Ergebnisse der Inneren Medizin und Kinderheilkunde / Advances in Internal Medicine and Pediatrics: Neue Folge

172 Pages·1982·5.14 MB·English

by  P. Frick, K. Kochsiek, G. A. Martini, A. Prader (eds.), J. Briner (auth.), G.-A. von Harnack

Ergebnisse der
Inneren Medizin und
Kinderheilkunde
49
Advances in
Internal Medicine and
Pediatrics
Neue Folge
Herausgegeben von
P Frick G.-A. von Harnack K. Kochsiek
G. A. Martini A. Prader
Mit 47 Abbildungen und 31 Tabellen
Springer-Verlag
Berlin Heidelberg New York 1982
lSBN-13: 978-3-642-68545-3 e-lSBN-13: 978-3-642-68543-9
DOl: 10.1007/978-3-642-68543-9
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Inhaltl Contents
Glomerular Lesions in Renal Allografts. With 16 Figures
J. Briner. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
Homocystinuria. With 4 Figures
H. Przyrembel . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 77
Congenital Chloride Diarrhea. With 27 Figures
C. Holmberg, J. Perheentupa. . . . . . . . . . . . . . . . . . . . . . . . . . .. 137
Glomerular Lesions in Renal Allografts
J. BRINER 1
1 Introduction........................................... 2
2 Material and Methods. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 2
3 Original Lesions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 4
4 Definitions............................................ 6
5 Recurrent Glomerulonephritis. . . . . . . . . . . . . . . .. ............. 8
5.1 Case Reports of Recurrent Glomerulonephritis. . . . . . . . . . . . . . . . 8
5.2 Recurrent Glomerulonephritis: General Discussion . . . . . . . . . . . .. 17
5.3 Recurrent Dense "Deposits" Disease. . . . . . . . . . . . . . . . . . . . . .. 21
5.4 Recurrent Membranoproliferative Glomerulonephritis Type I . . . . . 24
5.5 Recurrent Membranous Glomerulonephritis. . . . . . . . . . . . . . . . .. 26
5.6 Recurrent Focal and Segmental Glomerulosclerosis. . . . . . . . . . . .. 28
5.7 Recurrent Intra- and Extracapillary Proliferative Glomerulonephritis.. 31
5.8 Recurrent IgA Glomerulonephritis . . . . . . . . . . . . . . . . . . . . . . .. 31
5.9 Recurrent Glomerulonephritis in Systemic Lupus Erythematosus. . 32
5.10 Recurrent Glomerulonephritis in Schonlein-Henoch Syndrome. . . . 32
5.11 Recurrent Antiglomerular Basement Membrane Antibody 33
Glomerulonephritis . . . . . . . . . . . . . . . . . . . .. . ......... .
6 De Novo Glomerulonephritis. . . . . . . . . . . . . . . . . .. ........... 34
6.1 General Remarks. . . . . . . . . . . . . . . . . . . . . .. ........... 34
6.2 De Novo Membranous Glomerulonephritis. . . . . . . . . . . . . . . . . . 36
6.3 De Novo Membranoproliferative Glomerulonephritis Type I . . . . . . 39
6.4 De Novo Mesangial Proliferative Glomerulonephritis . . . . . . . . . . .. 42
6.5 De Novo Focal and Segmental Glomerulosclerosis. . . . . . . . . . . . . 44
6.6 De Novo Antiglomerular Basement Membrane Antibody
Glomerulonephritis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45
6.7 De Novo Glomerulonephritis After Administration of
Antilymphocyte Globulin. . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 45
7 Glomerulonephritis of Undetermined Pathogenetic Type . . . . . . . . . . . .. 46
8 Reactive Proliferative and Sclerosing Glomerular Transplant Lesions. . . . .. 48
9 Donor Glomerulonephritis (Preexisting Glomerulonephritis in the Graft). .. 50
10 Transplant Glomerulopathy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 51
11 Rejection Glomerulonephritis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 58
12 General Results. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 64
12.1 Proteinuria.......................... . . . . . . . . . . . . .. 64
12.2 Histocompatibility Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 66
12.3 Quantitative Determination of Glomerular Proliferation. . . . . . . . .. 66
13 Conclusion ................ . 69
14 Summary ................. . 71
References ................... . 72
Department of Pathology, University of ZUrich (Heads Prof. Chr. Hedinger, and
Prof. J.R. Rilttner)
2 1. Briner
Key words: Renal Transplantation - Renal Allograft - Glomerulonephritis Glome-
rular Transplant Lesions - Recurrent Glomerulonephritis - De Novo Glomeruloneph-
ritis - Donor Glomerulonephritis - Transplant Glomerulopathy - Rejection Glome-
rulonephritis
1 Introduction
In 1954 Merrill et al. first performed successful renal transplantation in man (Merrill
et al. 1956). Since then, kidney grafting has become a well-accepted therapy for ter-
minal renal failure.
Despite the fact that patient and graft survival have very much improved since the
first days, a large number of complications have been documented.
Whereas technical difficulties have largely been overcome, immunologic problems
due to differences in histocompatibility, resulting in rejection and the sequelae of im-
munosuppressive therapy, account for the majority of complications nowadays.
Glomerular lesions are very often seen in renal transplants. They were described
first by Glassock et al. (1968) in renal isografts and by Hamburger et al. (1964) in
renal allotransplants. Since then numerous reports have made clear that a number of
different lesions can be observed in the grafts.
The most common lesion in allografts is transplant glomerulopathy, which can be
considered to be the glomerular equivalent of chronic vascular rejection. Similarly
closely related to rejection are proliferative glomerular lesions, first called rejection
glomerulonephritis by Hamburger et al. (1964).
Whereas glomerulonephritis transmitted from donor to recipient within the kidney
transplanted has been documented only rarely, glomerulonephritis arising de novo in
the graft has occasionally been reported. According to the literature, recurrence of the
patient's original glomerulonephritis in the graft has been observed even more often.
Most of these lesions, some of which are very important for the fate of the trans-
plants, have been described in case reports only. There is a small number of major
surveys published (Busch et al.1971c;Mathew et al. 1975;Petersen et al. 1975;
Cameron and Turner 1977;Hamburger et al. 1978).
This paper presents the histologic, electron microscopic, and immunofluorescence
findings in a large series of 328 biopsies and nephrectomies of 177 patients, seen at
this institution during a 4-year period, and correlates these with the clinical findings.
2 Material and Methods
From 1 January 1975 to 31 December 1978254 renal transplant biopsies and 74 trans-
plant nephrectomy specimens were investigated at the Department of Pathology, Uni-
versity of Zurich.
During the same 4-year period, 251 renal transplantations (250 cadaver allotrans-
plantations and one syngeneic transplant in identical twins) were effected by the Renal
Glomerular Lesions in Renal Allografts 3
Transplant Unit (prof. F. Largiader) of the Department of Surgery A of the University
of ZUrich (Head Prof. A. Senniog).
Forty-three biopsies were carried out on renal allotransplants which did not resume
satisfactory function within 1- to 11/2 months after transplantation (group I). Eighty-
eight biopsies were effected because of rapid deterioration of function (group II) and
55 biopsies because of slow deterioration of function (group III). In cases where the
graft had never functioned satisfactorily or had ceased to function, 74 biopsies and
nephrectomies were carried out (group IV). Forty-nine biopsies were effected during
the course of surgical intervention (mafuly because of ureteropelvic or ureteral obstruc-
tion (group V). In order to elucidate the cause of proteinuria or to confirm the diagno-
sis of glomerulonephritis, 19 biopsies were carried out (group VI).
The biopsies received were immediately checked for the presence of glomeruli
under the dissecting microscope and divided into three portions:
1. The major portion selected for light microscopy was fixed in Dubosq-Brazil
solution for 3-6 h, transferred to 4% formalin, embedded in Paraplast, and sectioned
at 31lffi. The slides were stained with hematoxylin-eosin stain, PAS, Mallory triple
stain, and silver methenamine.
2. The portion of tissue selected for electron microscopy was cut into 1 mm3 pieces,
fixed by immersion in 2.5% phosphate buffered glutaraldehyde, rinsed in phosphate
buffer, and embedded into Epon 812. Thin sections of two to five glomeruli of each
biopsy were prepared, stained by uranyl acetate and lead citrate, and examined under
the transmission electron microscope.
3. The portion of tissue selected for immunofluorescence was snap frozen in Freon,
which was cooled by liquid nitrogen. Frozen sections were incubated with commercially
available goat antihuman sera (Behring-Werke) against kappa and lambda chains, IgG,
IgA, IgM, and occasionally IgD or IgE, as well as C3, Clq, C4, fibrinogen, and occasion-
ally also against HBs antigen and horse immunoglobulin.
Portions of tissue received at nephrectomy were similarly processed.
The renal tissue was obtained from 214 grafts of 177 patients and from seven donor
kidneys serving as controls.
All the biopsies and nephrectomies were analyzed by a standard method employing
a protocol with 24 criteria for glomeruli, 11 for tubuli, 9 for interstitial tissue, and 21
for capillaries, arteries, and arterioles. A similar protocol for electron microscopy com-
prised 31 criteria for glomerular changes.
The tissue was taken from the first graft of 176 patients, from the second graft of
34 patients, and from the third graft of four patients.
More than four-fifths of the specimens came from the first transplant and about
one~ixth from the second transplant. Whereas the ratio of the biopsy specimens to
nephrectomy specimens was about 4:1 for the first graft, there were relatively more
nephrectomy specimens from the second graft, the ratio being only 2:1 (Table 1).
The number of cells per average glomerulus was estimated in all cases. In a series of
87 biopsies (comprising 9 cases of recurrent glomerulonephritis, 17 cases of de novo
glomerulonephritis, 36 cases of transplant glomerulopathy, 18 cases of rejection glo-
merulonephritis, as well as 16 cases without cellular proliferation by light microscopy
and five donor kidneys which were used as controls) the number of glomerular cells
4 1. Briner
Table 1. Number of biopsies and nephrectomies investigated
Order of Biopsies Nephrectomies Total number Percentage
renal allograft of specimens
1. 213 58 271 82.62%
2. 36 15 51 15.55%
3. 5 1 6 1.83%
Total 254 74 328 100%
was counted, the number and rates of endothelial, mesangial, and epithelial cells and
the number of cells per glomerular area were determined.
Clinical findings recorded by the Transplant Unit (prof. F. Largiader) of the
Department of Surgery A (prof.A. Senning) and by the Nephrology section (prof.
U. Binswanger) of the Department of Medicine (Profs.P. Frick, A. Labhart, and
W. Siegenthaler) of the University of ZUrich and the following laboratory parameters
were checked in order to determine the actual function at the time of biopsy as well
as the ultimate course: blood pressure, amount of proteinuria and erythrocyturia, and
serum creatinine values.
Data on blood groups, HLA types, and HLA antibody titers determined by the
tissue typing laboratory (Frl. Retsch) of the Transplant Unit were also recorded.
3 Original Lesions
The type of the original lesion that led to renal insufficiency was determined from
clinical findings only in 46 of 177 (25.98%) patients. Histologic confirmation was
available in the remaining 131 of 177 patients (74.02%). A total of 144 diagnoses were
made in the 131 cases examined morphologically. In seven cases two lesions, and in
three cases three lesions were present; those were mainly cases of malformation
(agenesis, hypoplasia, and dysplasia) complicated by hydronephrosis or pyelonephritis
(Table 2).
The major cause of renal insufficiency leading to transplantation was glomerulo-
nephritis. It was present in 93 of 177 patients (52.54%). Histologic confirmation of
the diagnosis was done in 67 of 93 (73.11%) patients.
There was, however, a large number of cases where the original type of glomerulo-
nephritis could no longer be dermed precisely. These cases were classified as chronic
glomerulonephritis and comprised 43 of 67 (64.17%). Thus from the total number of
93 cases with glomerulonephritis, a precise morphologic diagnosis of the type of glo-
merulonephritis could be established in only 24 patients (25.80%).
This is a relatively low figure. It is caused equally by the facts that no biopsy was
effected and that the biopsy was carried out only late in the course (usually at the
time of transplantation) when the disease had already reached the end stage.
Glomerular Lesions in Renal Allografts 5
Table 2. Original renal lesions
Type of original renal lesion Determined by Total
Clinical Morphological
findings findings
Glomerulonephritis 26 67 93
Chronic GN 26 43 69
Focal GN 2 2
Focal and segmental 4 4
glomerulosclerosis
Membranoproliferative GN, type I a 7 7
Dense "deposits" disease 2 2
Membranous GN 3 3
Intra- and extracapillary 1 1
proliferative GN
Mesangial proliferative GN 2 2
Diffuse proliferative GN in SLE 2 2
Goodpasture's syndrome 1 1
Chronic interstitial nephritis 16 35 51
Chronic pyelonephritis 7 22 29
Analgesic nephropathy 9 13 22
Cystic disease of the kidney 0 13 13
Polycystic disease, adult type 11 11
Medullary cystic disease 1 1
Medullary sponge kidney 1 1
Other renal lesions 4 29 33
Hydronephrosis 6 6
Pelvic kidney 1 1
Dysplasia 4 4
Agenesis 4 4
Hypoplasia 3 3
Diabetic glomerulosclerosis 4 4
Malignant nephrosclerosis 4 4
Oxalosis 1 1
Tuberculosis 1 1
Hereditary nephritis 5 5
Total 46 144 190
a
Including one case of membranoproliferative GN in" shuntnephritis.
Chronic interstitial nephritiS was second as a cause of terminal renal failure in
this series [51 of 177 patients (28.82%)]. In slightly less than half of these cases
analgesic nephropathy was present.
6 J. Briner
4 Definitions
In addition to the glomerular changes secondary to ischemia, hypertension, and inter-
stitial nephritis, there are a number of primary glomerular lesions in renal allografts
characterized by cellular proliferation, mesangial sclerosis, and/or glomerular basement
membrane thickening. These changes resemble different types of glomerulonephritis
and the changes seen in thrombotic microangiopathies. They have been classified by
various authors (McPhaul et al. 1976; Cameron and Turner 1977; Hamburger et al.
1978) according to different pathogenetic mechanisms. The following groups have
been distinguished in our study:
1. Recurrent Glomerulonephritis (rec. GN). This is caused by the persistence of nephri-
togenic stimuli after transplantation. It is defmed as a glomerulonephritis with identical
clinical and morphologic findings (by light microscopy, immunofluorescence, and
electron microscopy) in the patient's original kidney as well as in the graft.
2. De Novo Glomerulonephritis (de novo GN). This lesion represents a true, newly
arising glomerulonephritis in the graft. It is not related to the host's response to the
graft and is therefore unrelated to rejection. Its clinical and pathologic fmdings are
essentially comparable to a glomerulonephritis arising in a nontransplanted patient.
3. Donor Glomerulonephritis (don. GN). The presence of preexisting glomerulonephritis
in the seemingly healthy donor results in the transmission of the lesion in the grafted
kidney into the host.
4. Transplant Glomerulopathy (TGP). This is part of the host's reaction to the graft.
It is characterized on light microscopy by glomerular capillary wall thickening, some-
times with reduplication of glomerular basement membrane (GBM), minor mesangial
expansion, and mesanglial cell proliferation. Occasional focal glomerular obsolescence
as well as focal and segmental sclerosis may be present. On electron microscopy the
broadening of the capillary wall is seen to be due to an electron-lucent thickening of
the lamina rara intema, occasionally with some fibrin deposition. Reduplication of
GBM due to the formation of a new basement-membrane-like material in the subendo-
thelial space is often present. Electron-dense deposits are notably absent in the sub-
endothelial space as well as in the mesanglial area (Cameron and Turner 1977). Deposi-
tion of IgM is often seen, but Clq and C3 are also present as well as IgG, IgA, and
fibrinogen.
In addition to these well-established entities, the following types of glomerular
lesions have also been distinguished:
5. Rejection Glomerulonephritis (rej. GN). This lesion, first described by Hamburger
in 1964, is also part of the host's reaction to the graft and thus resembles TGP. It is
characterized on light microscopy by GBM thickening and reduplication. Proliferation
of endothelial and mesangial cells may be prominent in early cases; it is less marked
in long-surviving grafts where mesangial sclerosis and focal glomerular obsolescence
predominate. Contrary to TGP, rej. GN is characterized by the presence of unequivocal
electron-dense deposits on electron microscopic examination. The depOSits are mostly
Glomerular Lesions in Renal Allografts 7
present in the subendothelial space, but are also found in mesangial areas and occasion-
ally within the GBM as well. The combination of deposits at various locations is typical
for rej. GN. Various immunoglobulins (mostly IgM, IgA, and IgG) are present in many
cases as well as C3, Clq, C4, and fibrinogen on immunofluorescence examination.
6. Reactive Proliferative Glomerular Lesions. In a number of cases glomerular prolife-
rative lesions can be observed that are subsequently shown by biopsy, nephrectomy,
or autopsy to be intimately related to and possibly caused by pyelonephritic scars or
infarcts.
7. Glomerulonephritis of Undetermined Pathogenetic Type. Several cases of clear-cut
glomerulonephritis as judged by clinical and morphologic data could not be classified,
as the type of original renal lesion could not be firmly established.
Rejection was divided into four groups and dermed as follows:
1. Acute Vascular Rejection. Swelling, detachment, necrosis, and proliferation of
endothelial cells in arteries, arterioles, and capillaries, often associated with
thrombosis, edema, and hemorrhage in the interstitial tissue.
2. Acute Cellular Rejection. Cellular interstitial inflltration mainly composed oflarge
lymphocytes and a few small lymphocytes.
3. Chronic Vascular Rejection. Thickening of the arterial and arteriolar wall due to
fibrosis of the intima and deposition of foamy macrophages, resulting in inter-
stitial fibrosis, tubular atrophy, and even (partially hemorrhagic) infarcation.
4. Chronic Cellular Rejection. Interstitial edema and fibrosis, associated with inter-
stitial cellular infiltration by small lymphocytes and many plasma cells.
The types and numbers of glomerular lesions observed are listed in Table 3.
Table 3. Glomerular lesions observed
Type of Patients Grafts Biopsies Nephrectomies Total
glomerular lesions Specimens
Recurrent GN 9 10 13 5 18
De novoGN 20 20 23 1 24
DonorGN 2 2 2 2
Glomerulonephritis of 6 7 7 7
undetermined pathogenetic type
Reactive proliferative 6 5 5 6
glomerular lesions
TGP 55 57 46 21 67
Rejection glomerulonephritis 39 39 39 10 49
Total 136 140 135 38 173