J. clin. Path., 1973, 26, 750-759

Clinical, light, and electron microscopy findings inidiopathic haematuria'F. ALEXANDER, R. LANNIGAN, AND R. BULL

From the Division ofPathology, Faculty of Medicine, The University of Calgary,Calgary, Alberta, Canada

SYNOPSIS The electron microscopic findings are reported in detail in 20 patients submitted to renalbiopsy with the major complaint or clinical finding of gross or microscopic haematuria. The lesionswere classified histologically into four groups: group 1, minor glomerular alterations; group 2,focal mesangial thickening and/or cellular proliferation; group 3, diffuse mesangial proliferation;and group 4, other lesions. The major ultrastructural alterations included irregularity in thicknessand density of the capillary basement membrane, with apparent discontinuity and bi- or multi-laminar splitting of the lamina densa. There were varying degrees of foot process fusion, visceralepithelial polykaryocytosis, and granular deposits related to the capillary basement membrane.Densities were found in the mesangial basement membrane-like material, which was often markedlyincreased in quantity. A few microtubular aggregates were observed in endothelial cell cytoplasm.Changes consistent with acute diffuse proliferative and membrano-proliferative glomerulonephritiswere also seen. The significant clinical findings, histological groups, and ultrastructural changes are

correlated.

Persistent, recurrent, and symptomless haematuriaremains a diagnostic problem for the clinician. Inthe elderly patient this is generally related to alesion of the urinary tract, sometimes neoplastic innature. In the younger patient, however, urologicalinvestigations are frequently negative and the lesionis clinically labelled 'focal' glomerulonephritis,especially if the onset of haematuria is related to anepisode of upper respiratory tract infection. If deaf-ness or ocular abnormalities are associated with thehaematuria, investigations of siblings and relativesmay disclose a familial disorder of uncertain geneticmake-up (Alport, 1927; Grace, Suki, Spjut, Eknoyan,and Martinez-Maldonado, 1970). The pathologicalchanges in patients with primary or symptomlesshaematuria have been graded by Glasgow, Mon-crieff, and White (1970) and Hendler, Kashgarian,and Hayslett (1972), on the basis of light microscopicchanges. The former found only two of 47 patientsto have significant glomerular disease, whilst the latterreported 18 cases of diffuse proliferative glomerulo-nephritis, seven cases of chronic glomerulonephritis,and two with acute proliferative and exudative

"This investigation was supported in part by grant MA-4551 from theMedical Research Council of Canada.Received for publication 16 July 1973.

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glomerulonephritis. Seymour, Spargo, and Penska(1971) found the changes in renal biopsies frompatients with asymptomatic haematuria to be oftensubtle and only visible with electron microscopy, andBurkholder, Dotin, Thomason, and Beach (1969),found normal renal biopsy on light microscopy innine cases of unexplained haematuria. Relativelylittle has been reported on the ultrastructural changesin the glomeruli in this condition. The purpose ofthis report is to document ultrastructural lesionsobserved in the glomeruli of these patients, whosemajor complaint or physical finding was gross ormicroscopic haematuria, in the absence of anyurinary tract abnormality, and to compare the lightand electron microscopy and clinical findings. Thesecases have accounted for approximately 10% ofrenal biopsies performed here during the past twoyears.

Materials and Methods

The 20 patients reviewed here were all submitted torenal biopsy because of haematuria, either of a grossnature causing the patient to consult his practitioneror microscopic when it was discovered on routineexamination. All but one of the patientshadrecurrenthaematuria before biopsy for periods varying from

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two months to 12 years. Eight patients had red cellcasts on at least one occasion and eight gave ahistory of upper respiratory tract infection associatedwith some of the episodes of haematuria. Thepatients' ages ranged from 7 to 56 years at the timeof onset or diagnosis of haematuria. Selection ofpatients was influenced by the policy at this centreof not performing renal biopsy on young childrenwith haematuria only. The clinical investigation wasnot uniform throughout the group as they werereferred from several centres, but renal or urinarytract neoplasms, renal calculi, hydronephrosis, andchronic urinary tract infections were excluded byintravenous pyelography and cystoscopy. None ofthe patients was hypertensive; there was no sub-cutaneous oedema and blood urea nitrogen andserum creatinine levels were normal, when performed.Before kidney biopsy all patients were screened fora possible bleeding disorder and none was found.Renal biopsy was performed by percutaneous oropen method and the specimens obtained wereprepared for light and electron microscopy. For theformer, the tissue was fixed in 10% formol-saline,paraffin embedded, and sectioned at 2 to 3 ,u.Sections were stained with haematoxylin and eosin(H & E), periodic acid-Schiff (PAS), and periodicacid-silver methenamine (PASM). The tissue forelectron microscopy was fixed in 5% glutaraldehyde,postfixed in osmium tetroxide, embedded in Epon,sectioned and stained with uranyl acetate and leadcitrate, and examined in a Philips 300 or AEI Corinth275 microscope.The light microscopy findings were classified into

four groups: group 1, minor glomerular alterations;group 2, focal mesangial thickening and/or prolifer-ation; group 3, diffuse mesangial thickening andproliferation; group 4, other lesions.

Results

LIGHT MICROSCOPY

Group I (four patients)Most of the glomeruli appeared normal, thoughoccasionally some thickening of the mesangialregion was suggested by H & E staining and con-firmed by PAS and PASM staining.

Group 2 (12 patients)The majority of the glomeruli showed some areasof increase in PAS and PASM positive material inthe mesangial region and a focal increase in thenumber of mesangial cells.

Group 3 (one patient)There was a diffuse increase in mesangial cellularity2

and PAS- and PASM-staining material within themesangial region.

Group 4 (three patients)Two of these patients showed features characteristicof membrano-proliferative glomerulonephritis withdiffuse mesangial proliferation of PAS- and PASM-staining material and cells, and marked thickeningof the capillary wall, often with duplication of thebasement membrane as seen with PASM staining.One patient showed acute diffuse proliferation of allpreexisting glomerular elements and occasionalpolymorphs, typical of a-cute diffuse proliferativeglomerulonephritis. This was the only patient seenduring the first known attack of haematuria.One patient (case 9) had two biopsies, the first in

1966 showing only minor mesangial thickeningcorresponding to group 1. Two years later there wasdiffuse mesangial thickening of moderate degreegenerally and quite severe in a few glomeruli withassociated mesangial hypercellularity. This lesionwas considered to have progressed from group 1 togroup 2 over the period of two years.

ELECTRON MICROSCOPY (16 CASES)

Group 1Few ultrastructural alterations were observed in thisgroup.Some increase in thickness was observed focally

on the endothelial aspect of the basement membranein two cases. This thickened area was electron pale.One case demonstrated focal splitting of the laminadensa with intervening pallor. There was an increasein basement-membrane-like material in the mesangialareas of two cases. Epithelial cell cytoplasm appearedswollen with numerous cytoplasmic inclusions andprominent endoplasmic reticulum. Vacuoles wereobserved in the endothelial cells.

Group 2The changes here were much more striking than ingroup 1. Irregularity in thickness of the capillarybasement membrane was observed to be due to focalincrease in the quantity of electron-pale material onthe endothelial aspect of the lamina densa in sevencases and to focal thinning of the total membrane infive cases, this being extremely marked in two cases(fig 1). No definite complete breach of the basementmembrane was seen, but in a very few areas it wasreduced severely, at one point to a mere filament-400A thick (fig 2). Three cases showed splitting of thelamina densa of the basement membrane into two ormore layers with intervening pale zones.

Electron-dense deposits of granular appearancewere present in seven cases. In five cases they were

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F. Alexander, R. Lannigan, and R. Bull

Fig 2Fig I

........;j..,

Fig 1 The basement membrane (BM) is extremely thinover the capillary loop (C). Epithelial cell foot processesare partly fused over the area where the structure of themembrane is indistinct. Normal BM thickness2000A°-35 OOOA°. x 14 000.

Fig 2 The capillary basement membrane (BM) showsirregularity, pallor, and extreme narrowing (-+) toapproximately 400A°. x 25 600.

Fig 3 Electron-dense areas (Ed) are noted in themesangium (Mes) and on the mesangial side of theoverlying basement membrane. x 8550.

Fig 3

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Fig 4

tV.,- ... Fig 5

Fig 4 A granular density (D) is present in the basementmembrane, extending towards the epithelial (Ep) aspect.The adjacent epithelial cell cytoplasm also shows markedelectron dense granularity. x 25 600.

Fig 5 Areas of very coarse open granularity (D)project on the epithelial side of the basement membrane.x 18240.

Fig 6 Microtubular structures-virus-like bodies (VLB)are noted in the endothelial cell cytoplasm. The basementmembrane is very irregular in contour and density-thinned to approximately 1500A° (-.) x 21 000.

OU.

Fig 6

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observed in the mesangial region (fig 3), and in onethey were also found in Bowman's capsule. Mesangialand poorly formed subendothelial deposits werenoted in three cases and subepithelial deposits wereseen in three. Only one case demonstrated a singlearea of dense granularity within the membrane andextending towards the epithelial aspect (fig 4).Granular electron-dense material was observed in theoverlying epithelial cell cytoplasm. The deposits onthe extreme epithelial aspect of the membrane wereof a much coarser granularity than elsewhere (fig 5).

Mesangial proliferation of basement-membrane-like material was a common finding, but hyper-cellularity was seen in the mesangial region in onlytwo cases. There was an abundance of cytoplasmicorganelles including myelin figures in the epithelialcells of several patients, and one demonstratedseveral binucleated epithelial cells-polykaryocytosis.

F. Alexander, R. Lannigan, and R. Bull

Foot process loss was a constant feature, but only ofa very focal nature and related to membraneabnormalities or deposits. Occasionally endothelialcell swelling and vacuolation was observed. Micro-tubular structures were present in the endothelialcell cytoplasm of one case (fig 6).

Group 3Only one patient fell into this category. The basementmembrane was variable in thickness with extremeirregularity of both epithelial and endothelial aspectsof the basement membrane and marked focal pallor.Splitting of the lamina densa was very marked in oneglomerulus and absent in another. Areas of granulardensity were incorporated between the layers of thesplit lamina densa over some capillary loops (fig 7).One small focus of coarse granular deposit was notedon the inner aspect of the basement membrane and a

Fig 7 Fig 8Fig 7 Very marked splitting and irregularity of the lamina densa of the basement membrane with granular electrondensities diffusely dispersed between the layers. Densities (D) are also observed more superficially. x 11 500.Fig 8 Two basement membranes surround a capillary loop C, with mesangial cell cytoplasm between them. Deposits(D) are noted on the inner aspect of the outer or true membrane. Numerous dense areas are also present in themesangium where there is a marked increase in basement membrane-like material. Foot processes are fused over thecapillary basement membrane. x 9800.

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Fig 9...

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Fig 9 Electron densities (Ed) are located on theepithelial side of the capillary basement membrane, withoutward extension of the membrane as in epimembranousnephropathy. Similar densities are located in themesangium. x 20 000.

Fig 10 Irregular diffuse deposition of electron-densematerial is spread throughout the basement membrane,which is of very variable dimensions. x 14 000.

Fig 11 Epithelial, endothelial, and mesangial cellproliferation are combined with electron-dense 'humps'(H). Electron-dense areas are also scattered inBowman's capsule (BC). x 10000.

Fig 11

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rare large deposit was present on the epithelial side.Focal mesangial proliferation of basement-mem-brane-like material and cells was observed.

Group 4This diverse group showed features characteristic ofthe light microscope diagnosis.The double membrane formation with interposed

mesangial cell cytoplasm of membrano-proliferativeglomerulonephritis or capillary mesangial inter-position was accompanied by electron-dense depositson the inner aspect of the outer or true membrane(fig 8). Over capillaries without double layers ofmembrane some deposits were located on the epi-thelial aspect with associated basement membranethickening as in epimembranous nephropathy (fig 9).Granular densities were also observed in the mesan-gium. In some capillary loops the membrane was

diffusely and irregularly involved with markedaccumulations of granular dense material (fig 10).The light microscope diagnosis of acute diffuse

proliferative glomerulonephritis was confirmedultrastructurally by finding epithelial, endothelialand mesangial cell proliferation. Numerous electron-dense 'humps' were present on the basement mem-brane and there were long granular densities inseveral areas of Bowman's capsule (fig 11).

Discussion

Considerable confusion has arisen over the use of theterm 'focal glomerulonephritis' by clinicians and

F. Alexander, R. Lannigan, and R. Bull

pathologists. The clinical term in its original form(Volhard and Fahr, 1914) relates to a symptomcomplex of haematuria associated with an attack ofupper respiratory tract infection. It has more

recently come into common usage for recurrent or

symptomless haematuria with or without evidence ofassociated upper respiratory tract infection. 'Focalglomerulonephritis' in a pathological sense, however,refers only to the anatomical distribution of glome-rular disease and may occur not only in patients withhaematuria, as seen here, but with a wide variety ofdisorders, including polyarteritis nodosa, Henoch-Schoenlein purpura, systemic lupus erythematosus(Heptinstall and Joekes, 1959; McCluskey, 1970),Goodpasture's syndrome (Benoit, Rulon, Theil,Doolan, and Watten, 1964), nephrotic syndrome(Habib and Kleinknecht, 1971), and subacutebacterial endocarditis (Heptinstall, 1966). It is clearthat the two modes of usage are incompatible withclear interpretation, but despite pleas from Lanniganand Insley (1965), Glasgow et al (1970), and Hendleret al (1972), old habits appear to die hard. It wouldseem that one of the terms 'symptomless', 'persistent',or 'recurrent' could be used clinically leaving morpho-logical terminology to the morphologists, or thelesion may be referred to as essential haematuriasince the aetiology is unknown. Arguments havealready been raised against the others as no one ofthem adequately describes the various possiblepresentations.The clinical, light, and electron microscopy find-

ings are shown in table I. The patients for this study

Case Age Sex H/o Dura- Degree Proteinuria Histo- Basement Membrane Mesangium Deposits Poly- TubularNo. (yr) at URTI tion (yr) of logical in Bow- karyo- Aggre-

Onset of Haema- <05 >0-5 Group Uneven Split- Dupli- Deposits Sclerosis Hyper- Deposits man's cytosis gatesHaema- turia g/24 hr g/hr 24 Thick- ting cation cellu- Capsuleturia ness larity

1 9 F + 6 Micro + 1 + + +2 18 M 3/12 Gross + 1 +3 5 M + 10 Gross + I4 23 F Micro l I +5 15 M 2/12 Micro - 2 + + +6 9 M Gross - 2 + + +7 29 F + 3 Gross - 2 l + + + +8 28 F + 3/12 Gross 2 + -49 16 F 2 Gross 1-1210 12 M 6/12 Micro l 2 + + +11 23 M + 1 0 Gross 212 43 F 5/12 Micro + 2 + +13 26 M 2/12 Gross - 2 + +14 17 F 6/12 Gross + 215 56 M 3/12 Gross + 2 + + + +16 9 M Gross 2 + + t +17 23 M + 2 6/12 Gross + 3 + + + + + +18 11 F + 1 2/12 Gross 4 ++ + + +1 9 11 M + 2 Gross + 4 + + + + + +20 7 F - Gross + 4 + + + +

Table Clinical, light, and electron microscopy findings in haematuria ofprobable glomerular origin

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were selected on the basis of the clinical indicationfor renal biopsy, namely, haematuria. This had beenrecurrent in all but one, in whom the biopsy wasperformed very soon after presentation for diagnosisof the cause of haematuria in this 7-year-old female.There was no history or evidence ofupper respiratorytract infection. Haematuria was marked and therewere red cell casts and protein in the urine. Noradiological evidence of urinary tract abnormalitywas found. This case therefore would not fit into aclassification of recurrent or persistent haematuria,but certainly fulfils the criteria for symptomlesshaematuria. The renal biopsy findings were those ofacute diffuse proliferative glomerulonephritis withultrastructural evidence of 'humps'. This finding is ofparticular interest in relation to the absence of anysore throat or skin lesion, no streptococcus isolatedfrom the pharynx, and no elevation of antistrepto-lysin 0 titre. The complement level first done 10 daysafter biopsy ranged from 60 to 95 units over aperiod of three weeks. Are 'humps' diagnostic ofacute poststreptococcal glomerulonephritis?Kimmel-stiel, Kim, and Beres (1962) originally considered ittempting to look at them as pathognomonic forglomerulonephritis, but Herdson, Jennings, andEarle (1966) have suggested that with the possibleexceptions of serum sickness and poststreptococcalexacerbations of chronic glomerulonephritis 'humps'may be pathognomonic of acute poststreptococcaldisease.

Since the time of biopsy one year ago this patienthas continued to have proteinuria and microscopichaematuria with no evidence of renal functionalimpairment.Of the four patients in group 1, two had gross

haematuria, one at regular intervals over a periodof 10 years. In this case the haematuria was firstdiscovered when the patient was in hospital for atonsillectomy after repeated attacks of sore throat.A streptococcal aetiology was not documented. Asecond patient also gave a history of upper respiratorytract infection. Proteinuria was light in all four, theheaviest recorded level being 30 mg% on one occa-sion in one patient.

In group 2 (12 patients), nine had gross haema-turia and red cell casts were recorded in three. Threeof these patients had a definite association betweenupper respiratory tract infections and episodes ofhaematuria and one had an elevated antistreptolysin0 titre with a history suggestive of previous acuteglomerulonephritis. Proteinuria at the last determin-ation was more than 0 5 g/24 hr in five patients, thehighest level recorded being 1 3 g/24 hr in one patient.In one patient the level of proteinuria rose from0-2 g/24 hr at the onset of haematuria to 0-9 g/24 hrtwo months later. In another it fell from a level of

2-4 g/24 hr to 0<1 g/24 hr two years later. Para-doxically the lesion in this patient's repeat biopsy wasconsidered to have progressed from a classificationof group 1 to group 2 over the same period.The group 3 patient had repeated gross haema-

turia, a maximum recorded proteinuria of 2 g/24 hr,and gave a history of sore throat and haematuriatwo and a half years before biopsy. The clinicallesion at that time was suggestive of an acuteglomerulonephritis but biopsy was not performed.There was no evidence of renal insufficiency.

All three patients in group 4 had gross haema-turia, two with red cell casts. The patient with acutediffuse proliferative glomerulonephritis has alreadybeen discussed. One case of membrano-proliferativeglomerulonephritis had 15 g protein per 24 hours,whilst the other showed a progression of proteinuriafrom <0 5 g/24 hr to 0 9 g/24 hr in a period of 14months. A history of numerous upper respiratorytract infections was obtained from the former patient.Two years before biopsy, one of these episodes wascomplicated by gross haematuria. Later, haematuriadeveloped four days after the development of peri-tonsillar abscess and it has been recurrent since then.

In general the degree of proteinuria was greaterin the patients with the more severe renal lesions.However, the finding of proteinuria in associationwith haematuria is not necessarily an indication ofsevere renal disease. In groups 1 and 2, 33% of thepatients had both haematuria and proteinuriagreater than 0 5 g/24 hr, and Rapoport, Deveber,and McLean (1970) reported similar findings in 65%of 33 patients with focal proliferative nephritis. Alevel of less than 0 5 g of protein daily associatedwith primary haematuria was excreted by two ofnine patients showing the severe histological lesionsof chronic glomerulonephritis or active proliferativeglomerulonephritis (Hendler et al, 1972). In one ofthe patients in our study repeat biopsy showed adeterioration according to histological grading(from grade 1 to grade 2) but the level of proteinuriahad decreased. Renal biopsy remains the only way todetermine accurately the degree of morphologicalinvolvement of the glomerulus and only after long-term follow-up will the significance of the variety ofglomerular lesions be fully appreciated.

Electron microscopy studies in haematuria havepreviously demonstrated various changes-a focalincrease in basement membrane material in axialzones and a variability of basement membranethickness from loop to loop (Lannigan and Insley,1965; Singer, Hill, Rosenberg, Marshall, andSwenson, 1968; Glasgow et al, 1970). Lannigan andInsley also described electron-dense material con-sidered to resemble fibrinoid closely applied to theouter side of the basement membrane, in Bowman's

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space, and in the axial zone closely applied to theinner surface of the basement membrane. Hendleret al (1972) found mesangial osmiophilic deposits inone patient, and subepithelial humps in two patientswith active proliferative glomerulonephritis. Humpswere also seen in six of 31 patients with recurrenthaematuria and electron-dense deposits were notedon the endothelial aspect of the basement membrane(Singer et al, 1968). The most common changesobserved in this study were variation in membranediameter, particularly thinning and alterations indensity with numerous foci of pallor and depositsof granular electron-dense material mainly in themesangial region, but also related to the capillarybasement membrane. Large open granular depositssimilar to those described here have been seenpreviously in the congenital nephrotic syndrome(Alexander and Campbell, 1971). Splitting of thelamina densa was a most unusual feature and wasextremely marked in the patient in group 3, wheregranular densities were present within the area ofsplitting and multilamination. Red cells were seenin Bowman's space in only one glomerulus and nored cells were found in the process of migration fromthe capillaries to Bowman's space. It is thereforeimpossible to decide the significance of the basementmembrane changes though it is obviously tempting toconsider the areas of very marked thinning of themembrane as causally related to the escape of redcells. The presence of a normal configuration oflamina densa, rara interna and externa, epithelialcell foot processes, and fenestrated endothelium inmany areas of thinning may suggest a developmentallesion rather than a degenerative one. The possi-bility of a relationship between the thin capillarymembrane and resolution of damage to the mem-brane by an immunological lesion must also beconsidered. Granular electron densities consideredto represent antigen/antibody complex depositionwere fairly commonly observed in these cases, butonly in one case were densities obviously related tomembrane splitting which might lead to thinning.The antigenic stimulus to antigen/antibody complexformation and deposition is unknown in patientswith haematuria of glomerular origin in the absenceof one of the recognized entities such as acutepoststreptococcal glomerulonephritis. Nothing canbe added here to speculation on the relationship ofessential haematuria to poststreptococcal infectionas discussed previously (Singer et al, 1968; Glasgowet al, 1970; Rapoport et al, 1970). Only six of thepatients in this study gave any history of sore throator other exciting factor, in keeping with the relativelack of association with upper respiratory tractinfection, trauma, or exercise found by Burkholderet al (1969) in their investigation of 237 cases of

F. Alexander, R. Lannigan, anid R. Bull

haematuria, 10 of which were considered due toglomerular disease.

In one patient small tubular structures were seenin the endothelial cell cytoplasm. These are similarto the virus-like particles found in glomerularendothelial cells in systemic lupus erythematosus(Fresco, 1968; Norton, 1969). Grausz, Earley,Stephens, Lee, and Hopper (1970) suggest that suchvirus-like particles may be present in the glomerularendothelium of nearly all patients with SLE andthat the inclusions could be a very early diagnosticfinding that is present years before the appearanceof clinical and laboratory findings generally con-sidered necessary for the diagnosis of systemiclupus erythematosus. They have also been found inrenal biopsy material from a patient with sclero-derma, one with Goodpasture's syndrome (Norton,1969), and one with membranous glomerulo-nephritis (Grausz et al, 1970). Duffy (1969) reportedsimilar tubular myxovirus-like particles in theepithelial cytoplasm of a case of lipoid nephrosis.Whilst these structures have been most frequentlyobserved in kidney biopsy material from patientswith SLE they have been observed in numerous othersituations in a great variety of disorders by Baringer(1971). He feels that the unique appearance of theseaggregates and their distribution within the endo-plasmic reticulum of endothelial cells suggests thatthey may represent a common cellular reaction to avariety of injuries. The suggestion of a possiblediagnosis of SLE in this patient with haematuria isof interest in view of the documentation later in herhistory of the haematuria becoming so severeduring pregnancy that this had to be terminated.Serum complement was normal.

Polykaryocytosis has been discussed fully bySpear, Slusser, Schulman, and Alexander (1971) intheir discussion of cystinosis and has been previouslyreported in Waldenstrom's macroglobulinaemia(Argani and Kipkie, 1964), and Goodpasture'ssyndrome (Pirani and Salinas-Madrigal, 1968;Proskey, Weatherbee, Easterling, Green, and Weller,1970). The pathogenesis of polykaryocytosis in thecase of focal glomerulonephritis reported here isunknown.The position of renal biopsy in the investigation of

essential haematuria is a point of considerabledisagreement. There are those who would advocaterenal biopsy for all cases of essential haematuria asthey would for all cases of unexplained renal disease,whilst others feel that little is gained and the com-plications though infrequent may be very severe.In the majority of cases of essential haematuria littleinformation may be gained from biopsy, but thereremains the fact that renal biopsy is the only way todetermine accurately the degree of morphological

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involvement of the glomerulus. It is the only way

to rule out a more severe variety of renal diseasesuch as membranoproliferative, latent, or chronicglomerulonephritis, and to determine the trueprognosis in these cases after full documentation andlong-term follow up. Burkholder et al (1969) pointout that often these patients want to have biopsiesperformed to allay suspicion and fear of cancer or

progressive renal disease.

Very sincere thanks are due to Dr B. M. Churchilland Dr E. L. Atkins who performed the renal biopsieson these patients, and to Dr L. McLeod, Dr H.Mandin, and Dr M. Davidman for clinical docu-mentation and permission to carry out the investi-gations on their patients.

References

Alexander, F., and Campbell, W. A. B. (1971). Congenital nephroticsyndrome and renal vein thrombosis in infancy. J. clin. Path.,24, 27-40.

Alport, A. C. (1927). Hereditary familial congenital haemorrhagicnephritis. Brit. med. J., 1, 504-506.

Argani, I., and Kipkie, G. F. (1964). Macroglobulinemic nephro-pathy: acute renal failure in macroglobulinemia of Walden-strom. Amer. J. Med., 36, 151-157.

Baringer, J. R. (1971). Tubular aggregates in endoplasmic reticulumin Herpes-Simplex encephalitis. New Engl. J. Med., 285,943-945.

Benoit, F. L., Rulon, D. B., Theil, G. B., Doolan, P. D., and Watten,R. H. (1964). Goodpasture's syndrome: a clinico-pathologicentity. Amer. J. Med., 37, 424 444.

Burkholder, G. V., Dotin, L. N., Thomason, W. B., and Beach, P. D.(1969). Unexplained haematuria. J. Amer. med. Ass., 210,1729-1733.

Duffy, J. L. (1969). Myxovirus-like particles in lipoid nephrosis.New Engl. J. Med., 281, 562-563.

Fresco, R. (1968). Tubular (myxovirus-like) structures in glomerulardeposits from a case of lupus nephritis. Fed. Proc., 27, 246.

Glasgow, E. F., Moncrieff, M. W., and White, R. H. R. (1970).Symptomless haematuria in childhood. Brit. med. J., 2, 687-692.

Grace, S. G., Suki, W. N., Spjut, H. J., Eknoyan, G., and Martinez-Maldonado, M. (1970). Hereditary nephritis in the negro.Arch. intern. Med., 125, 451-461.

Grausz, H., Earley, L. E., Stephens, B. G., Lee, J. C., and Hopper, J.(1970). Diagnostic import of virus-like particles in the glomeru-lar endothelium of patients with systemic lupus erythematosus.New Engi. J. Med., 283, 506-511.

Habib, R., and Kleinknecht, C. (1971). The primary nephroticsyndrome of childhood: classification and clinicopathologicstudy of 406 cases. Path. Ann., 6, 417-474.

Hendler, E. D., Kashgarian, M., and Hayslett, J. P. (1972). Clinico-pathological correlations of primary haematuria. Lancet, 1,458-463.

Heptinstall, R. H. (1966). Pathology of the Kidney, pp. 315-333.Little, Brown, Boston.

Heptinstall, R. H., and Joekes, A. M. (1959). Focal glomerulo-nephritis: a study based on renal biopsies. Quart. J. Med., 28,329-346.

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