Journal of the American Society of Nephrology S159

Mesangiocapillary Glomerulonephritis

G. D’AmiCo1 and F. Ferrario

G. D’Amico, F. Ferrario, Division of Nephrology, SanCarlo Borromeo Hospital, Milano, Italy

(J. Am. Soc. Nephrol. 1992; 2:S159-Sl#{243}#{243})

ABSTRACTThe clinical and histological features of idiopathicmesangiocapillary glomerulonephritis (MCGN) havebeen reviewed, with a survey of the most recentliterature, including the retrospective analysis of thedata of the Italian Study Group of Renal Immuno-pathology on 368 patients. In both major types of

MCGN, six morphological variants have been char-acterized (classical MCGN, nodular MCGN, exuda-tive MCGN, focal segmental MCGN, MCGN with mas-sive deposits, and crescentic MCGN) that have dif-ferent etiologic, pathogenetic, or clinical outcomecorrelates. Actuarial renal survival 10 yr after renalbiopsy has been calculated with life-table analysisto be 60 to 65% in type I MCGN, without significant

differences between treated and untreated patients;none of the therapeutic regimens tested up to nowfor this disease have been independently demon-

strated to be efficacious. As for the pathogenesis,the interrelationships between the three mechanismsthat contribute to the development of the morpho-

logical features of the disease (accumulation of

electron-dense deposits on the subendothelial sideof the glomerular basement membrane or within theglomerular basement membrane; mesangial prolif-eration and peripheral interposition; and inflow of

inflammatory cells, mainly monocyfes) have beendiscussed, and the role of hypocomplementemia

and circulating nephritic factors (NFa and NFt) hasbeen analyzed. Available evidence suggests thatMCGN is an immunocomplex-mediated disease, thedeposition of immune deposits being the initiatingphenomenon, whereas the morphologic changesand complement system activation are secondaryevents.

Key Words: Idiopathic glomerulonephritis. subendothellal

deposits, hypocomplementemia, nephritic factors

I Correspondence to Dr. 6. DAmico, Division of Nephrolo9y, Son Carlo Borro-

meo Hospital, Via Plo H, 3, 20153 Milano, Italy.

1046-6673/02 10-5159$03.00/0Journal of the American society of NephrologyCopyright C 1992 by the American Society of Nephrology

T he term mesangiocapiblary gbomerubonephritis(MCGN), or alternatively membranoproliferative

GN, has been proposed for the histopathobogic entitycharacterized by: ( 1 ) intense gbomerular hyperceblu-

larity mainly due to mesangiab proliferation involvingboth cells and matrix; (2) thickening of peripheralcapillary walls by subendothebiab immune depositsand/or intramembranous dense deposits of unde-fined origin; (3) mesangial interposition into the cap-iblary wall, with splitting of the basement membrane(giving a “double contour” or “tramtrack” appearanceby light microscopy) and new formation of the sub-

endothebiab basement membrane. We prefer to callthis entity “mesangiocapillary GN,” because this des-ignation places emphasis on a basic diagnostic fea-

tures of the disease, namely the dependence of pe-ripherab capillary wall thickening on mesangiab in-

terposition.This entity includes forms of unknown cause (idi-

opathic MCGN) and forms associated with systemicand infectious disorders (Table 1 ). Therefore, it des-

ignates a morphologic pattern that needs to be inte-grated within an etiobogic context whenever possible.

MCGN is a rare disease, and its incidence seems tohave decreased in the developed countries of the

world over the past two decades (1 ,2). After a periodof intensive study at the end of the 1 960s and duringthe 1 970s, the interest of investigators in this diseasehas suddenly faded, in spite of the many remaining

questions.We will comment on some of these unresolved

questions, taking advantage of the experience of theItalian Study Group of Renal Immunopathology(ISGRIP), which has recently completed a retrospec-

tive analysis of the histologic and clinical features of368 patients with idiopathic mesangioprobiferative

GN, mainly adults (3). One of us (F. Ferrario) actedas Coordinator of the Group and did the morphobogi-cal review of the biopsy material for the entire pop-ulation of patients.

HISTOLOGY

Two major and distinct categories of idiopathic

MCGN have been identified, often referred to as typeI and type II (4-7). In type I, there are glomerubar

subendothebial immune deposits and duplication of

the peripheral gbomerubar basement membrane(GBM); in type II, dense homogeneous deposits ofmaterial occupy and expand the lamina densa ofmany renal basement membranes (gbomerubar, tu-

bular, and arteriobar). A variant of type I MCGN,

Mesangiocapillary Glomerulonephritis

5160 Volume 2 . Supplement 2 . 1992

TABLE I . Classification of MCGN�

PrimaryIdiopathic MCGN

Secondary (Associated with Other Diseases):Systemic immune complex disease

SiEEMC type II cryoglobulinemia

Chronic iiver DiseasesCirrhosis

Infectious DiseasesSubacute endocarditisHepatitis BMalariaSchistosomiasisinfected ventricuioatrial shunt

Neoplasmsieukemia and lymphoma

a Abbreviations: SLE. systemic lupus erythomatosus; EMC. essentialmixed cryoglobulinemia.

designated type III MCGN, has been described in thepast few years. It differs mainly in the simultaneouspresence of subendothelial and subepithelial depos-its, associated with the lamination and disruption of

the lamina densa of GBM (8-10).

In our opinion, the main classification must berestricted to types I and II to acknowledge the consid-enable ultrastructurab and probable pathogenetic dif-ferences between them. “Variant 3” could be regarded

as one end of a spectrum rather than as a separatetype, because epimembranous deposits are found in

both major types of MCGN (20% in the cases studiedby ISGRIP) and their numbers may vary in repeatbiopsies (1 1). The accurate analysis of the largeamount of biopsy material by the investigators of theISGRIP suggested that in both major types of MCGNthere are at beast six morphologic variants, with the

following different etiobogic, pathogenetic, or clinicaloutcome correlates.

“Classical” MCGN

“Classical” MCGN (Figure 1) demonstrates preva-lent and massive mesangial proliferation and mes-

angial matrix expansion. This form should also in-dude, as a subgroup, the “lobular” pattern character-ized mainly by more marked mesangial expansionoccluding the capillary bumina of some loops. (1 55 of329 patients with type I MCGN studied by the ISGRIPwere classified in this group.)

Nodular MCGN

Nodular MCGN is characterized by centribobubar

sclerosis of the expanded mesangium (Figure 2) andis always associated with microaneurysmatic diba-

tion of glomerular capillaries (Figure 3). This form,also presenting the disruption of anchoring points at

Figure 1. Classical pattern of MCGN. Massive mesangialproliferation and mesangial matrix expansion. Diffuse thick-ening of the capillary walls with double contour appear-ance. Trichrome, x250.

Figure 2. Nodular pattern of MCGN. Massive mesangialmatrix expansion with diffuse centrolobular sclerosis.Periodic acid-Schiff, x250.

Figure 3. Nodular pattern of MCGN. Microaneurismatic di-lation of glomerular capillaries and concentric expansionof mesangial matrix with nodules formation. Silver stain,x400.

D’Amico and Ferrario

Journal of the American Society of Nephrology S161

which peripheral capillary loop basement mem-

branes attach to mesangial stalks, and probably due

to a mesangiobytic process similar to that describedin nodular diabetic nephropathy (12), was found in

60 of 329 cases of type I MCGN studied by the ISGRIP.Many of the features that characterize type I MCGN

were present in these patients (e.g. , mild mesangialproliferation and segmental peripheral interposition

with thickening of the GBM, subendothebial depositswith the immunofluorescence (IF) pattern of “periph-eral lobular” deposition of C3 and immunogbobubin G

(IgG), hypocomplementemia in one third of the cases),suggesting that it is a variant of such GN. However,the Italian investigators think that it should be dis-tinguished from the “lobular” type I MCGN, becausethe morphogenetic mechanism of nodule formationwith concentric enlargement of the mesangiab matrix

is strictly associated with microaneurysmatic dila-tions developing for unknown reasons (more severe

mesangial damage with consequent mesangiolysis?more severe intracapiblary hypertension? more se-vere vascular damage?). Moreover, in none of the 17repeat biopsies from patients who had non-nodularvariants of MCGN in the first biopsy could any trans-

formation into the nodular pattern be identified, con-firming that this variant of MCGN is not the latesclerotic stage of the classic variant, as the lobular

pattern is.

Exudative MCGN

Although moderate infiltration of neutrophibs andmononuclear inflammatory cells is often present inthe classical form of type I MCGN, the infiltration ofinflammatory cells, mainly monocytes, was massivein 1 3% of the patients studied by the ISGRIP, whereas

mesangiab proliferation and peripheral interpositionwas less marked than in the “classical” type I. Sub-epitheliab deposits frequently coexisted with the sub-

Figure 4. Exudative pattern of MCGN. Clearly visible doublecontour aspect of thickened GBM due to interposition ofthe infiltrating inflammatory cells. Trichrome, x I .000.

endothebiab deposits, and the clearly visible “double

contour” aspect of the thickened GBM was due to the

subendothebiab interposition of the infiltrating in-flammatory cells rather than to mesangiab interpo-

sition (Figure 4). This variant of proliferative-exuda-tive GN, which closely resembles the morphologic

pattern of the secondary forms of bupus proliferative

GN, of cryogbobulinemic GN, and of the GN associatedwith other infectious diseases (subacute bacterial en-

docarditis, shunt nephritis, schistosomiasis, ma-lana), is not classifiable “sensu stricto” as an MCGN,if we agree that mesangial proliferation and periph-eral interposition, producing thickening and dupli-

cation of the basement membrane, are the hallmarks

of this GN. The frequent associations with an acutenephritic syndrome, macroscopic hematuria, andmarked hypocomplementemia at onset are also typi-cab of acute proliferative GN. However, the chronicclinical course, with persistent hypocompbemen-

temia, the immunohistobogic features of diffuse sub-endothelial deposition of C3 (and often also IgG or1gM), and the persistence of mesangiab activation inlater stages, when infiltrating blood-borne cells are

reduced in number, sharply differentiate this type of

GN from the acute postinfectious GN, and character-ize this morphological entity as a variant of MCGN.

Focal Segmental MCGN

In 1 3% of the patients in the ISGRIP study, themorphological features of the classical type I MCGNwere present, but they were restricted to segments ofthe gbomerular tuft. Some investigators tend to clas-sify this GN as a distinct entity (13,14). However,repeat biopsies showing that focal segmental gbomer-ular lesions could progress to diffuse MCGN and that,

when diffuse MCGN improves, it may pass through

the features of focal MCGN (1 5) suggest that segmen-

tab MCGN is a less aggressive disease or a stage ofless marked damage during the natural course of theclassical MCGN. The fact that the subendothebiabdeposition of C3 and IgG, seen by IF, is often diffused

to all tufts within each gbomerubus confirms thishypothesis.

GN With Massive Deposits

In a small number of the patients studied by theISGRIP (4%), the thickening of the GBM was due tosubendothelial massive deposits that could not be

classified as amyboid, bight chains, or cryogbobubins(Figure 5). The deposits seem, even by electron mi-croscopy, to be amorphous (Figure 6). The mesangiab

proliferation is very mild, but the IF pattern and thepersistent hypocompbementemia allow classification

of this GN as a variant of MCGN. Further studies arenecessary to characterize the composition of the ma-

teriab that accumulates in this GN.

Mesangiocapillary Glomerulonephritis

5162 Volume 2 . Supplement 2 #{149}1992

PATHOGENESIS

Figure 5. GN with massive deposits. Diffuse thickening ofGBM due to massive subendothelial and intraluminal de-posits. Trichrome, x250.

Figure 6. GN with massive deposits in subendothelial andintraluminal position. Subepithelial deposits are also evi-dent. Electron microscopy. x6,000.

Crescentic MCGN

In 2% of the patients with type I MCGN, coexistingeither with the classical lobular pattern or the nod-

ubar pattern, circumferential crescents were foundin more than 70% of gbomerubi at the time of biopsy,which was performed because of a clinical syndromeof rapidly progressive deterioration of renal function.It is well known that such a severe pattern can beseen in all types of idiopathic or secondary GN. It isworth emphasizing that although the variants de-

scribed above were selected from the large populationof patients with type I MCGN, a similar spectrum ofvariants might also be found in patients with type IIMCGN.

What is the interrelationship between the threemechanisms that seem to contribute to the develop-ment of the morphological features of MCGN: (1)

accumulation on the subendothelial side of the GBM(type I) or within the GBM (type II) of electron-densedeposits that are probably immune complexes (ICx)in the first type and deposits of undefined origin in

the second? (2) mesangial proliferation involving

both cells and matrix, with a tendency of the acti-vated mesangium to expand to the peripheral capil-lary walls and to interpose in the subendothebial

space, causing the specific splitting (“double contour”appearance) of the GBM? or (3) inflow of blood-borne

inflammatory cells, mainly monocytes?The accumulated experience with experimental

models of chronic immunecomplex-induced GN andwith humans, in whom ICx deposit on the internalaspect of the GBM (chronic infectious diseases, sys-temic bupus erthyomatosus, type II EMC), suggests

that deposits come first and are responsible for theother two mechanisms, a secondary activation of themesangium that expands to the periphery of capillarywalls with cytoplasmic extensions that engulf thedeposits, as well as the inflow of leukocytes. How-ever, these two mechanisms of defense are not nec-

essanily activated to the same extent. When we lookat the broad spectrum of lesions that can be associ-

ated with the protracted deposition of ICx and com-plement in humans, we see that in some cases (lupus,cryogbobubinemic GN, the exudative variant of idi-opathic MCGN), the prevaibing mechanism of defenseis the accumulation of monocytes and neutrophils inthe subendothelial space; this is also responsible for

the thickening and duplication of the GBM, withmesangial interposition being quite rare. At the otherend of the spectrum, as in the classical type I idi-

opathic MCGN, there is little or no cell influx, andmesangial activation with peripheral interposition is

the prevailing mechanism of defense.It is possible that not only the amount, but also the

nature and composition, of the subendothebiab depos-its accounts for the endothelial damage and the pre-vailing cytokine-mediated activation of mesangium

or inflammatory cells, mainby monocytes. It is also

possible that the recruitment of monocytes and pob-ymorphonuclear cells is the prevaibing mechanismwhen immune complexes are deposited acutely onthe subendotheliab aspect of the GBM, whereas mes-angial activation and peripheral interposition are a

later, more chronic phenomenon, favored by the cy-tokine-mediated stimulation of resident gbomerular

cells induced by the infiltrating monocytes. However,in some circumstances (cryogbobulinemic GN and

some cases of idiopathic MCGN), monocyte infiltra-tion can be demonstrated even in less-acute stages

D�Amico and Ferrario

Journal of the American Society of Nephrology 5163

of the disease, in the absence of evident mesangial

interposition.When immunocomplexes are deposited on the in-

ternab side of the GBM, it can be postulated thatmesangiab interposition is a consequence of such

deposition of complement and immunoglobubins. Theregression of the mesangial expansion when exoge-nous bacterial antigens are eliminated from the body,as in shunt nephritis, confirms this hypothesis. How-

ever, it is more difficult to believe in it when theinterposed mesangium contains no deposits or when

such deposits stain only with complement, withoutaccompanying immunogbobulins. It is possible thatother mechanisms of injury of the capillary wall,

especially if they induce endotheliaJ damage and its

detachment from the basement membrane, may alsoeventually stimulate the accumulation of plasma pro-teins and the ingrowth of the mesangium in theresulting subendothebial space, independent of thepresence of deposits in such space (16).

A very characteristic feature, when the sequenceof immunopathogenetic events described above (i.e.,

long-term accumulation of electron-dense deposits inthe context or on the internal aspect of the GBM,recruitment of monocytes, and chronic mesangialactivation with peripheral interposition) take place is

the frequent coexistence of a protracted hypocomple-mentemia. In idiopathic MCGN, the association withbow complement bevels is so frequent that this GNhas also been calbed “hypocomplementemic GN.”

However, the cause of hypocomplementemia in idi-opathic and secondary MCGN, its relationship to thepathogenesis, and its possible role in perpetuating

the gbomerular disease are still obscure. We also donot yet understand why in some cases (type II idi-

opathic MCGN) the activation of the alternative path-way is the prevailing phenomenon, whereas in other

cases (type I idiopathic MCGN, lupus nephritis, cry-oglobubinemic GN, shunt nephritis), there is activa-tion of the classical pathway.

Similarly, it is unknown whether the hypocomple-mentemia is always a secondary phenomenon, de-

rived from increased consumption triggered by sub-

endotheliab or intramembranous deposits, or whetherit may precede such deposition and favor it. This

latter hypothesis was proposed many years ago (17-1 9), because patients with MCGN have an increased

incidence of inherited deficiencies of various comple-ment components, and such deficiency could impairclearance of antigen-antibody complexes in responseto viral or bacterial infections, leading to increasedrenal deposition and to the development of GN.

The rarity of such inherited deficiencies in MCGN,

the fact that MCGN can occur and progress withoutconcomitant hypocomplementemia, and the findings

that low complement levels may normalize in pa-

tients with idiopathic hypocomplementemic MCGN

after renal transplantation, only to accompany the

recurrence of the disease in the transplanted kidneyand that the GN can recur after transplantation even

in some patients who had normal complement pro-files before transplantation (20), suggest that the

capillary wall changes come first and that hypocom-

plementemia is a consequence of the gbomerular dis-ease.

It has been recently demonstrated that the gbomer-

ulus of patients with idiopathic MCGN is a trigger ofthe alternative activation pathway in vitro (21). How-ever, there is no evidence that complement activationIn sttu in the gbomerulus actually affects the serumlevels of components of the system. Instead, it is nowevident that hypocomplementemia can be ascribedto at beast two circulating compbement-reactive mo-dalities: ( 1 ) the activation of the classical pathwayproduced by circulating immune complexes and (2)

the presence in the blood of anticompbement auto-antibodies, called “nephnitic factors” (NF) (22-26). Atbeast two nephritic factors have been described, onethat acts on the amplification loop of the complementcascade (NFa) and the other that acts on the terminal

pathway (NFt). The activation of the classical path-way by circulating immune complexes is probablythe major mechanism responsible for hypocomple-mentemia in idiopathic type I MCGN, in lupus ne-

phritis, and in shunt nephritis, whereas the effect ofthe circulating nephritic factor of the amplificationloop (NFa) is probably the major mechanism respon-sible for the hypocompbementemia of type II idi-opathic MCGN (22). However, nephritic factors aresometimes found in sera of patients of the formergroup (23). Even among patients with type I idi-

opathic MCGN, different circulating complement-re-active modalities may be set into operation and hy-pocomplementemia may be multifactorial in origin,

the classical pathway being activated in some; inothers, the presence of the nephritic factors NFt orNFa might better explain the abnormalities of the

serum complement profile (23). In other words, dif-ferent nephritic factors can be present in the samemorphological type of MCGN, and the same nephritic

factor can coexist in heterogeneous types of MCGNwith quite different abnormalities of gbomerular ul-trastructure, such as type I and type II idiopathicMCGN.

To make things more complicated, neither circu-bating nephritic factors nor hypocomplementemiaper se appears to be correlated with the clinicalcourse of the different types of primary or secondary

MCGN (27-29); therefore, they are not of value formonitoring the course or predicting the final outcome

and, when persistently present, can only be consid-ered markers of this group of gbomerular diseases.

Obviously, even in idiopathic MCGN, as in most

diseases of immunologic origin including a number

Mesangiocapillary Glomerulonephritis

Sf64 Volume 2 ‘ Supplement 2 . 1992

of gbomerubonephritides, genetic predisposition hasbeen investigated by looking at the major histocom-

patibility complex on the short arm of chromosome6, which includes the genes coding for the determi-nants of the human leukocyte antigens A, B, C, andD regions, as well as the complement protein factors

B, C2, C4A and C4B. It has been recently reported

that the extended hapbotype human leukocyte anti-gen B8, DR3, SCO 1 , GLO2 is significantly more fre-

quent in patients with type I MCGN than in normalcontrols (30) and that patients with this extended

hapbotype had a higher incidence of renal insuffi-

ciency than did those without it. These data arecompatible with the presence of a gene on this ex-tended hapbotype that predisposes to type I MCGN. Itis not yet known whether patients with type II MCGNhave the same increased frequency.

NATURAL HISTORY AND TREATMENT

In recent years, studies of the bong-term course ofidiopathic MCGN have been carried out in a smallnumber of patients because of the rarity of the dis-ease. All of these studies indicated that the prognosis

is generally unfavorable, but they did not clarify

which factors may adversely influence the progres-sion to end-stage renal failure.

In 1990, two mubticenter studies, one from Ger-many (3 1 ) and the other from the ISGRIP (32), ana-

byzed the bong-term prognosis of sufficiently largepopulations of patients with type I MCGN: 220 pa-tients in the German study, and 259 patients in the

TABLE 2. Renal function at the end of follow-up intwo retrospective multicenter studies in patientswith idiopathic type I MCGN#{176}

Schmitt et a!.(1990)(31)

ISGRIP(1990)

No. of Patients 220 259Patients with <15 yr at 5.5 13.2

Onset (%)Mean Duration of Follow-

Up (months)From the time of biopsy 59 60From apparent onset 83 78

Patients With Normal 27 40Renal Function (i�)

(%)Patients With Impaired 25 29

Renal Function (%)Patients With End-Stage 26 26

Renal Failure (RDT orTransplantation) (%)

Patients who Died (%) 22 5

a (Lx) Serum creatinine �1.3 in the German study. �1.5 in the Italianstudy.

Italian one (Table 2). Both were mainly adult popu-bations: only 5.5% of the German patients and 13.2%

of the Italian patients were younger than 1 5 yr at thetime of biopsy. The duration of follow-up was 59

months on average (median, 50 months) from thetime of biopsy, 83 months (median, 60 months) from

the apparent onset in the German study, and 60(median, 42 months) and 78 months (median, 72

months) in the Italian study. At the end of this obser-vation period, only 27 and 40% of patients main-

tamed a normal renal function, whereas 22 and 5%had died; the calculated acturial renal survival 10 yr

after renal biopsy was 64% in the German and 60%in the Italian populations of patients with type IMCGN. The ISGRIP study also showed no differencein renal survival in comparison with 28 patients withtype II MCGN similarly analyzed.

In both studies, the values of many clinical andhistologic parameters as prognostic indicators were

tested. Even though the choice of the parameters toevaluate and the statistical methods used for theunivariate and multivariate analyses were not com-pletely comparable, the results obtained were rather

similar (Table 3). In the Italian study, but not in the

German one, the severity of proteinuria appeared tobe a bad prognostic sign. The importance of theinterstitial damage (inflammatory infiltration and/or

fibrosis) as a prognostic indicator deserves some com-ment. As already shown for membranous nephropa-

thy (33), IgA nephropathy (34,35), and focal gbomer-uboscberosis (36), in MCGN (31), too, it can be hypoth-esized that the existence of a cell-mediatedmechanism of interstitial damage, partly independ-

ent of the concomitant glomerular damage (eventhough possibly triggered by it), is probably respon-

sibbe for the progression of the disease to end-stagerenal failure (37,38). In the two studies, differentcriteria were adopted to classify the varioussubgroups of patients according to the extent andtype of gbomerular damage, and to evaluate the rela-tive risk of renal death by the actuarial survival

TABLE 3. Clinical and histologic parameters thatwere associated with a less favorable outcome intwo large cohorts of patients with idiopathic type IMCGN

Schmitt et a!.(1990)(31)

ISGRIP(1990)

Elevated Serum Creatinine Yes YesHypertension Yes YesHeavy Proteinuria No YesGlomerular Sclerosis No NoInterstitial Damage (Infiltra- Yes Yes

tion of Cells and Fibrosis)Arteriolar Hyalinosis Not Evaluated Yes

D’Amico and Ferrario

Journal of the American Society of Nephrology S165

curves of the Kaplan and Meyer methods. Therefore,

the results of the analyses are difficult to compare.In the German study, renal survival was compared

in five subgroups corresponding to five grades ofincreasingly severe gbomerular changes. Only

subgroup 5 with crescents was associated with aworse prognosis, in comparison with the other four

subgroups, in which segmental, classical, and bobu-bar variants were included (nodular pattern was not

considered to be a separate subgroup). In the Italianstudy, both the crescentic and the nodular variantshad a significantly worse prognosis than did the clas-

sicab lobular variant, the focal segmental variant, the

exudative variant, and the variant characterized bymassive subendotheliab deposits.

In both studies, actuarial renal survival was cab-

culated separately for the subgroups of treated anduntreated patients (52 versus 38% of patients in theItalian study; 57 versus 43% in the German study),

including among the treated patients, all of thosegiven anti-inflammatory (steroids or nonsteroidabanti-inflammatory drugs) and/or cytotoxic (cycbo-

phosphamide or azathioprine) drugs for at least 2

months. No difference between treated and untreated

patients could be found. Although, in the treatedgroup, the different patients were given differenttypes and combinations of drugs for variable periods

of time, the results of this rough retrospective statis-tical analysis confirm the general impression that

the above-listed classes of drugs do not have a de-monstrable effect on the progression of idiopathic

MCGN. The ISGRIP is now completing a multicenterrandomized trial to confirm the efficacy of antiplate-

let agents (ticbopidine is being tested), shown in 1984by Donadio et a!. (39) in a relatively small number of

patients with the combination of dipyridamole plusaspirin.

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24. Clardy CW, Forristal J, Strife CF, et at. : Aproperdin dependent nephritic factor slowly ac-tivating C3, C5, and C9 in membranoprobifera-tive gbomerubonephritis, types I and III. Clin Im-munob Immunopathob 1 989;50:333-347.

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27. McEnery PT, McAdams AJ, West CD: The effectof a high dose alternate day prednisone regimenon the natural history of membranoproliferativegbomerubonephritis. Medicine 1 985;64:401 -424.

28. Vallota EH, Forristal J, Davis NC, et al.: TheC3 nephritic factor and membranoprobiferativenephritis: Correlation of serum levels of the ne-phritic factor with C3 bevels, with therapy andwith progression of the disease. J Pediatr1972;80:947-959.

29. Schena FP, Pertosa G, Stanziale P, Vox E, Pe-coraro C, Andreucci V: Biological significanceof the C3 nephritic factor in membranoprolifer-ative gbomerubonephritis. Clin Nephrol 1 982; 18:240-246.

30. Welch TR, Beischel L, Balakrishnan K, Quin-lan M, West CD: Major-histocompatibility-com-

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3 1 . Schmitt H, Bole A, Reineke T, Mayer-Eichber-ger D, Vogi W: Long-term prognosis of mem-branoprobiferative gbomerubonepliritis type I. Ne-phrob 1 990;55:242-250.

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33. Alexopoulos E, Seron D, Hartley RB: Immunemechanisms in idiopathic membranous neph-ropathy: The robe of the interstitial infiltrates.Am J Kidney Dis 1 989; 13:404-412.

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35. Alexopoulos E, Seron D, Hartley RB: The robeof interstitial infiltrates in IgA nephropathy: Astudy with monocbonal antibodies. Nephrol DialTransplant 1 989;4: 187-195.

36. Wehrmann M, Boffle A, Held H, et at. : Long-term prognosis of focal scberosing gbomerubo-nephritis. An analysis of 250 cases with partic-ubar regard to tububo-interstitiab changes. ClinNephrol 1990;33:1 15-122.

37. D’Amico G: Role of interstitial infiltration ofleukocytes in gbomerular disease. Nephrob DialTransplant 1 988;3:596-600.

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39. Donadio JV Jr, Anderson CF. Mitchell JC:Membranoprobiferative gbomerubonephritis: Aprospective clinical trial oT platlet-inhibitor ther-apy. N Engl J Med 1984;310:1421-1426.