Glomerulonephritis with mesangial depositsof IgA unassociated with systemic diseaseAllan Katz, md, cert path; Brian J. Underdown, ph d; Joe O. Minta, ph d; Irwin H. Lepow, md, ph d

Typical features of IgA-associated nephritis were found inrenal biopsies from 16 of 355 consecutive patients.Generalized segmental mesangial proliferationwas noted in biopsies from most patients, and densedeposits were detected by electron microscopy in mesangialregions of approximately 50% of biopsies. Immunofluorescentstudies showed IgA to be the predominant immunoglobulinin glomeruli; IgG was present in less than 50% ofbiopsies and IgM in only 12%. The serum IgA value was

significantly increased (P < 0.001) in 50% of patientsand the mean IgA/IgG ratio was significantly increased(P < 0.001) for the patient group as a whole, which suggestsa selective increase in IgA. Mesangial deposits of C3 were

present in 15 of 16 biopsies and properdin was notedin all biopsies tested; C4 was not demonstrated in anybiopsy. This suggests activation of the alternativecomplement pathway. The results of this studysupport the concept that IgA-associated nephritis is a

unique condition that in some patients gives rise to idiopathicrecurrent hematuria. Although the prognosis is good inthe majority of patients, the renal disease may progress.

Les caracteristiques types de la nephrite associee aux

IgA ont ete retrouvees dans les biopsies renales de16 patients sur une serie totale de 355 patients consecutifs.Une proliferation segmentaire generalisee du mesangiuma ete observee dans la biopsie de la plupart des patients,et des depots denses situes dans les regions dumesangium ont ete detectes au microscope electroniquedans environ 50% des biopsies. Les etudesd'immunofluorescence ont demontre que lesimmunoglobulines predominantes dans les glomerulesetaient les IgA; les IgG etaient presentes dans moinsde 50% des biopsies et les IgM dans seulement 12%.Les valeurs d'lgA seriques etaient augmentees de faconsignificative (P < 0.001) chez 50% des patients et le rapportmoyen Iga/IgG etait significativement augmente (P < 0.001)pour I'ensemble des patients, ce qui indique une

augmentation selective des IgA. Des depots de C3 dansle mesangium ont ete retrouves dans 15 des 16 biopsies

From the department of pathology, St. Michael's Hospital, Toronto;the department of medical genetics and medicine, Institute ofImmunology, University of Toronto; the division of experimentalpathology, department of pathology, University of Toronto; and thedepartment of medicine, University of Connecticut Health Center,Farmington, CT

Reprint requests to: Dr. A. Katz, Department of pathology, St. Michael'sHospital, 30 Bond St., Toronto, ON M5B 1W8

et la properdine etait presente dans toutes les biopsiestestees; la fraction C4 n'a pu etre demontree dans aucune

biopsie. Ceci suggere une activation de la deuxiemeroute du complement. Les resultats de cette etudesoutiennent le concept voulant que la nephrite associeeaux IgA soit une affection unique qui chez certains patientsdonne lieu a une hematurie idiopathique a repetition.Bien que le pronostic soit bon dans la majorite descas, cette affection renale peut prendre un caractereevolutif.

The clinical condition idiopathic recurrent hematuria maybe associated with diverse pathologie and immunohisto-chemical findings in the kidney and undoubtedly includesa heterogeneous group of diseases.1One such condition is IgA-associated nephritis, first de¬

scribed by Berger.2 In addition to persistent microscopichematuria, and often recurrent episodes of gross hematuria,the characteristic features of this disease include mesangialdeposits of IgA and C3 in biopsies and dense depositsdetected by electron microscopy. The demonstration ofother immunoglobulins in glomeruli has varied in differentstudies, as has the histologic appearance, incidence andclinical course.3"6The following study of all patients from 10 metropolitan

Toronto hospitals during 1971-73 with IgA in glomerulibut no systemic disease or well recognized pathologie con¬

dition was undertaken to clarify some of the above featuresand to determine the prognosis. Also, serologic and com¬

plement studies were carried out to investigate the patho¬genesis of the renal disease.

Materials and methods

Immunopathologie methods ,

Needle and wedge biopsies of kidney were examinedby light microscopy, the direct immunofluorescent (DIF)technique7 and electron microscopy. Details of these meth¬ods have been described.8'9

Secretory component studiesRabbit antiserum to human secretory component (SC)

was prepared as described elsewhere.10 The antiserum wasmade specific for SC by absorptions with an IgA myelomadimer conjugated to Sepharose 4B, normal human serum

conjugated to Sepharose 4B and soluble lactoferrin. Theabsorbed antiserum gave a single line when tested by

CMA JOURNAL/FEBRUARY 7, 1976/VOL. 114 209

immunoelectrophoresis with whole human whey and re-acted with both isolated SC and human secretory IgA.SC in renal biopsies was demonstrated by the indirect

immunofluorescent (IIF) method with fluorescein-conjug-ated sheep antirabbit IgG prepared by the method ofBeutner, Sepulveda and Barnett.11 The conjugate had a

fluorescein:protein (F/P) molar ratio of 2 and was usedat a dilution of 1:8 in phosphate-buffered saline (PBS). Theanti-SC antiserum was used at varying dilutions from un-diluted to 1:20 after absorption with human group ABerythrocytes. To increase the possibility of demonstratingSC in renal biopsies the tissue was reduced with 0.01 Mdithiothreitol in 0.1 M TRIS hydrochloride, pH 8.0, thenalkylated with 0.022 M iodoacetic acid. Human large andsmall intestinal biopsies were used as positive-strainingcontrols.

Measurement of serum globulinsConcentrations of IgG, IgA and IgM were quantitatively

determined in serum by radial immunodiffusion (immuno-plates from Hyland Laboratories, Los Angeles, California).IgE concentrations were determined by double-antibody ra¬

dioimmunoassay (RIA) by the method of Gleish, Averbeckand Smedlund,12 with mI-IgE isolated from myeloma serum

(kindly supplied by Dr. R. Mclntyre, Dartmouth, NewHampshire). Secretory IgA concentrations in serum weredetermined by a standard double-antibody RIA method.13Sera were stored at .20° or at .70°C until tested.

Complement studiesConcentrations of C3 and C4 in serum were quantita¬

tively determined by radial immunodiffusion (immunoplates

and standards from Meloy Laboratories, Springfield, Vir-ginia). C4 was demonstrated in renal biopsies with fluor-escein-conjugated goat antiserum to human C4 (Meloy Lab¬oratories) by the DIF method. The conjugate gave a singleprecipitin line when reacted in agarose against normal hu¬man serum and a line of identity with purified human C4at 1 mg/ml. Normal human kidney tissue from a patientundergoing partial nephrectomy for renal calculi was usedas a negative-staining control and biopsies from two patientswith lupus nephritis were used as positive-staining controls.C3PA (properdin factor B) was estimated in serum byradial immunodiffusion (immunoplates and reagents fromCustom Reagent Laboratories Incorporated, San Diego,California).

Properdin was demonstrated in kidney biopsies by theIIF method, as described by Rothfield and colleagues,14by means of a rabbit antiserum to purified human proper¬din, prepared as described elsewhere,15 and fluorescein-conjugated sheep antirabbit IgG. The antiserum was ab¬sorbed with human RP (normal human serum renderedproperdin-deficient by incubation with zymosan at 17°Cfor 1 hour) before use.16 Normal human kidney was usedas a negative-staining control and biopsies from three pa¬tients with membranoproliferative nephritis and two patientswith lupus nephritis were used as positive-staining controls.

Results

Clinical dataGlomerular deposits of IgA were found in 61 patients

from a total of 355 consecutive renal biopsies. Patients wereremoved from the study for the following reasons: insuf-

Table I.Clinical and laboratory findings in 30 patients with glomerular deposits of IgA

'"Serum creatinine (creat.), mg/dl; blood urea nitrogen (BUN), mg/dl; creatinine clearance (Ccr), ml/min.fReceiving prednisone therapy.{"Essential hypertension for 10 years".210 CMA JOURNAL/FEBRUARY 7, 1976/VOL. 114

ficient biopsy material (5), end-stage renal disease on biopsy(7), systemic diseases (10), renal allografts (3), membrano¬proliferative nephritis (4), membranous nephritis (1) andpoststreptococcal nephritis (1). The remaining 30 patientswere divided into two groups (Table I).Group I consisted of 16 patients (mean age, 29 years;

male:female ratio, 13:3) with mild histologic abnormalitiesin the biopsy specimen, who were normotensive and didnot have the nephrotic syndrome or persistent functionalimpairment at the time of initial presentation. All had mi¬croscopic hematuria at the time of biopsy and nine had hadone or more episodes of gross hematuria as well. Sorethroat or upper respiratory tract infection either precededor accompanied hematuria in four patients.

FIG. 1.Patient 12: Increase in mesangial matrix with localhypercellularity (periodic acid-Schiff [PAS]; originalmagnification, x300).

Group II was composed of 14 patients (mean age, 34years; male:female ratio, 1:1) with more severe histologicabnormalities, or hypertension or some degree of functionalimpairment. Hematuria was noted in 12 patients and in 6it was gross. An upper respiratory tract infection wasdocumented in two patients. An elevated antistreptolysin-Otitre was not found in any patient. Results of antinuclearantibody testing were negative in all patients and LE cellswere not found in any of the nine patients tested.A family history of renal disease was obtained in only

one patient (no. 26).Pathologie findingsThe terminology of Muehrcke and colleagues17 is used

as follows:. Generalized: all or almost all glomeruli affected.. Focal: only some glomeruli affected.. Diffuse: the entire glomerulus affected.. Local or segmental: only one or more areas of a

glomerulus affected.Group I: The commonest finding was a generalized seg¬

mental increase in mesangial matrix with or without in¬creased cellularity (Fig. 1), defined as the presence of fouror more cells in a mesangial region.6 Focal, segmental mes¬

angial lesions were seen in three biopsies. One biopsy ap¬peared normal by light microscopy. A rare localized area offibrinoid necrosis was noted in glomeruli of one patient andan occasional glomerular fibrin thrombus was seen inanother. Hyalinization of approximately 25% of glomeruliwas noted in one biopsy (patient 12).

Biopsies of 15 patients were examined by electron micro¬scopy. All showed localized increases in mesangial matrixand, in some cases, in mesangial cells. Dense deposits werepresent in the mesangium in eight biopsies (Fig. 2) and a

single intramembranous dense deposit was also seen in one

biopsy (patient 7). Questionable rare dense deposits were

present in the mesangium in three biopsies (patients 2, 6and 16). The biopsies of four patients (nos. 1, 3, 4 and 10)did not contain any deposits.Group II: Generalized local mesangial proliferation was

found in biopsies of 11 patients, five showing diffusemesangial lesions in some glomeruli as well (Fig. 3). Only

FIG. 2.Patient 9: Electron-dense deposits in mesangialregion (original magnification, x 100 000).

FIG. 3.Patient 23: Diffuse proliferation of mesangialmatrix and cells (PAS; original magnification, x480).

CMA JOURNAL/FEBRUARY 7, 1976/VOL. 114 211

focal, segmental mesangial lesions were noted in three biop¬sies. Approximately one third of glomeruli were totallyhyalinized in four biopsies. Moderate to severe focal tubularatrophy and interstitial fibrosis were noted in eight biopsies.Other glomerular lesions seen were small epithelial crescents,adhesions, rare fibrin thrombi in capillaries and focal fi¬brinoid necrosis in the biopsy of one patient (no. 23).

Electron microscopic studies revealed dense deposits inthe mesangial region in 10 of 14 biopsies, with occasionalsubendothelial deposits in two biopsies. No deposits wereseen in the biopsies of two patients (nos. 20 and 27), andin two other biopsies (patients 18 and 22) questionable de¬posits were seen. Interposition of the mesangium betweenthe basement membrane and the endothelium was seen inan occasional glomerular capillary in biopsies from twopatients.

Immunofluorescent studies

Results of direct immunofluorescent studies are summar¬ized in Table II. In both groups generalized, diffuse mesan¬

gial deposits of IgA were detected in all biopsies (Fig. 4).IgG was present in less than 50% of biopsies and IgM inonly 12%. The relative intensity of staining was consistentlystronger for IgA than for the other immunoglobulins exceptin patient 26; this was never the case in biopsies frompatients with lupus nephritis and was rare in other biopsies(one patient with membranoproliferative nephritis and one

patient with cirrhosis and chronic nephritis).FIG. 4.IgA deposits in mesangial regions of glomerulus(direct immunofluorescent stain; original magnification, xl60).

Table II.Results of direct immunofluorescent studies* in the 30 patients

'"Intensity of staining graded from 0 to 4 + in a diffuse mesangial distribution unless otherwise stated.ND= not done.

212 CMA JOURNAL/FEBRUARY 7, 1976/VOL. 114

IgGIgAIgMIgA/IgGIgM/IgG

1361416148

0.3190.118

± 357± 185±57± 0.14± 0.06

1116440120

0.3970.103

± 328± 125±70±0.06± 0.03

1153233136

0.2100.127

± 234± 96±78± 0.087± 0.099

0.010.001

>0.050.001

>0.05

>0.050.001

>0.050.001

> 0.05

?Calculated by Student's /-test for significance of difference between mean values of patient and control groups.fA group of 30 male and 30 female healthy individuals; values determined 2 years before the study.

Secretory componentSC was not detected in glomeruli of any biopsy tested;

in group I 13 of 16 biopsies were tested and in group II,6 of 14. Positive staining of tubular epithelium was seenin some biopsies. Controls showed positive staining forSC along the luminal borders of intestinal glands andsurface epithelium. No staining of intestinal plasma cellswas seen, however.

Serum globulinsMean values for patient groups I and II and a control

group are shown in Table III; estimations were done in15 of 16 patients in group I and 6 of 14 in group II. Onlyone patient (no. 26) was receiving any medication (pred¬nisone). Compared with the control mean values, the IgGmean value was significantly increased in group I (P < 0.01)and the IgA value in groups I and II (P < 0.001), butthe IgM values were not significantly different. IgG valueswere elevated in three patients in group I and in one patientin group II. IgA values were above the 95% normallimit in eight patients in group I and three in group II.The mean IgA/IgG ratio was also significantly increased(P < 0.001) in groups I and II but the IgM/IgG ratiowas not. In three patients of group I and three patientsof group II IgA/IgG ratios were elevated. In contrast, IgMvalues and IgM/IgG ratios were within the normal rangein all patients.

FIG. 5.Properdin in mesangial regions of glomerulus(indirect immunofluorescent stain; original magnification, xl60).

The mean secretory IgA value in the serum in six patientsof group I was 11.8 ± 0.84 ng/ml not significantlydifferent from the mean value in serum from a group of14 healthy individuals (9.7 ±3.6 ng/ml). In contrast, themean value in three patients with ulcerative colitis was

significantly elevated (P < 0.001), at 23.3 ± 7.4 ng/ml.Complement studiesSerum C3 values were normal in 11 patients and elevated

in 2 patients from group I (mean, 170 ± 44 mg/dl) andnormal in 3 patients tested from group II. Serum C4 valueswere within the normal range in seven patients tested, sixfrom group I and one from group II (mean, 35 ± 9 mg/dl).C4 was not demonstrated in glomeruli of any biopsy tested(nine patients from group I and one from group II).Control biopsies from two patients with lupus nephritisshowed strongly positive glomerular staining.

Properdin studiesC3PA values in serum were normal in six patients and

elevated in one patient from group I and normal in twopatients from group II. A decreased value was not foundin any patient. The mean value was 249 ± 29 /xg/ml.

Properdin was demonstrated in mesangial regions ofglomeruli (Fig. 5) in nine biopsies tested from patients ingroup I and in six biopsies from more recent, similar cases.The distribution of staining was similar to that of IgA.Control sections of normal human kidney gave negativeresults, as did sections in which PBS and normal rabbitgamma globulin were substituted for antiproperdin serum.

Follow-upGroup I: Information was available from 12 of 16 pa¬

tients. The mean duration of follow-up from the onset ofdisease was 43 months (range, 7 to 132 months). Allpatients in this group had normal renal function and theurinary sediment showed evidence of active glomerulo¬nephritis with persistent microscopic hematuria. Either pro¬teinuria was absent or less than 1 g/d of protein was beingexcreted. Borderline elevation of diastolic blood pressurewas noted in two patients (nos. 6 and 12) after a follow-upof 30 and 132 months, respectively. One patient had anelevated urine uric acid value and another had a depressedserum C3 value on two occasions, associated with recur¬rence of gross hematuria. One patient (no. 12) had inter¬mittent edema.

Group II: Information was obtained from 10 of 14patients. The mean duration of follow-up was 33 monthsfrom the onset of disease (range, 4 to 62 months). A slightdecrease in creatinine clearance was noted in two patients(nos. 21 and 28) after 28 and 24 months, respectively. Theurinary sediment of seven patients showed evidence ofactive glomerulonephritis and one patient (no. 23) followedfor 41 months had severe proteinuria (> 3 g/24 h). Bloodpressure was elevated in five patients (nos. 20, 21, 25,28 and 30) from 12 to 62 months after the onset of diseaseand was borderline in two others (nos. 17 and 26). Also,

CMA JOURNAL/FEBRUARY 7, 1976/VOL. 114 213

two patients had increased values for serum and urine uricacid.

Discussion

Our findings reaffirm the generalized nature of thepathologic process in most cases of IgA-associated nephritisand the variable frequency with which IgG and 1gM canbe demonstrated, which is in agreement with previousreports.3'5

The patients in group I account for approximately 4.5%of all cases of glomerulonephritis in our renal biopsy series.In previous reports from France and the United States theincidence of IgA-associated nephritis has varied from 2to 18% *2,4 The reasons for this variability are probablyrelated to differences in the criteria used for patient se-lection.

The similarities in clinicopathologic, immunofluorescentand serologic findings between groups I and II suggest thatsome of the patients in group II may have belonged ini-tially to group I. In two of our patients from group I,borderline elevations in diastolic pressure, with intermittentedema in one of the two, have developed on follow-up.Progression of renal disease has also been documentedpreviously by serial biopsies.5

Biopsy features in our patients that appear to be asso-ciated with a less favourable prognosis are a large per-centage of hyalinized glomeruli, moderate to severe tubularatrophy and diffuse glomerular lesions.

In this report, as well as in previous ones,3'5"8 IgA hasbeen the predominant immunoglobulin in glomeruli bothin frequency of occurrence and relative intensity of staining,although in one study of persistent or recurrent hematuria61gM was found more frequently. However, in the latterinstance immunofluorescent studies were done in only ap-proximately 30% of patients.

Unresolved questions in the pathogenesis of IgA-asso-ciated nephritis concern (a) the nature of the IgA in thekidney, (b) the reason for its localization in the mesangiumand (c) the possible relation of IgA to renal damage.The nature of the IgA in the glomeruli has been sug-

gested as antigen-antibody complexes,"5'8'.9 secretory IgA,'4IgA aggregates,3'19 or nonspecific deposition as a conse-quence of injury.19 To date there is no direct proof for thepresence of IgA antigen-antibody complexes in this condi-tion. Infectious agents, including viruses,'0 have been sug-gested as possible antigens, although none have been de-monstrated. Lowance, Mullins and McPhaul' were unableto find anti-IgA antibodies in the serum by agglutination ofIgA-coated erythrocytes. Also, when biopsies were testedby immunofluorescence with fluorescein-conjugated IgG nobinding was detected, which suggests that IgA in glomeruliwas not an antibody to IgG.We were unable to demonstrate SC in glomeruli, as was

also the case in a previous study.3 Weak staining for SCin biopsies from an occasional patient has been reported.4'3The association of upper respiratory tract infections withboth onset and exacerbations of renal disease suggests amucosal origin of renal IgA. But we did not find elevatedserum secretory IgA values in six patients tested, althoughthis does not rule out a mucosal origin for either the serumIgA or the glornerular deposits of IgA.

The elevation of the mean serum IgA value, together withan increase in the mean IgA/IgG ratio of patients in groupsI and II, indicates a preferential increase in IgA. A similarfinding has recently been reported by others.18"1 IgA hasalso been reported to be increased in nasal secretions ofseveral patients with IgA-associated nephritis.'8The elevated IgA values could be explained by antigenic

stimulation or a genetic predisposition to the preferential

production of antibodies of this class, or both. Furtherstudies will be necessary to clarify this point. Elevationsin concentration of serum IgA have been previously re-ported in anaphylactoid purpura,22 and familial thrombocyt-openia and nephritis.23 Nonspecific presence of IgA second-ary to glomerular injury is unlikely in view of its consistentlocalization, its occurrence alone in some cases withoutother immunoglobulins, and the relatively greater intensityof staining for IgA.

Several possible explanations for the mesangial localiza-tion of immunoglobulins in this condition have been sug-gested from the results of animal experiments; these includethe formation of complexes in antibody excess,. the forma-tion of large complexes,. the presence of high-affinity pre-cipitating antibodies26 and the formation of aggregates.27Another possibility is formation of antibody with specificityfor mesangial components. In this regard, a kidney eluatefrom a patient with IgA nephritis was found to localize inthe mesangium of normal human kidney.3When serum from our group I patients was tested against

normal human kidney by the hF method immunoglobulinwas not detected. There is no good evidence that any ofthe above mechanisms are involved in the mesangial local-ization of IgA in this condition.The final consideration in the pathogenesis is the way

in which renal damage could be mediated by IgA. Thedeposition of properdin and the absence of C4 in glomerulinoted in this study and in others2'19 are compatible withactivation of the complement system by the alternativepathway. Also, aggregated IgA-myeloma proteins have beenreported to activate the alternative pathway in vitro.28 Thealternative pathway has been implicated in acute poststrep-tococcal, membranoproliferative, lupus, and focal nephritisin one patient whose serum IgA was found to activate C3,C5 and C7 in the cold.29'30The lack of depression of serum concentrations of C3,

C4 and C3PA in most patients may reflect either slowconsumption, increased synthesis or transient depression ofcomplement components. In one of our patients C3 wasdepressed twice, during exacerbations of renal disease. Pre-vious reports3'2 have described several patients with lowserum C3 values.The association of IgA deposits in both renal31 and skin

diseases32 with components of the alternative complementpathway, often with elevated serum IgA values, suggeststhat IgA may be important in the pathogenesis of theseconditions. IgA-associated nephritis may provide a valuablemodel for study of possible mechanisms of IgA-mediatedimmune injury.

We thank the following physicians for their cooperation in thisstudy: Drs. A. Rapoport, G. DeVeber, M. Johnson, M. Gold-stein, D. Thompson, C. Saiphoo, R. Charron, W. Berry, L.Wiertz, M. Shafran, H. Coopersmith, M. Stuparyk and D.Davidson.

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