normal Serum C4 % normal Serum C4 <50 % normal C3 nephritic factor present

1671

(n = 69)

Typett (n = 35)

1.16 26.2 f 18.3 88% 19% 62% 33%

1.05 17.7 f 14.9 89% 38% 55% 28%

t

75.0 f 46.37 36% 97.2 f 44.1t 9% 27%

t::; t;:; [291

(31)

(27) (27) (30)

50.9 f 37.5 66% 112.7 f 59.3 15% 60%

SignHicance of Dtfference (P) NS’ 0.02 NS NS NS NS 0.02 0.01 NS NS 0.002

Numbers in brackets refer to the numbers of observations when these are less than the total number of patients. NS = not significant (p >0.05) by the Student t test or x2 test when appropriate. t Mean f 1 SD given for C3 and C4 estimations (normal ranges 60 to 160 percent and 50 to 165 percent normal pooled serum, respectively, mean f 2 SD). l

[ 221. C3 (since 1966) and C4 (since 1970) were measured using radial immunodiffusion into agar-containing monospecific antiserum specimens from sheep or goats. C3 nephritic factor activity was measured by conversion of C3, added in the form of whole fresh normal serum, by the test serum in vitro. The appearance of fast-migrating components (C3b) was detected by crossed immunoelectrophoresis

]221. Glomerular filtration rates were measured by the singleinjection 51Cr-labeled EDTA method of Chantler et al [31]; 24-hour urinary protein excretion was determined by the biuret method; urea and creatinine were measured by standard AutoAnalyser protocols.

RESULTS Clinical Patient Data at Onset. The age distribution of the patients with type I and type II mesangiocapillary glomerulonephritis is shown in Figure 3, and the distribution of patients between children (younger than 15 years at onset) and adults (older than 15 years at onset) is shown in Table I. Significantly more children than adults had type II glomerulonephritis, the mean and median ages at presentation being lower for type II when compared with type I (Table II and Figure 3). The mode of onset is shown in Tabfe Ill for types I and

TABLE Ill

II mesangiocapillary glomerulonephritis; there is no difference in the modes of presentation between the two types. A comparison of other clinical features in the two types is shown in Table II. Microscopic hematuria was almost invariable, macroscopic hematuria was common in both types, and the difference in incidence of macroscopic hematuria approached but did not reach statistical significance. The other clinical features showed no difference between the two types, except that five of 35 patients with type II mesangiocapillary glomerulonephriiis had partial lipodystrophy, compared with none of 68 with type I disease (chi-square = 10.2, p
Presentation of Patlenfs with Types I and II Mesanglocaplllary Glomerulonephrttls

Mode of onset

Type f

Type tt

Acute glotnerulonephritis Recurrent hematwia Persistent proteinwia

11 (16%) 6 (7%) 19 (27%)

7 (20%) 4(11%) 5 (14%)

Nephrotic syndrome

33 (48%) 69 (66%)

19 (55%) 35 (34%)

February 1993

Total 18 (20%) I 10 (10%) 24 (23%) 52 (50%) 104

Stgnlticance x = 2.76 p = 0.91 (NS)

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TABLE IV

Comparison of Features at Onset In Children and Adults with Type I Mesangiocaplllary Glomerulonephrltis ChildhoodOnset All

Sex Males Females FemaleMale ratio Hematuria Microscopic Macroscopic Onset Acute glomerulonephritis Recurrent hematuria Persistent proteinuria Nephrotic syndrome Glomerular filtration rate <80 ml/ miWl.73 m2 Blood pressure 95 mm Hg or more <60% normal % normal <50% normal nephritic factor present

yr)

015

v)

ChildrenversusAdults: Significance (PI

32 37 1.18:1

14 1.56:1

80 (88%)

22 (96%)

13’(19%)

8 (35%)

11(16%) 6 (9%) 19 (27%) 33 (48%) 43 (62%)

7 (30%) 4(17%) 1 l1 5(22%) 12 7(31%) } 9 (39%)

34 (74%)


[681

23 (33%)

5 (22%)

17 (37%)

NS

[27l

76.0 f 46.37 25 (36%) 97.2 f 44.17 6 (22%) 6(21%)

65.3 f 54.4 12 (57%) 84.8 f 43.4 5(31%) 5(31%)

81.6 f 41.8 17 (37%) 107.3 f 44.9 1(12%) 1(6%)

NS NS NS NS 0.02

[681

C3 % normal

C3 C4 C4 C3

((15

AdultOnset

;::;

9

23 23 l.OO:l 38 (83%) 5(11%) 4(9%) 2 (4%) I 6 ;; ;;;;;, 40

NS

NS
0.002

Numbers in brackets refer to numbers of patients studied when these are less than the total available (69). NS = not significant (p >0.05) by the Student t test or x2 test when appropriate. t C3 and C4 concentrations are expressed as percent of pooled normal serum f 1 SD (normal ranges C3 60 to 160 percent, C4 50 to 200 percent, mean f 2 SD). l

glomerulonephritis. The children presented significantly more often with macroscopic hematuria, either as a part of an acute nephritic illness or as recurrent hematuria, than did the adults. The presence of hypertension approached but did not reach statistical significance at the level of 1:20, the adults showing more frequent hypertension at onset. The adults had significantly lower glomerular filtration rate at diagnosis. The complement concentrations were the same in both groups, but C3 nephritic factor was more commonly found at first examination in children than in adults; only 30 to 69 patients were investigated at onset, however. Table V presents the same analysis for patients with type II mesangiocapillary glomerulonephritis. Again, the similarities are more obvious than the differences. Children with type II glomerulonephritis were more often female and more commonly presented with macroscopic hematuria than similar adults, and the adults were more often hypertensive at onset. There was no difference in the incidence of lowered glomerular filtration rate; children with type II disease more commonly showed C3 nephritic factor activity in the serum at presentation, but there was no difference in the C3 or C4 concentration. Table VI presents a similar analysis of all the patients with mesangiocapillary glomerulonephritis, both types I and II, divided into children (younger than 15 years at

180

onset) and adults (older than 15 years at onset). Overall, as might be expected from the data for the individual types, children more frequently presented with hematuria, either with an acute nephritic syndrome or recurrent hematuria. The frequency of the latter presentation is worth noting, since one in 10 of our patients with mesangiocapillary glomerulonephritis, the majority of them children, presented in this fashion. Adults more often had a raised blood pressure and reduced glomerular filtration rate, but the complement findings do not differ strikingly between children and adults except for the greater frequency of C3-splitting activity in the serum in children, which just reached significance at a 1:20 level. Renal Biopsy Findings. Results are presented (Figure 4) only for the percentage of glomeruli affected by crescents, as defined earlier, and the proportion of sclerosed glomeruli in the initial biopsy specimens. In type I, 29 specimens (42 percent) showed no crescents, whereas 40 showed 5 to 70 percent crescents; likewise, 29 specimens showed no sclerosed glomeruli, whereas 40 showed up to 60 percent sclerosed glomeruli. Children and adults showed similar data in both respects. In type II mesangiocapillary glomerulonephritis, only 13 of 35 initial biopsy specimens showed no crescents (37 percent), whereas a higher proportion (20 of 35,57 percent) showed no sclerosed glomeruli.

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IDIOPATHIC

TABLE V

MESANGIOCAPILLARY

GLOMERULONEPHRITIS-CAMERON

Comparison of Features at Onset in Children and Adults with Type II Mesangiocapillary Glomerulonephritis

All

ChildhoodOnset ((15 Yr)

Adult Onset Of5 Yr)

17 ia 35 1.05:1

a 14 22 1.75:1

9 4 13 0.44: 1

31(89%) 6 (17%)

19 (86%) 5 (23%)

12 (92%) 1 (a%)

Onset Acute glomerulonephritis

7 (20%)

16 (27%)

00

Persistent proteinuria

5 (14%)

4 (18%)

1 (a%)

4(11%) 19 (55%) 23 (64%)

4 (18%) a (37%) 14(61%)

12 (34%)

4 (18%)

a (62%)

50.9 f 37.5+ 23 (66%) 112.7 f 59.3+ 4 (15%) 16 (64%)

49.2 f 36.0 16 (73%) 106.2 f 60.0 3 (16%) 15 (71%)

56.7 f 41.6 7 (54%) 125.5 f 55.7 1(14%) 4 (57%)

Sex Males Females Female:Male

ratio

Hematuria Microscopic Macroscopic

Recurrent hematuria Nephrotic syndrome Glomerular filtration rate <60 ml/ min11.73 m* Blood pressure 95 mm Hg or more C3 C3 C4 C4 C3

ET AL

% normal <60% normal % normal <50% normal nephritic factor present

1281

Children versus Adults: Significance (P) 0.04

NS’ NS (0.08)

0.02

ii :(a” (83%) 1I1 l2 9 (69%)

NS 0.0001 NS NS NS NS 0.048

Numbers in brackets refer to numbers of patients studied when these are less than the total available (35). * NS = not significant (p >0.05) by the Student t test or x2 test when appropriate. + C3 and C4 serum levels given as percent of normal pooled serum f 1 SD (normal ranges C3 60 to 160 percent, C4 50 to 200 percent, mean f 2 SD).

TABLE VI

Comparison for Onset Data of All Children and All Adults with Types I and II Mesanglocapillary Glomerulonephrltis ChildhoodOnset All

Sex Males Females FemaleMale Onset age (yr) Hematuria

Adult Onset (>15 Yr)

Significance

17 28 1.651

32 27 0.84: -

9i(aa%) 19 (is%)

41 (91%) 13 (29%)

50 (85%) 6 (10%)

Acute glomerulonephritis Recurrent hematuria Persistent proteinuria Nephrotic syndrome Glomerular filtration rate <60 ml/min/ 1.73 m2

ia(17%) 10 (10%) 24 (23%) 52 (50%) 66 (63%)

13 (29%) a(ia%) I 21 9 (20%) 15(33%) I 24 23 (51%)

5 (a%) 2 (3%) \ 7 15 (24%) 37 (63%) I 52 43 (73%)

Blood pressure 95 mm Hg or more

34 (33%)

9 (20%)

24 (42%)

65.6 f 44.4’ 48 (47%) 103.5 f 49.7+ 10 (19%) 25(41%)

57.1 f 42.2 28 (62%) 97.2 f 47.6 6 (23%) 20 (54%)

71.1 f 46.5 24 (42%) 112.2 f 51.2 2(11%) 4 (23%)

ratio

Microscopic Macroscopic Onset

C3 C3 C4 C4 C3

49 55 1.12:1 23.6 17.6

((15 Yr)

% normal <60% normal % normal <50% normal nephritic factor present

11031

ilO21 ‘;504;’

1:;;

NS’

i

NS 0.014

<0.0001 0.01 0.0001 NS NS NS NS
Numbers in brackets refer to numbers of patients studied when these are less than the total available (104). NS = not significant (p >0.05) by the Student t test or x2 test when appropriate. + C3 and C4 serum levels given as percent of normal pooled serum f 1 SD (normal ranges C3 60 to 160 percent, C4 50 to 200 percent, mean f 2 SD). l

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IDIOPATHIC

MESANGIDCAPILLARY

TYPE

GLOMERULONEPHRITIS-CAMERON

30

II MCGN

25

‘5

TYPE

ET AL

I MCClf

In

1

10

10

5

5

0

0

5

5

10

10 lChitdren

15

15

1 20

J

20 I 25 IU

30 1

0

I

I

20

40

I

1

,

60

80

100

J

1 0

I

I

I

20

40

1

I

,

60

80

100

01

Figun, 4. Percentage of sclerosed glomemli, and glomeruli involved by crescents covering more than 50 percent of the glomerular circumfvnce. Chit&en are indicatedby the aMr areas and adults (> !5 years at onset) by the &ht areas. In the lefl diagam, data are shown for type II mesangiocapili~ glomerulonephritis, and on the right for type 1. In each diagram, the proportion of sclerosed glomeruli are shown below the line, and the proportion of glomeruli with crescents above the Ihe. Crescents and sclerosis are features of both typs of mesangiocapiiiaty glomerulonephritis. but few patients show extensive crescents or extensive sclerosis at the time of biopsy.

Thirteen biopsy specimens (36 percent) showed more than 20 percent crescents. Sclerosis was rather less common in the type II specimens, only two showing more than 20 percent sclerosed glomeruli (6 percent), as compared with 12 of 69 (28 percent) in the type t specimens; this may reflect the fact that, on average, the initial biopsy was carried out later in the course of type I disease (mean TABLE VII

lmmunofluorescent Flndings In Mesanglocapillary Glomerulonephritis

196 Type 1 Percent Type II Percent

15 months) than in type II disease, in which 88 percent were performed within six months of onset, Table VII compares the immunofluorescent findings in type I and type II mesangiocapillary glomerulonephritis at first biopsy. In type I, a distinct pattern of peripheral C3, often accompanied by one or more immunoglobulins (usually IgG) was seen (Figure 1). Clq was visible in a similar pattern in almost two-thirds of biopsy specimens, but C4 was seen less commonly, in just under one-third. The pattern in type II contrasted sharply. More than one-third of the biopsy specimens gave negative results for all reagents tested, including C3, despite specific antiserum and positive control samples. In specimens with positive results, the usual finding was C3 in isolation, or in association with fainter deposits of IgM. The C3 was often present in bright masses in the mesangium, with much fainter linear staining of the peripheral capillary walls (Figure 2). The mesangial masses sometimes showed the “ring” appearance as described by Kim et al [32], but we did not observe the double tramline in the peripheral wall they described. Since immunofluorescent data were available for only 47 biopsy specimens, a detailed breakdown of childhood and adult cases is not presented. There did not appear to be any differences; in particular, of six type II specimens with no immunofluorescence even for C3, two were from adults and four from children. Follow-up Data. The most recent status of the 69 patients with type I disease followed for two to 21 (mean 8.3 f 5.3 SD) years and the 35 patients with type II disease followed for two to 16 (mean 7.7 f 3.7 SD) years is shown in Table VIII; survival is summarized by the life-table method in Figure 5. Twenty-four patients with type I and 11 with type II had been followed for more than 10 years. During the follow-up period, 60 percent of the patients died, underwent dialysis or transplantation, or showed a reduction in filtration rate accompanied by .persistent proteinuria. All patients with “uremia” defined in this way had proteinuria except one, whose glomerular filtration rate rose from 22 to 40 ml/min/1.73 m* over nine years of follow-up, and whose proteinuria remitted completely at this subnormal glomerular fil-

17129 59 O/18 0

IgM

IgA

C3

15129 52 5118 28

10129 35 O/18 0

27/29’ 93 13/18+ 72

Clq

c4

Fibrin

All Negative

24124 58 l/l4 7

6120 30 0111 0

6/29 21 6Jl7 35

2129 7 7118 39

Usually bright, peripheral. f Usually mesangial, with or without faint linear staining of capillary l

782

Felxuary

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IDIOPATHIC

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GLOMERULONEPHRIT1S-CAMEfWN

ET AL

tration rate, after seven years of follow up study. Forty-three patients (38 percent) were “dead” (used here to mean actual death or the need for dialysis or transplantation): 49 percent of patients with type II and 38 percent of patients with type I. Three patients with type I and one patient with type II did not die directly because of renal failure: one had myocardial infarction, one had carcinoma of the bladder, and two had cerebral hemorrhages zsociated with uncontrolled hypertension, precipitated in both by treatment with corticosteroids. All but one were uremic at the time of death. Thus, only one of the 43 deaths was unrelated to uremia. When deaths and deterioration in renal function (hereafter called “uremia”) are considered together, there was no difference between the incidence of renal death and uremia in types I and II mesangiocapillary glomerulonephritis (Table VIII), nor was there when “deaths” alone were considered (chi-square = 1.10). This is reflected in the similarity in the survival curves in Figure 5, only the small group (n = 13) of adult patients with type II disease showing a rather poorer survival, which did not reach significance from the other curves on log-rank testing. However, within the group of patients with type I disease and for all patients together, the prognosis for “uremia” was significantly poorer in adult patients than in children (chi-square = 6.85, p
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1 - TYPO

ET AL

- TYPe u

1

Figure 5. Top, survival and status at last follow-up evaiuation in patients with mesangiocapillaty glomeruionephritis. The survival curves were calculated by the method of Cutler and Ederer (58) and show data for patients of all ages with both tvpe I and type II (heav)r Mnes)and &I% for each of these two groups for children and for adults (lighter lines). None of the curves differ from each other when tested by the iogrank method (59), although the adult patients with type II mesangiocapillaty glomerulonephritis approach significance when compared with similar children (p = 0.08). The most recent status is shown at top r/ghf: OK = well, normal urine, normal renal funct;on; PP = persistent protein&a with or without a nephrotic syndrome but wik9 normal renal function; CRF = giomerular filtration rate of less than 80 mU mini 1.73 m2 and persistent proteinuria with ot without a nephrotic syndrome; D, RDT, TX = dead, regular dialysis treatment, or transplantation. Data are presented for each of types I and II mesangiocapillary glomerulonephritis for patients above and below the age of 15 at apparent onset. In type I mesangiocapillary glomerulonephritk, children have a significantly better prognosis than adults (p
. All

type II . Children type II A Adults type Ii

30

20

0 All type I 0 Children type I dr Adults

IO

type I

0 0

5

10

15

20 Types

0 All children l All adults

0

;

(types I and II) (451 (types I and II) (59)

1 5

0

Years

TABLE IX

I znd II

I 10 lrDm

1 I5

I 20

onset

Long-Term Behavior of Serum C3 and C4 Concentrations in Types t and II Mesangtocaptltary Glomerulonephrttts TYP 11

Number of patients Number with serial C3 observations C3 always low’ c3 low, then normal C3 normal, then low C3 always normal

35 34 18 5 3 8

Number with serial C4 observations C4 always low+ C4 low, then normal C4 always normal

29 :I

C3NeF observations

30

C3 nephritic factor present C3 nephritic factor appeared later

25

‘9

26 (76%) (24%)

4 (16%) (84%)

69 52 7 15 I 27(52%) 5 25 (48%) 38 1 51 32

z1

104 88 25 20 1 53(61%) 8 33 (39%) 67

6 (19%)

;)

(81%)

57

10 (34%)

‘9

29 22 (73%)

Total

TYP’

10(15%) (65%)

59 32 (54%)

l C3 low = less than 60 percent normal reference serum. + C4 low = less than 50 percent normal reference serum. C3 nephritic factor = abi!ity of serum to split C3 in added normal human serum, assessed by crossed immunoeiectrophoresis.

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TABLE

X

Effect

MESANGIOCAPILLARY

GLOMERULONEPHRITIS-CAMERON

ET AL

of Clinical Features on Outcome

Factor Possfbly Influencing Prognosis Child or adult (< or >15 yr) Hematuria at onset Nephrotic syndrome at onset Nephrotic syndrome at any time Blood pressure elevated at onset Glomerular filtration rate decreased at onset

“Dead” versus Alive

TYP 1 “Uremla”T versus Perslstsst Protelsuria and RemissIon

NSt NS 0.01 0.001 0.03 (0.07)


“Dead” = dead, dialysis, or transplantation. + “Uremia” = “dead” or persistent disease with glomerular $ NS = p >0.05 (x2 test).

“Dead” versus Alive (0.07) NS NS 0.04 NS NS

Type II “Uremia” versus Persistent Protelnurla and Remission NS NS NS NS NS NS

All “Uremia” versss “Dead” versus Alive NS 0.003 0.02 0.0001 NS NS

Proteisuria and Remission 0.003 NS NS 0.003 NS NS

l

filtration

the activity disappeared with time. Samples were not collected at fixed intervals and studied systematically, however. Factors Influencing Prognosis. A number of clinical and histologic features present at first assessment were analyzed individually to attempt to determine groups with a particularly good or a particularly poor prognosis, so that treatment might be applied or avoided in a rational fashion. Table X shows the correlations between the most recent status of the patients an average of eight years from apparent onset. These have been analyzed for both the correlation between “death” (as defined earlier) and the presence or absence of initial clinical features, and also the correlation between “uremia” as defined earlier (“deaths” plus those with reduced renal function) and the presence or absence of initial clinical features, since this latter figure may give a better idea of the numbers of patients who ultimately will have renal failure. In type I, children did worse than adults with respect to the onset of “uremia,” but macroscopic hematuria at onset did not affect prognosis for either death or “uremia,” except that when patients with types I and II were considered together, renal “death” was more frequently found in patients with proteinuria and without macroscopic hematuria. This difference was also evident when data for the presence of a nephrotic syndrome were examined, both for patients with type I and the group as a whole. The difference in prognosis was particularly strong for those with nephrotic syndrome at any point in the illness; this appeared at onset or within the subsequent three months in all but two of the 69 patients who were or became nephrotic. Prognosis in nephrotic patients was worse for both “death” and “uremia,” and log-rank testing of the survival curves (Figure 6) also showed a significantly poorer outlook in nephrotic patients. Hypertension and (surprisingly) initial renal function were useless as prognostic indi-

rate <80

mUmin/

1.73 m2.

cators in the group as a whole; however, in type I, hypertension was associated with a greater frequency of “death,” and reduced renal function at onset with a greater frequency of “uremia.” The histologic features in relation to prognosis are analyzed similarly in Table Xl. Lobularity of the glomerulus was not examined, since this is an imprecise and subjective assessment, and a previous study (33) had not suggested that it contributes to a more accurate prognosis. The presence of any sclerosed glomeruli was strongly associated with a poorer prognosis, especially for uremia, but also for death. The presence

1 OK

PP

CRF Dead/

MIT/ TX

Figure 6. Survival in patients with and without nephrotic syndrome. Log-rank testing shows that the difference between all cases (heavy lines) is signifkant at the 0.00 1 level. The difference for types I and II separately (N&t lines) is similarly significant. Data for the most recent status of the patients is shown at the top right (abbreviations as in Figure 5). Again, the difference is significant, at the p = 0.000 1 level.

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ET AL

Effect of Histologic Features on Prognosis

TABLE XI

Type

Type II

1

f versus “Uremia”

“Dead”’ versus Alive Sclerosis (+ or -) Crescents (+ or -) < or >20%

Persistent Preteinuria and Remission

0.08 NSS NS

“Dead” versus Alive

0.0004 0.001 0.005

* “&ad” = dead, dialysis or transplantation. t ‘Uremia” = “dead” or persistent disease z NS = p >0.05 (x2 test).

filtration

of even a single large crescent (more than 50 percent of the glomerular circumference) was also associated with a poor prognosis for “uremia,” but only in the combined type I and type II data with “death.” The survival curves illustrate this difference (Figure 7). Use of a higher proportion of glomeruli affected by large crescents did not improve the accuracy of prognosis; data on 18 patients with more than 40 percent of the glomeruli affected by large crescents are given in Table XII. Of 18 patients, only seven still have renal function, reduced in two and grossly reduced in a third. Only four patients have normal function, and in two, the follow-up periods are only two and a half and three and a half years.

crescents + 100

90 60

10

-G .t 2

c?

60

Nocrescents 50

p.o.02

*

40

i \

30

0 Type

I

10 0

\ \ h

crescents

0 All A Type II

20

No crescents f

0

1

I

1

5

10 Years from on8.3

15

I 20

Figure 7. Survival in patients with mesangiocapillary glomerulonephritis with and without crescents in the renal biopsy specimen. Data are shown for all patients with and without crescents (heavy lines) and for type I and II separately (light lines). The difference between the heavy lines approaches, but does not reach significance at a 1:20 level (p = 0.07). The most recent status of the patients is shown top right (abbreviations as in figure 5). The difference here is significant (p = 0.02).

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Persistent Proteinuria and RemIssIon

NS NS NS

with glomerular

All

“Uremia” versus

0.01 0.002 NS

rate<80

mVmirV1.73

“Uremia” versus “Dead” versus Alive 0.03 0.02 NS

Persistent Protelnurla and Remieeion 0.01 0.0001 0.02

m*.

Treatment: From 1963 to 1970, during which 35 patients with type I disease and 10 with type II included in this paper were seen, corticosteroids and cytotoxic agents (azathioprine, 2 mg/kg per 24 hours, or cyclophosphamide, 3 mg/kg per 24 hours) were used in the majority of patients, all with nephrotic syndrome or declining function. The results, discussed previously [2,7], were disappointing: therefore, from 1971, we ceased routine treatment of patients with either type of mesangiocapillary glomerulonephritis. However, from 1971 to 1978, those with a high proportion of crescents in the renal biopsy specimen, a rapid decline in renal function, or both were treated with combined anticoagulation and immunosuppression (hepariniwarfarin and dipyridamole) for one year [34]. Ten patients with type I disease and eight with type II were treated with this regimen, all but four being children, a total of 18 of 59 patients seen between 1971 and 1978. At latest observation, three patients with type I disease and two with type II had normal renal function, one without urinary abnormality, and another patient with type I had chronic renal failure; the remainder required dialysis (11 of 18 patients), and one died of renal failure without dialysis. Transplantation. Thirteen grafts (five from live donors, eight from cadaver donors) were placed into 10 recipients with type II mesangiocapillary glomerulonephritis. One graft never functioned, and two patients died early in the postoperative course, one with a functioning graft. Another graft failed after six years. At last follow-up evaluation, six of the 10 recipients had functioning grafts four months and eight years following grafting, and recurrence of the intramembranous electrondense material was noted in all seven grafts studied. This recurrence possibly contributed to graft failure in one graft only [35]. One patient has resumed dialysis. Fourteen grafts (one from a live donor) were placed in 11 recipients with type I mesangiocapillary glomerulonephritis. One patient died in the postoperative period, and two died three months later, one with a functioning graft. Three additional grafts failed up to two years later, and two of these three patients resumed regular dialysis. Another graft suffered early (three

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IDIOPATHIC

Follow-up to Death or Dialysis

A90 (yr)

Percent Cresosnts

18

80

Nephrotic syndrome

2

47

66

3 4

10 11

60 60

Persistent proteinuria, nephrotic syndrome Nephrotic syndrome Nephrotic syndrome

5

52

60

Nephrotic syndrome

6

55

57

Nephrotic syndrome

7

20

50

Persistent proteinuria

6 9 10

70 19 22

50 49 48

Acute renal failure Nephrotic syndrome Nephrotic syndrome

11

27

47

Nephrotic syndrome

12

21

45

Persistent proteinuria

Type n 13

7

82

14

4

80

15

7

60

Acute glomerulonephritis Acute glomerulonephritis, acute renal failure Nephrotic syndrome

16

11

50

Nephrotic syndrome

Type 1’

GLOMERULONEPHRITIS-CAMERON

ET AL

Mesanglocapillary Glomerulonephritiswith More Than 40 Percent Glomeruli Affected by Large Crescents

TABLE XII

Patient Number

MESANGIOCAPILLARY

Presentation

Treatment

1

17

12

46

Nephrotic syndrome

18

14

45

Nephrotic syndrome

Status

(yr)

Recenl Glomerular Filtration Rate (ml/min11.73m*)

Immunosuppressive and cytotoxic agents+ Nil

0.6’

Dialysis, therapy failed, recurrent disease

-

4.5

Dialysis

-

Nil Immunosuppressive and cytotoxic agents Immunosuppressive and cytotoxic agents* Immunosuppressive and cytotoxic agents Prednisane and azathioprine Nil Prednisone Prednisone and azathioprine Immunosuppressive and cytotoxic agents Prednisone and azathioprine

3.5 3.5

Persistent proteinuria Dialysis, therapy failed

109 -

7.5

Dialysis, therapy failed

-

2.0

Nephrotic syndrome

47

11.0

Chronic renal failure

0.4 11.0 4.5

Dead, renal failure Nephrotic syndrome Dialysis, died later

P=reat 420 ~molllffer -

Immunosuppressive and cytotoxic agents Prednisone and azathioprine Immunosuppressive and cytotoxic agents and cytotoxic agents Prednisone and azathioprine Nil

33 -

4.0

Died, renal failure

-

2.5

Persistent proteinuria

104

7.5

Persistent proteinuria

142

0.2

Dialysis, died later

-

5.5

Persistent proteinuria

106

2.0

Dialysis

-

8.0

Therapy

8.5

Dialysis, (therapy failed)

-

Second biopsy after rapid decline in renal function; first biopsy showed no crescents. + Prednisone, azathioprine, dipyridamole, hepariniwarfarin. $ Treatment stopped because of gastrointestinal bleeding. l

weeks) destruction by recurrent disease with extensive crescents, in a patient with previous crescentic mesangiocapillary glomerulonephritis (Table XII). At last follow-up evaluation, six of 11 recipients had functioning grafts six months to 10 years post-transplantation: two resumed dialysis (one dying fater) and three were dead. Recurrence of the disease was noted only in the single case mentioned, of seven graft biopsy specimens studied and five nephrectomy specimens examined; three of the latter five grafts had functioned for several months. Pregnancy. In type I mesangiocapillary glomerulonephritis, 20 pregnancies occurred in seven of 29 women who had active disease during reproductive years. These pregnancies resulted in eight live births,

five spontaneous abortions, and seven induced abortions. In type II mesangiocapillary glomeruionephritis, there were nine pregnancies in five of 14 women with active disease; these resulted in five live births and four induced abortions. Five of these pregnancies (resulting in three terminations and two live births) occurred in a single patient. Deterioration of maternal renal function during pregnancy was not observed. CGMYENTS Mesangiocapillary glomerulonephritis may be found in a variety of clinical settings, which are summarized in the reviews of Cameron [ 131, Habib, Levy, and coworkers [6,14], and Kim and Michael [ 151. All such

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GLOMEIWL~NEPHRITIS-CAMERON

cases have been excluded from this study, with the exception of patients with type II mesangiocapillary glomerulonephritis and partial lipodystrophy [25]. However, the great majority of patients show no obvious clinical associations and thus are classified as having “idiopathic” disease. The classification of patients with biopsy features characteristic of mesangiocapillary glomerulonephritis has been a source of controversy. The first controversy concerns whether those patients with intramembranous dense deposits may be considered to have a variety of mesangiocapillary glomerulonephritis [36,37]. The main case for regarding the two as distinct is the observation that, although the majority of patients with type II show a pattern of mesangiocapillary glomerulonephritis on optical microscopy, some do not-eight of 11 in one study [37]. However, all of our patients with dense deposits showed a pattern of mesangiocapillary glomerulonephritis. The resemblances between types I and II mesangiocapillary glomerulonephritis are more striking than the differences; in particular, persistent hypocomplementemia has been reported only very rarely in patients with other than either type I or type II disease. The distinction between types I and II mesangiocapillary glomerulonephritis can be made with certainty in difficult cases only on electron microscopy; however, in the majority of cases, linear deposits of type II disease or the peripheral discontinuous deposits of type I disease can be distinguished readily on optical microscopy. Only when type II deposits are not prominent is there difficulty, and the specimen may be misclassified as indicating type I disease. Use of several stains to identify the deposits in the paraffin-embedded material as herein described minimized the chance of such mistakes. However, recutting and restaining of the 41 biopsy specimens obtained before 1970, from which material was available only for optical microscopy, resulted in reclassification of five specimens, all from type I to type II mesangiocapillary glomerulonephritis. A further controversy concerns the question of whether patients with mesangiocapillary glomerulonephritis should be further subdivided to include a “type Ill.” This suggestion was put forward independently by Anders, Thoenes, and their colleagues [28,29] and Strife et al [30] following observations on low-power electron micrographs of silver-impregnated material, which allows excellent distinction between deposits and basement membrane material. These authors described complex alterations of the basement membrane, with deposits incorporated within it, as well as subendothelial deposits, often associated with subepithelial deposits and “spikes,” and suggested that these patients should be regarded as comprising a distinct subgroup of patients with mesangiocapillary glomerulonephritis.

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ET AL

However, analysis of our own data on such patients does not suggest any differences between these patients and those who have type I mesangiocapillary glomerulonephritis, like the findings of most other observers (Habib, personal communication, 1979) and we prefer to classify patients with “type Ill” disease together with those who have type I. Features at Onset. We examined children and adults with mesangiocapillary glomerulonephritis of both types to see if the different histopathologic patterns are reflected in important clinical differences or outcome in either age group, and if children and adults in either group show consistent differences. The differences in the immunofluorescent patterns in types I and II (Table VII) agree with those reported previously [ 14,23,24,39], except that the proportion of patients with type II mesangiocapillary glomerulonephritis who showed negative immunofluorescent results, even for C3, was greater. There was no difference between adults and children in this respect, so the fact that our series contained adults cannot explain the difference. Also, we did not find the early components of Clq and C4 so frequently present in biopsy specimens from patients with type I disease as did Levy et al [24] or Davis and Cavallo [39]. The age at apparent onset was seen to be lower in type II (Figure 1 and Table Ill), which was rare in old age. Clinical presentation of types I and II was similar (Table II and Ill). The only other differences were evident in the complement system, C3 being lower than C3 nephritic factor more commonly in type II, as previously reported by Habib, Levy, and colleagues [ 14,241. In contrast to their data, however, the C4 concentrations at presentation did not differ. When the data for adults and children with types I and II disease are considered separately (Tables IV and V), no further differences appear. Thus, our patients with types I and II mesangiocapillary glomerulonephritis are characterized more by resemblance than by difference, which agrees with previous conclusions [8,11,23,26]. When adults and children with mesangiocapillary glomerulonephritis are compared (Tables V and VI), children presented more frequently with macroscopic hematuria and were less frequently hypertensive at onset; in type II mesangiocapillary glomerulonephritis, they also showed a less frequent reduction in glomerular filtration rate. C3 nephritic factor was more commonly present in children than in adults in both types of mesangiocapillary glomerulonephritis, but serum C3 and C4 concentrations were indistinguishable. The proportion of crescents and sclerosed glomeruli were not different in the initial biopsy specimens in children and adults (Figure I), nor in types I and II disease. Few patients presented with extensive crescents (more than 40 or more than 60 percent glomeruli); thus, “crescentic mesangiocapillary glomerulonephritis” is rare.

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IDIOPATHIC

Follow-up Data. In general, both types of mesangiocapillary glomerulonephritis are progressive. Table VIII and Figure 3 indicate that more than half those affected are dead, are undergoing dialysis, or have undergone transplantation, and a further third are uremic, within only 10 years. During this time, only seven of 104 patients showed remission with normal renal function, along with a single further patient in whom proteinuria resolved but reduced renal function persisted. It can be predicted from Figure 3 that, after about 20 years, some 90 percent of patients will have renal failure and only about 10 percent will show remission. The long-term prognosis in mesangiocapillary glomerulonephritis is worse than in any other form of apparently primary idiopathic glomerulonephritis. There was no difference in prognosis in types I or II mesangiocapillary glomerulonephritis, as suggested previously [9, lo], although the small number of adults with type II disease appeared to fare rather worse than the others (Figure 3). In type I mesangiocapillary glomerulonephritis, and when types I and II are considered together, children do better than adults (Table VIII); when type II is considered alone, there is a strong but not statistically significant, trend in the same direction. Thus, children with mesangiocapillary glomerulonephritis fare better than adults with regard to “uremia.” The same is not true when renal death is the end-point (Figure 3). Children do better for 10 years, however, from 10 to 15 years, their results become as poor as the results in adults, suggesting that children show renal failure more slowly than adults do, but that the proportion with renal failure is the same at the end. Magil et al [27] noted a similar shape to the curve of adult and childhood mortality in an analysis confined to type I mesangiocapillary glomerulonephritis, with an increased early mortality in adults. They also reported that all their adult males with type I mesangiocapillary glomerulonephritis showed renal failure during their study, significantly more frequently than the females. In our study, 13 of 23 (56 percent) adult males and five of 15 (33 percent) adult females with type I disease had terminal renal failure (p = 0.02); the proportion of “uremic” patients (18 of 23 versus 15 of 23) was, however, identical. Data from adults with type II disease are too limited to allow comparison of the two sexes. The long-term behavior of the serum complement levels (Table IX) bore no relationship to prognosis, as described previously [33,40]. In only 25 of 80 patients were all C3 values below the lower limit of normal; thus, persistent hypocomplementemia, although common in patients with mesangiocapillary glomerulonephritis, is by no means invariable, again as reported previously [2]. A higher proportion of patients who had type II disease showed a low C3 level in all observations (18 of 34) when compared with patients who had type I (seven of 52).

MESANGIOCAPILLARY

GLOMERULONEPHRITIS-CAMERON

ET AL

The effect on outcome of age at onset has already been mentioned. The type of onset influenced outcome, but analysis was complicated by the fact that a nephrotic syndrome developed in many patients after an acute nephritic onset. Perhaps because of this, death was only slightly more likely when onset was marked predominantly by proteinuria, but the most prominent differences emerged when the presence of nephrotic syndrome at any time in the course of the disease was considered (Table X and Figure 4), as reported previously [27,30,33]. Hypertension was a surprisingly poor guide to outcome, and an initial reduction in glomerular filtration rate correlated with a significantly poorer prognosis only for patients with type I disease. Two histologic features were analyzed: sclerosis and crescents (Figures 1 and 5, and Table Xl). The presence of even a single sclerosed glomerulus or a single large crescent in the biopsy specimen significantly affected prognosis (Table Xl). Rather surprisingly, this correlation did not become stronger when an increasing proportion of crescents was seen (Table Xl). These observations agree with previous observations [33], but the impact on survival is rather small (Figure 4); the main effect is seen during the first 10 years, and prognosis equalizes thereafter. Thus, again, it seems that crescents determine a more rapid early decline into renal failure, not the ultimate outcome. Only five patients with type I and three with type II had more than 60 percent crescents (“crescentic mesangiocapillary glomerulonephritis,” Table XII). Treatment. We can offer no specific proved treatments for mesangiocapillary glomerulonephritis. Our original results with immunosuppression alone were not encouraging [2,7], but McEnery et al [41] have suggested recently a beneficial effect in children, predominantly with type I mesangiocapillary glomerulonephritis, using alternateday corticosteroids in a dose of 60 mg. These uncontrolled data are provocative, but it should be noted that the 1O-year survival of our own children with type I disease (some of whom were treated) is 75 percent (Figure 3) and that their 90 percent survival is well within 95 percent confidence limits (not shown) for these data. A controlled trial of this regimen in children has been underway for five years in the International Study of Kidney Diseases in Children, but no beneficial effect has emerged to date [42]. Kincaid-Smith [43] suggested that combined treatment with corticosteroids, cyclophosphamide, and dipyridamole resulted in survival rates much higher than previously observed in adult nephrotic patients with mesangiocapillary glomerulonephritis, most of whom were also hypertensive and had reduced renal function. We [34] have used a similar regimen, principally in children, apparently with good short-term results in patients with the most severe disease, especially those with crescents and/or documented rapid fall-off in renal

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function. In the longer term, however, only one-third of 18 patients with severe mesangiocapillary glomerulonephritis so treated still have renal function, and the potential risks of the treatment must be weighed carefully against the possible benefits. Cattran et al [44] have made a preliminary report on a collaborative controlled trial of the use of cyclophosphamide, warfarin and, dipyridamole (but no prednisone) in 63 patients, which showed no difference between treatment and control groups after three years. Donadio et al [45] have reported encouraging preliminary results in a prospective controlled trial of dipyridamole in mesangiocapillary glomerulonephritis. There is ample evidence of platelet activation in patients with mesangiocapillary glomerulonephritis [46-481 and this approach, either alone or in combination, deserves further attention, if only because of the lack of toxicity of the agents used. Transplantation. It is now clear that recurrence of intramembranous electron-dense deposits within the basement membranes of the allografted kidney is a regular, probably invariable, feature of type II mesangiocapillary glomerulonephritis [ 16,34,49]. Destruction of the graft, however, is rare [49], although Kim and Michael [ 151 described a patient with type II disease in whom two successive grafts were destroyed by recurrent disease. Early reports in the literature dealing with selected individual patients suggested about 50 percent serious recurrence in type I disease [49], but our data, presented herein, suggest a better prognosis (one of eight grafts with established function), and, in this, we agree with Hamburger et al [50] who found a recurrence rate of only 18 percent. Six other grafts placed in a total of 10 patients failed because of rejection, and the recurrence rate may be even lower. Patients with extensive crescent formation may be more prone to recurrence, as in our patient, who resembles closely the patient described by McCoy and his associates [51]. Pregnancy. It has been suggested that pregnancy in mesangiocapillary glomerulonephritis carries a particularly unfavorable prognosis for maternal renal function [52], although there are very few data in the literature [53]. Our results are not in accord with this suggestion; however, in general, those women who became pregnant and whose pregnancies were allOWed to continue were those with good renal function and without hypertension, even though all had continued

proteinuria. If pregnancy were continued in patients with both reduced renal function and hypertension, it is possible that a decline in maternal renal function might be seen, as in a number of other forms of glomerulonephritis [53]. Pathogenesis. The clinical data presented herein throw no new light on the question of the pathogenesis of the two types of mesangiocapillary glomerulonephritis. Type I bears many of the hallmarks of an immune complex disorder, whereas type II disease is a unique lesion, with no human or animal analogue to date. The striking association between partial lipodystrophy, type II mesangiocapillary glomerulonephritis, C3 nephritic factor, and persistent hypocomplementemia [24] remains unexplained. Type I mesangiocapillary glomerulonephritis has been reported in association with partial lipodystrophy in two patients, however [25,54], and circulating immune complexes are as common in type II as in type I mesangiocapillary glomerulonephritis [55]; Williams et al, unpublished data]. Strips of densedeposit-like material may be seen within the glomerular basement membrane in some patients with classic acute post-streptococcal glomerulonephritis [9], and subepithelial “humps” are relatively common in type II mesangiocapillary glomerulonephritis [ 10,i 11. This suggests that type II mesangiocapillary glomerulonephritis could be an unusual form of immune complex disease, but the findings on immunofluorescent study do not support the suggestion. The usual findings along the basement membrane most probably represent a nonspecific fixation with no immunologic significance. However, the nature of the bright masses of C3 found in the mesangium in many patients is unknown. The recurrence of the material in allografted kidneys clearly indicates dependence on a humoral factor, and it is difficult to reconcile the suggestion of Galle and Mahieu [ 161 of a primary metabolic abnormality of basement membrane synthesis with this observation. Local activation of C3 by some as yet undescribed mechanism is possible, and the interesting association of type II mesangiocapillary glomerulonephritis with candidiasis [56] is worth noting, since Candida antigen activates complement via the alternative pathway. An additional patient with intravenous narcotic addiction associated with type II mesangiocapillary glomerulonephritis has been described also [ 57 1. The stimuli to proliferation, sclerosis, and progression are unknown.

REFERENCES 1.

2.

190

West CC, McAdams AJ, McGonville JM, Davis NC, Holland HG: Hypocomplementemic and normocomplementemic persistent (chronic) glomerulonephritis; clinical and pathologic characteristics. J Pediatr 1975; 67: 10891112. Cameron JS, Glasgow EF, Ogg CS, White RHR: Mem-

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3.

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branoproliferative glomerulonephritis and persistent hypocomplementemia. Br Med J 1970; 4: 7-14. Herdman RC. Pickering RJ, Michael AF, et al: Chronic glomerulonephritis associated with low serum complement activity (chronic hypocomplementemic glomerulonephriiis). Medicine (Baltimore) 1970; 49: 207-226.

IDIOPATHIC

4.

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