Saturday 20 June 1970
PATHOLOGY OF THE NEPHROTIC
SYNDROME IN CHILDREN
A Report for the International Study of
Kidney Disease in Children*
JACOB CHURG
Mount Sinai School of Medicine, City University of
York, N.Y.
RENEE HABIB
Unité de Recherches surles Maladies du Metabolisme chez
l’Enfant, Hôpital des Enfants Malades, Paris
RICHARD H. R. WHITE
Children’s Hospital, Birmingham, England
The renal biopsy findings in 127 pre-
Summary
viously untreated children with the
nephrotic syndrome of recent origin are reported.
"Minimal changes" were observed in 98 (77%)
patients, and most responded to corticosteroid therapy.
In addition to the well-known forms of chronic
glomerulonephritis, two distinct but less well recog-
nised conditions are described. In one, focal sclerosing
lesions involve the glomeruli to an increasing extent,
and may ultimately lead to renal failure; in its early
stage the condition may be difficult or even impossible
to distinguish from
"
minimal changes ". Most cases
are steroid-resistant. In the other condition there is
mild mesangial thickening and proliferation similar to
that observed in resolving post-streptococcal nephritis.
Although some cases may be steroid-resistant and the
clinical course protracted, the prognosis is generally
favourable.
Introduction
DURING a prospective study of the nephrotic syn-
drome, conducted by members of the International
Study of Kidney Disease in Children, renal biopsy
specimens were obtained from a large number of
untreated pasdiatric patients with disease of recent
origin. The pathological findings of the nephrotic
syndrome have been well reviewed by Heptinstall.2
Many of the reported data have been based on clinical
material referred for investigation on account of
diagnostic or therapeutic problems. This new material,
obtained systematically in a prospective study, pre-
sented us with an opportunity to re-examine the histo-
logical features and describe them in detail, to form an
impression of the relative frequency of individual renal
lesions, and to relate them to the clinical course.
Detailed correlations between the renal changes and
the clinical and laboratory findings will be published
subsequently. In this report we briefly describe the
morphological classification which we have evolved
from our experience of unselected biopsy material, and
*
The organisation of the study was described in an earlier report
(Lancet, 1970, i, 959).
7660
which we propose to use as a basis for future thera-
peutic trials.
Material and Methods
Renal biopsy specimens from 127 previously untreated
children with the nephrotic syndrome have been examined
and classified. In addition, renal tissue from subsequent
biopsy or necropsy was available in 7 of these patients.
New All specimens were processed and cut in the pathology
laboratories of the participants’ own hospitals. Alcoholic
Bouin’s solution and 10% formol-saline were the two fixa-
tives used mainly. Four unstained slides were submitted
to each of us and stained in our laboratories, using hxma-
toxylin and eosin (H.E.) and periodic acid/Schiff (P.A.S.) in
all cases, and either periodic acid/silver methenamine
(P.A.S.M.) or trichrome, or both, when required. Electron
microscopic examination was not carried out.
The slides were examined independently by each one of
us and the results recorded in detail on a form designed for
subsequent computer-analysis. This form included over
80 questions designed to evaluate and to grade the patho-
logical changes in the glomeruli, tubules, blood-vessels, and
interstitium. Although most sections were of 3-5 . thick-
ness, allowances had to be made occasionally for greater
thickness, in interpreting the findings. At the time of
examination we possessed no information about the patients
other than age, sex, and race. On completion of the
azathioprine trial we met to re-examine all the slides and
reach our final diagnoses. Only then were the histological
findings correlated with the clinical features and response
to therapy
Results
The 127 patients were assigned on the basis of the
initial renal biopsy specimen to one of the following
categories:
1. Minimal Changes (98 Patients)
The essential feature of this group was the absence
of any conspicuous abnormality on light microscopy.
The existence of fusion of the epithelial-cell foot-
processes3 in this group is well known, but it is not a
specific feature and occurs in all patients with massive
proteinuria. Some swelling of the visceral epithelial
cytoplasm could usually be seen on optical microscopy.
In some specimens, a slight increase of mesangial
matrix (basement-membrane-like fibrils) was observed,
while in others there was very slight and usually focal
hypercellularity. However, neither of these features was
of sufficient degree to warrant the description " sclero-
sis " or " proliferation ". Likewise, the presence of an
occasional sclerosed glomerulus without any tubular
atrophy, or the association of normal glomeruli with
dilated tubules showing thinning of their epithelium,
or slight focal tubular atrophy, was accepted as falling
under the heading of " minimal changes ".
2. Focal Sclerosing Glomerular Lesions (12 Patients)
This group was characterised by the presence of
glomerular sclerosis which was of both focal and seg-
mental distribution. The fully developed picture
(fig. 1), seen in a few relatively advanced cases, included
1300
Fig. 1-Advanced "focal sclerosing disease."
Glomeruli show a variety of lesions from minimal through
segmental to almost total sclerosis. There is tubular dilatation,
tubular atrophy, and interstitial fibrosis. (Reduced by a third
from x 140.)
normal and partly and completely sclerosed glomeruli,
with accompanying tubular atrophy and interstitial
inflammatory changes. In view of the short duration
of illness in most patients, however, the lesion was
usually seen in its early stage, when it involved only
one or two lobules (fig. 2) or sometimes only part of one
lobule of a few glomeruli, the others showing " minimal
changes ". In 4 patients sclerosed areas showed a
slight increase of mesangial cells. In 7 patients these
areas were hypocellular acellular, and hyaline
or
material could be observed in the capillary walls and
lumens. In some instances the sclerosed lobule was
locally adherent to the capsule, and the overlying
epithelial cells were hypertrophic and hyperplastic,
occasionally forming small crescents.
In 1 case the majority of glomeruli showed " minimal
changes " but a number were completely sclerosed.
However, the sections showed widespread focal tubular
atrophy which, we believe, could only be explained by
the biopsy having missed more extensive glomerulo-
sclerosis. We therefore classified the specimen as focal
disease rather than " minimal changes ".
3. Diffuse Proliferative Glomerulonephritis (14 Patients)
(a) Exudative.-Although the nephrotic syndrome
may occur during the course of acute post-streptococcal
glomerulonephritis, it is usually a transient event. Such
Fig. 3-Mesangial proliferative glomerulonephritis.
Increase in cells and fibrils in the mesangial stalks. Capillaries
well preserved. (Reduced by a third from x 590.)
in left lower part of
Fig. 2-Focal segmental glomerular lesion
glomerulus.
The upper part shows only minimal change. (Reduced by a
third from x 560.)
patients were not admitted to the study, and we did
not, therefore, encounter this lesion in our series.
(b) Mesangial.-Specimens from 4 patients showed a
slight but diffuse increase of mesangial cells, accom-
panied by a moderate increase of mesangial fibrils
(fig. 3), which took up P.A.s. and P.A.S.M. stains well.
The capillaries were widely patent and their walls were
of normal thickness; epithelial proliferation and adhe-
sions were absent. The lesion is very similar to that in
patients with resolving post-streptococcal nephritis.4
(c) Focal.-We encountered no examples of the focal
type of proliferative glomerulonephritis described in
adults by Heptinstall and Joekes5 which, in children,
occurs mainly in nephritis complicating Schonlein-
Henoch purpura.As we noted earlier, slight hyper-
cellularity was occasionally observed in specimens
showing focal sclerosing lesions.
(d) With crescents.-Specimens from 4 patients con-
tained epithelial crescents in addition to showing vari-
able mesangial proliferation and sclerosis (fig. 4).
Crescents were generally of small or moderate size,
causing incomplete obliteration of the urinary spaces.
The large " occluding " crescents which involve the
majority of glomeruli in rapidly progressive nephritis7
were not a prominent feature in these cases. Tubular
atrophy and interstitial fibrosis were roughly propor-
tional to the extent of glomerular sclerosis.
Fig. 4-Proliferative glomerulonephritis with a small crescent.
(Reduced by a third from x 530.)

Fig. 5—Lobtilar (membranoproliferative or mesangio-capillary)
glomerulonephritis.
(Reduced by a third from x 560.)
(e) Membranoproliferative (mesangio-capillary).--6
patients showed this lesion, in which there is a charac-
teristic combination of both mesangial proliferation
and sclerosis with diffuse thickening of the capillary
walls (fig. 5). The latter is apparently due to the
infiltration of mesangial components (both cellular and
fibrillar) between the capillary basement membrane
and the lining endothelium (i.e., the subendothelial
zone), and leads to progressive narrowing of the lumen.
When mesangial proliferation and sclerosis are marked,
the glomerular tufts assume a lobulated appearance.
The occurrence of this lesion as an entity was first
recognised by Habib et al.,8 although Jones 9 and
Churg and Grishman 10 have previously drawn atten-
tion to the " double or split basement membrane "
revealed by silver staining in " lobular " or in " sub-
acute " glomerulonephritis. West et al.111 demonstrated
persistently reduced serum-plc-globuhn levels in simi-
lar patients, and Ogg et al.12 subsequently confirmed
these findings.
4. Membranous (Extramembranous or Epimembranous)
Nephropathy (2 Patients)
The essential feature of this condition is diffuse
thickening of the capillary walls (fig. 6) owing to the
deposition of immune globulins on the outer (sub-
epithelial) aspect of the capillary basement membrane.
These deposits, which can be demonstrated by P.A.S.M.
"
staining, are interrupted by spiky " projections from
the basement membrane, which gradually encircle the
deposits and incorporate them into the greatly thickened
stnlcnlre.i3 Proliferation is usually absent.
DISTRIBUTION OF RENAL BIOPSY SPECIMENS OBTAINED FROM 127
NEPHROTIC CHILDREN, ACCORDING TO GLOMERULAR CHANGES,
STEROID-RESISTANCE, AND DEATHS
1301
Fig. 6-Membranous (extramembranous or epimembranous)
nephropathy.
(Reduced by a third from x 450.)
is rare in children,14,18 and in the present series we
encountered only 2 cases; 1 of these was atypical in
that definite membranous transformation was accom-
panied by conspicuous mesangial proliferation.
5. Advanced Chronic Glomerulonephritis (1 Patient)
The specimen from 1 patient showed such extensive
glomerular sclerosis, tubular atrophy, and interstitial
fibrosis that the original disease could not be positively
identified. Possibly it was the terminal stage of
focal glomerular disease, as there was no sign of
proliferation.
The frequency distribution of the morphological
variants described above is shown in the accompanying
table, which also indicates the number of patients in
each category who failed to respond to a standard
8-week course of prednisone therapyand the number
of deaths. Steroid-resistance was common in all
patients except those with minimal changes and
mesangial proliferative glomerulonephritis. Since the
progessive lesions evolve slowly, the number of deaths
recorded here is not a true indication of the ultimate
mortality.
Discussion
Histological classification of the nephrotic syndrome
has been debated ever since Munk 15 introduced the
term " lipoid nephrosis ". Munk used this term to
designate an entity which he believed to represent a
degenerative process in the tubules, unrelated to
glomerulonephritis. Subsequent workers 16,17 drew no
distinction between the two conditions, pointing to
This lesion
patients who in life had manifestations of " lipoid
nephrosis " but who eventually died in urazmia and
at necropsy were found to have renal changes of
chronic glomerulonephritis. Thus the term " lipoid
nephrosis " has outlived its clinical usefulness, for
patients with more serious disease may present clini-
cally in an indistinguishable manner. However, the
group of patients showing " minimal changes " on
biopsy is said to be distinguishable from the other
groups by features in addition to the histological find-
ings. These features include a younger age-distribution,
a preponderance of affected boys, and infrequent
occurrence of hypertension and hasmaturia, which are
transient when they do occur.18Moreover, it has been
reported that these children generally have highly
1302
selective proteinuria and respond promptly to corti-
costeroid therapy, although most tend to relapse.l8,la
Morphological classification has little significance
unless related to the clinical picture. Studies are now
in progress to determine how the individual histo-
logical features correlate with the clinical and labora-
tory data. It is already obvious that the focal sclerosing
glomerular lesions and various forms of proliferative
glomerulonephritis account for the majority of steroid
non-responders and cases of renal failure. " Focal
sclerosing glomerular disease " is not an entirely new
entity; Fahr 20 long ago recognised that patients with
"
lipoid nephrosis " progressing to renal failure showed
focal glomerular damage, and McGovern 21 more
recently observed the development of focal glomerular
sclerosis in a number of patients with the nephrotic
syndrome who showed only minimal changes on initial
biopsy. Hayslett et al.22 reported 3 patients who
developed focal sclerotic lesions in the course of the
nephrotic syndrome and who eventually died in renal
failure. Grishman and Churg 23 and Gubler 24 have
collected a large number of cases with " focal disease ".
With careful examination of biopsy sections one can
usually recognise the first signs of glomerular sclerosis
very early in the disease and thus correctly predict
the clinical course.
We do not know whether focal sclerosis develops
concomittantly with the onset of proteinuria, or
follows it after an interval. In support of the former
sequence, the post-mortem study of Rich 25 drew
attention to the fact that progressive focal glomerulo-
sclerosis begins in the juxtamedullary glomeruli and
gradually spreads outwards. Thus a small renal biopsy
specimen or one which samples only the outer cortex
may miss the disease in its early stages. This might
explain at least some of the cases which we classified as
" minimal changes ", in patients who were steroid-
resistant and who eventually died in renal failure (see
table). We have so far been able to examine necropsy
material in only 1 of these patients, and found
advanced but still focal glomerular sclerosis. Possibly
electron microscopic examination of early cases may
shed light on the condition by revealing minor but
fundamental changes in the " normal " glomeruli
which are not visible by optical microscopy.
Only 1 child with membranoproliferative glomerulo-
nephritis and none of those with crescents or mem-
branous nephropathy lost their proteinuria during an
8-week course of prednisone. The study was not
designed to assess the effect of prolonged treatment.
However, 3 of the 4 patients with pure mesangial
proliferation responded to prednisone, although 1
subsequently relapsed frequently. Because the cases
are few, it is not yet possible to establish the histo-
logical limits and clinical significance of this group. A
similar morphological appearance can be observed
during the healing phase of post-streptococcal
nephritis, in both adults4 and children,26.27 but this
does not in itself imply that the xtiology of this lesion
is invariably streptococcal. It occurs in a minority of
nephrotic patients, both adults 28 and children.14
A similar lesion has recently been reported in some
children with recurrent hxmaturia .29
When, at the beginning of the study, we designed
our tentative morphological classification, we made no
provision for mesangial proliferation as an entity.
During our final meeting it emerged that two of us
classified these 4 patients under the " mesangial
" "
hypercellularity subdivision of minimal changes ",
while the third pathologist included them under
"
proliferative glomerulonephritis ", which originally
was given no subdivisions. The mixed response of
these patients to steroid therapy suggests that this
lesion might belong rightly to either group; this is
being further examined, by reference to such addi-
tional features as hypertension, haematuria, serum-
Plc-globulin levels, and proteinuria selectivity. In
another series,18 mesangial proliferation was found in
8 of 145 nephrotic children. All had microscopic
haematuria and impaired proteinuria selectivity, while
2 were hypertensive at onset; although 6 out of 7 were
initially steroid-resistant, only 1 continued to have
proteinuria over a long period. These findings suggest
that the lesion is a true variant of proliferative
glomerulonephritis, with a tendency to heal similar to
that of the post-streptococcal form.
We thank the pathologists of the participating clinics: Dr. B.
Bennett, Dr. A. H. Cameron, Dr. T. Feldkamp-Vroom, Dr. A.
Gibson, Dr. R. W. McDivitt, Dr. F. Mota, and Dr. H. Wada;
and the U.S. Public Health Service (contract no. PH86-67-285),
the Kidney Foundation of New York, the John Rath Foundation,
the Lipper Foundation, Burroughs Wellcome & Co. (U.S.A.)
Inc., and the Schering Corporation for financial support.
Requests for reprints should be addressed to J. C., Mount Sinai
School of Medicine, Department of Pathology, Fifth Avenue at
100th Street, New York, N.Y. 10029.
REFERENCES
Abramowicz, M., Arneil, G. C. Barnett, H. L., Barron, B. A.,
1.
Edelmann, C. M., Jr., Gordillo, G. P., Greister, I., Hallman, N.,
Kobayashi, O., Tiddens, H. A. Lancet, 1970, i, 959.
2. Heptinstall, R. H. Pathology of the Kidney; p. 355. Boston, 1966.
3. Farquhar, M. G., Vernier, R. L., Good, R. A. J. exp. Med. 1957,
106, 649.
Jennings, R. B., Earle, F. P. J. clin. Invest. 1961, 40, 1525.
4.
Heptinstall, R. H., Joekes, A. M. Q. Jl Med. 1959, 28, 329.
5.
Royer, P., Habib, R., Mathieu, H., Verneil, G., Gabilan, J-C.,
6.
Desprez, P. Sem. Hôp., Paris, 1963, 39, 2621.
7. Berlyne, G. M., Baker, S. B. de C. Q. Jl Med. 1964, 33, 105.
8. Habib, R., Michielsen, P., de Montera, E., Hinglais, N., Galle, P.,
Hamburger, J. in Ciba Foundation Symposium on Renal Biopsy
(edited by G. E. W. Wolstenholme and M. P. Cameron); p. 70.
London, 1961.
9. Jones, D. B. Am. J. Path. 1957, 33, 313.
10. Churg, J., Grishman, E. ibid. 1959, 35, 25.
11. West, C. D., McAdams, A. J., McConville, J. M., Davis, N. C.,
Holland, N. H. J. Pediat. 1965, 67, 1089.
12. Ogg, C. S., Cameron, J. S., White, R. H. R. Lancet, 1968, ii, 78.
13. Ehrenreich, T., Churg, J. in Pathology Annual 1968 (edited by
S. C. Sommers); p. 145. New York, 1968.
14. White, R. H. R. Proc. R. Soc. Med. 1967, 60, 1164.
15. Munk, F. Med. Klin. 1916, 12, 1019, 1047, 1073.
16. Bell, E. T. Renal Diseases. Philadelphia, 1950.
17. Vernier, R. L., Brunson, J., Good, R. A. Am. J. Dis. Child. 1957,
93, 469.
18. White, R. H. R., Glasgow, E. F., Mills, R. J. Lancet (in the press).
19. Cameron, J. S. Br. med. J. 1968, iv, 352.
20. Fahr, Th. Pathologische Anatomie des Morbus Brightii in Handbuch
der speziellen pathologischen Anatomie und Histologie (edited
by F. Henke and O. Lubarach); vol. VI. Berlin, 1925.
21. McGovern, V. J. Austral. Ann. Med. 1964, 13, 306.
22. Hayslett, J. P., Krassner, L. S., Bensch, K. G., Kashgarian, M.,
Epstein, F. H. New Engl. J. Med. 1969, 281, 181.
23. Grishman, E., Churg, J. in Discussion of the Symposium on the
Nephrotic Syndrome. 2nd Annual Meeting, American Society of
Nephrology, Washington, D.C., Nov. 25-26, 1968.
24. Gubler, M. C. Thesis, Paris, 1969.
25. Rich, A. R. Bull. Johns Hopkins Hosp. 1957, 100, 173.
26. Hutt, M. S. R., White, R. H. R. Archs Dis. Childh. 1964, 39, 313.
27. Dodge, W. F., Spargo, B. H., Bass, J. A., Travis, L. B. Medicine,
Baltimore, 1968, 47, 227.
28. Lawrence, J. R., Pollak, V. E., Pirani, C. L., Kark, R. M. ibid.
1963, 42, 1.
29. Glasgow, E. F., Moncrieff, M. W., White, R. H. R. Br. med. J. (in
the press).