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Renal involvement during graft-versus-host disease following
haematopoietic cell transplantation for multiple myeloma has never been
described. We report a case
of a recipient who developed nephrotic
syndrome and membranous glomerulonephritis 22 months after the graft and
six months after Cyclosporine withdrawal. Symptoms resolved
when immunosuppressive
therapy was reinstituted Introduction
The
occurrence of renal disorders
after haematopoietic cell transplantation (HCT) and graft-versus-host
disease (GVHD) is a rare event
[
Table
1
]
and has been described in a limited number of patients
[
1-9
]
.
In general, important
alterations of the glomerular permeability occur and all the patients
develop heavy proteinuria and/or nephrotic syndrome.
The renal damage seems to be the consequence of antibodies induced
by GVHD although the precise mechanism that may alter glomerular
capillaries is still unknown.
Symptoms develop irrespective of
the original illness. Interestingly,
in some cases renal involvement has
been detected after Cyclosporine (CsA) withdrawal and the
glomerular leakage of proteins decreased or disappeared after the
reinstitution of the immunosuppressive therapy. In
the present report we describe a patient who received HCT for multiple
myeloma and developed membranous glomerulonephritis (MG) with nephrotic
syndrome. p.
Case A
54-year-old man underwent a non T cell depleted HCT from his HLA-
identical brother for treatment of multiple myeloma IgG
l
on February 1997. At that time although Bence-Jones protein (
l
light chain) was present in the urine, there was not evidence of renal
impairment since
serum
creatinine and 24 h proteinuria were within normal limits.
He was conditioned with melphalan followed by cyclophosphamide and
total body irradiation. To prevent GVHD, from day -1 CsA and methotrexate
at high dosage were administered. A
few days after HCT he developed a Grade I GVHD of the skin requiring the
addition to the treatment of methyl-prednisolone subsequently discontinued
on May 1997. The
initial dose of CsA was 100 mg twice a day then gradually tapered off and
finally withdrawn in June 1998. The
patient remained without therapy and free of symptoms until the end of
December 1998 when he was admitted to our Hospital for the appearance of
nephrotic syndrome with pedal edema and a gain of 4 Kg in body weight.
Arterial blood pressure was 150/105 mmHg.
A normochromic and normocytic moderate anaemia (haemoglobin 9.4
g/dl; hematocrit 27.3%; RBC 3.030.000/mm3 ), mainly
related to the conditioning therapy, was present. White blood cell
count was 7770/
m
L,
platelet count 408000/
m
L,
serum creatinine 1.8 mg/dl, urea 59 mg/dl, albumin
2.5 g/dl, cholesterol 277 mg/dl.
Proteinuria was 7 g/24-hour. Immunoglobulins
were: IgG 512 mg/dl, IgA
65mg/dl IgM 59mg/dl. No evidence
of monoclonal band was seen in the serum electrophoresis, but the
persistence of a minimal disease was indicated by a
k
/
l
ratio of 0.74.
On
February 1999 a percutaneous renal biopsy was performed to establish the
underlying disease. On light
microscopy 22 glomeruli were seen, 8 of them completely sclerotic. In the
remaining 14 different findings were found in different glomeruli.
Most of the glomeruli had a normal appearance without significant
alterations. In others a
segmental damage with enlargement of the mesangial regions was apparent
[
Fig.1
]
.
In all glomeruli the basement membranes were thin and the silver stain did not
revealed any “spikes”.
Focal areas of tubular atrophy, fine interstitial fibrosis with a
small number of chronic inflammatory cells were also present. The wall of
small arterioles was moderate thickened. Congo Red staininig for amyloid
was negative. By immunofluorescence a granular deposition of antisera
against IgG [Fig.2
]
,
IgA, C3 and
k
and
l
chains along the external side of the basement membrane was detected in
all glomeruli. The intensity
of the fluorescence was approximately similar for immunoglobulins and
light chains. By electron microscopy the capillary wall was altered for
the presence of electron dense globular material in the sub-epithelial
aspect of the basement membrane [Fig.3].
Furthermore, large areas of effacement of foot process in several
capillaries were present.
In addition,
the mesangium was
moderately enlarged
with an increased
number of cells and matrix. By the combination of light and electron
microscopy a diagnosis of membranous
glomerulonephritis at an early stage of development was made. The large
number of sclerotic glomeruli that may indicate a preexisting renal
disease was attributed to the coexistence of hypertension.
Approximately
one month after renal biopsy, the
patient was readmitted for treatment. Serum creatinine was 1.5 mg/dl and
urea 59 mg/dl. Proteinuria
was 6.5 g/24 h. The search
for antinuclear antibodies, antibodies to native DNA, cryoglobulins and
immune-complexes was negative; C3 and C4 levels were within the normal
range. Seventy-five days after the onset of the nephrotic syndrome 100 mg
twice a day of CsA and 25 mg/day of prednisone were given. Thereafter, CsA
was adjusted at a dosage of 150 mg/day to maintain serum level between 100
and 200 ng/ml, and prednisone was decreased to 12.5 mg/day and then
withdrawn 2 months later. After
26 weeks of treatment, the
proteinuria decreased to 190 mg/24 h and the nephrotic syndrome completely
recovered. Anaemia was still present in last controls. Discussion
In
Table 1 the major characteristics of patients in which renal involvement
developed after allogeneic HCT are listed. Most of the patients were
affected by lymphoma or
leukemias. The development of
GVHD was either immediate or lasting several months after the
transplantation. MG was the prevailing pathologic finding
although minimal change disease with nephrotic syndrome was also
found
[
1;5
]
.
The high frequency of positive ANA seen in five out of ten patients may be
explained by the variety of autoantibodies detected during GVHD [10]. The
role played by CsA is intriguing. Renal symptoms develop either during
full dose therapy
[
3
]
,
during tapering
[
4
]
or after discontinuation of the
drug
[
2
]
.
CsA affects
cell-mediated immunity, is
nephrotoxic with involvement
of tubules and arterioles,
but the occurrence of MG has
never been described. The
possibility may be advanced that withdrawal or insufficient
immunosuppression may enhance the production of antibodies and the genesis
of renal damage. This hypothesis is supported by the efficacy of CsA
treatment on the disappearance of proteinuria in recipients of HCT or in
patients with idiopathic MG
[
1-9;
11
]
.
However, a cell-mediated immune injury cannot be completely excluded
because a defect in T-cell populations has been detected in MG and in
minimal change nephrotic syndrome
[
11;
12
]
.
GVHD is a life-threatening very complex disease involving several
tissues and organs, more often the skin, gastrointestinal tract and the
liver mimicking biological and clinical symptoms of systemic lupus
erythematosus or other immune-complex mediated disorders
[
13
]
.
It appears to be induced by the presence of autoantibodies against
major histocompatibility complex minor antigens produced by the
interaction between donor’s alloreactive T-helper cells and
recipient’s autoreactive B-cells
[
2;4;6
]
.
GVHD has an acute or chronic evolution and it is one of the most
important causes of morbidity and mortality following HCT.
The renal involvement in GVHD is occasional and may be attributed
to deposition on glomerular capillaries of immune-complexes as
hypothesised in idiopathic forms of MG.
Alternatively, antibodies may bound to antigens already planted on
the epithelial aspect of the glomerular basement membrane, as demonstrated
with tubular antigens in experimental models of MG
[
3;14
]
.
In this regard a number of reports have demonstrated that IgG4
predominates in idiopathic or secondary MG [15;16] suggesting that the
initiating glomerular antigen may predominantly stimulate a Th2-type
nephritogenic immunoresponse
[17]. On
the basis of available information MG in our patient was interpreted as
renal manifestation of chronic GVHD.
This conviction is also supported by the results obtained in the
murine model of GVHD in which parental-strain lymphocytes injected into F1
hybrid recipients produce a lupus-like nephropathy with glomerular
alterations reminiscent of MG, nephrotic syndrome and different classes of
autoantibodies including anti native-DNA and anti renal tubular antigens
[
4
]
.
Genetic
influences in the occurrence of MG may be excluded since the HLA aplotype
of our patient (A2, A3;
B51(5), BW4; DR W 13(W6), DR W 8, DR W 52; DQ W 1, DQ W4) is not
considered to be susceptible to develop MG [18]. It
is tempting to speculate that in our patient different classes of
antibodies induced by GVHD may have elicited glomerular lesions and
activated the processes responsible for the development of MG which
involves Th2 lymphocytes and IgG4 formation. CsA therapy by blocking T
helper cells proliferation may have reduced IgG4 production and the
consequent glomerular damage. Acknowledgement
We
wish to give special thanks to Dr. F. Pilato, Dipartimento di Anatomia
Patologica, Dr L. Allegri and
Dr L. Carnevali, Dipartimento di Clinica Medica, Nefrologia e Scienze
della Prevenzione, Università degli Studi, Parma, Italy. References
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