Full text of DOI:10.1016/S0272-6386(00)70066-7

RENAL BIOPSY TEACHING CASE
A 37-Year-Old Woman With Systemic Lupus Erythematosus
and Acute Allograft Failure
Monica P. Revelo, MD, Paisit Pauesakon, MD, Mark Weidner, MD, J. Harold Helderman, MD,
Robert G. Horn, MD, and Agnes B. Fogo, MD
INDEX WORDS: Systemic lupus erythematosus (SLE); recurrent glomerulonephritis; kidney transplant.
ber 1998, a routine physical examination showed edema of
the lower extremities, and laboratory tests showed increased
HE RENAL BIOPSY is considered the gold
standard method for the diagnosis of the
T
serum creatinine (7.2 mg/dL), nephrotic-range proteinuria
(3.8 g/24 h), congestive heart failure, and pleural effusion.
Hemodialysis was necessary for her renal failure. Labora-
tory data showed positive antinuclear antibody (ANA) (1:
80), elevated double-stranded anti-DNA (30.2 IU/mL), and
low level of C3 (53 mg/dL). A renal biopsy in December
1998 showed proliferative lupus nephritis (World Health
Organization [WHO] class IV) with moderate chronicity.
She continued to progress despite increased immunosuppres-
sion, and an elective renal transplant was planned.
Her medical history included breast implants in 1988;
hypothyroidism since 1990 treated with levothyroxin; low
left ventricular systolic function, hypertension for 7 years,
which worsened considerably before she started dialysis,
and left eye legally blind since birth.
processes that cause graft dysfunction. Complete
morphological studies must be systematically
applied to these samples to specifically assess the
etiology of those processes. The likelihood of a
particular etiology largely depends on the inter-
val since transplantation. In the early posttrans-
plantation period, most cases of renal dysfunc-
tion are etiology by acute tubular necrosis,
reperfusion injury, acute rejection, drug toxicity,
obstruction, surgical complications, or infection.
Later in the time course, other causes of graft
dysfunction include chronic transplant nephropa-
thy, cyclosporine toxicity, and recurrent or de
novo glomerular diseases. However, recurrent
disease also should be considered in some cases
in the immediate posttransplantation period.
We present a renal transplant recipient with
systemic lupus erythematosus (SLE) and early
allograft dysfunction and rapid graft failure. The
serial biopsies and complete morphological stud-
ies permitted a specific diagnosis in this case.
Her family history was positive for diabetes and SLE,
recently diagnosed in her father. Her mother, sister, and two
daughters were in good health. Her social history was
negative for tobacco or alcohol usage, intravenous drug
abuse, or sexually transmitted disease. Review of systems
was otherwise unremarkable.
Physical examination showed a well-developed, well-
nourished 37-year-old woman with height of 168 cm and
weight of 54 kg. Blood pressure was 170/98 mm Hg, heart
rate was 82 beats/min, and she was afebrile. There was a
functioning left forearm fistula with a strong bruit and thrill,
but no skin erythema was present. She had a prominent S2
and very soft S1. The remainder of the physical examination
was within normal limits. Results of admission laboratory
tests were unremarkable. Chest radiograph showed marked
cardiomegaly and evidence of old granulomatous disease,
but no active infiltrate or effusion. Serological tests were
negative for hepatitis B, hepatitis C, human immunodefi-
ciency virus, and cytomegalovirus. The histocompatibility
studies showed 0 HLA antigen match with the donor and
negative cytotoxic cross-match.
CASE REPORT
A 37-year-old white woman was admitted to our institu-
tion in July 1999 for an elective living nonrelated kidney
transplant. She was diagnosed 8 years earlier with SLE at an
outside hospital and was treated then with a course of
prednisone (80 mg/d) for 6 months. She tolerated her treat-
ment well and had no symptoms related to SLE until 1996,
when she developed malar rash without joint pain. In Septem-
The patient received a living unrelated renal transplant
from her husband on July 1, 1999. On the day of transplanta-
tion, there were no clinical signs of activity of SLE. A
baseline kidney donor biopsy was performed as part of a
protocol study and showed no significant histopathologic
changes. Her immunosuppression consisted of cyclosporine
A (250 mg twice daily), prednisone (10 mg three times
daily), and randomization to either mycophenolate mofetil
or RAD, a rapamycin derivative. No induction therapy was
used. The patient also received antihypertensive drugs (ateno-
lol 50 mg/d, nifedipine 60 mg twice daily) and prophylaxis
for Pneumocystis carinii pneumonia (dapsone 1 g/d). The
From the Department of Pathology and Division of Ne-
phrology, Vanderbilt University, and Private Laboratory for
Renal Biopsy Pathology, Nashville, TN.
Received and accepted as submitted December 27, 1999.
Address reprint requests to Agnes B. Fogo, MD, Depart-
ment of Pathology, C3310 Medical Center North, Vanderbilt
University Medical Center, Nashville, TN 37232-2561.
E-mail: agnes.fogo@mcmail.vanderbilt.edu
2000 by the National Kidney Foundation, Inc.
0272-6386/00/3506-0029$3.00/0
doi:10.1053/ajkd.2000.7495
௠
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American Journal of Kidney Diseases, Vol 35, No 6 (June), 2000: pp 1242-1247

SLE AND ALLOGRAFT FAILURE
1243
allograft had immediate function, and the serum creatinine
steadily decreased to 1.1 mg/dL by postoperative day 3 with
excellent urine output. Ultrasound and renogram showed
good flow and function of the graft. Other laboratory tests
showed positive ANA (1:40) and anti-DNA (1:160) and low
C3, 34 mg/dL (reference range, 88 to 201 mg/dL), and low
C4, 6 mg/dL (reference range, 15 to 45 mg/dL), and hemato-
crit 32%. The patient presented malar rash on postoperative
day 3 and was discharged on postoperative day 4.
rosing features. In many loops there were large plaque-like
subendothelial deposits, associated with circumferential mes-
angial interposition. Moderate diffuse interstitial fibrosis and
extensive tubular atrophy were present, accompanied by a
moderate infiltrate of lymphocytes and plasma cells. Immu-
nofluorescence (IF) microscopy showed ‘‘full house’’ stain-
ing with immunoglobulins and complements in mesangial
areas and capillary loops. Electron microscopy (EM) showed
mesangial and subendothelial deposits without reticular ag-
gregates.
On postoperative day 5, her serum creatinine increased to
1.5 mg/dL associated with arthralgias, myalgias, and diminu-
tion in renal function. An ultrasound indicated no obstruc-
tion or leak. A renogram showed worsened renal function.
Cyclosporine levels were not elevated (217 mg/mL). She
was admitted for an elective transplant biopsy, with a clini-
cal differential diagnosis of acute rejection, recurrence of
lupus nephritis, or less likely hemolytic-uremic syndrome.
This biopsy showed mild acute cellular rejection and mesan-
gial deposits (see below). She was then treated with bolus
methylprednisolone and antithymocyte globulin (75 mg/d).
The patient was then stable until postoperative day 10,
when she was noted to have increasing oxygen requirements
and back pain. Her serum creatinine had progressively gone
up to 6.1 mg/dL. On postoperative day 11, prothrombin time
was 16.3 seconds, partial thromboplastin time was 92.3
seconds, and hematocrit was 25%. A renogram showed
marked dysfunction, and Doppler ultrasound showed almost
no flow to the cortex. Antibodies against HLA-DR antigen
of the donor were detected in the serum, indicating humoral
rejection. She was taken to the operating room and under-
went a transplant nephrectomy, which she tolerated with no
complications.
Biopsy of the transplanted kidney at baseline showed no
significant histopathologic changes by light microscopy (LM)
with no deposits by IF and EM and no reticular aggregates.
A second biopsy of the graft performed on postoperative
day 6 showed features of acute rejection with mild tubulitis
and an associated mild lymphocytic infiltrate involving
approximately 5% to 10% of the biopsy specimen (Fig 1),
without evidence of endothelialitis. There were occasional
interstitial neutrophils and very rare eosinophils. Rare red
blood cell casts were present in tubules, and there was mild
fibrosis and tubular atrophy involving approximately 5% to
10% of the sample. Two of the 22 sampled glomeruli
showed global sclerosis, and open glomeruli showed only
rare neutrophils and mononuclear cells in capillary loops. IF
showed 1ϩ (scale, 0 to 3ϩ) granular, mesangial staining
with C3 (Fig 2), and C1q and nuclear staining with C3.
Immunoglobulin A (IgA) and IgM were negative, and IgG
showed only faint accentuation of the glomerular basement
membrane (GBM). EM studies showed normal GBM thick-
ness without subepithelial or subendothelial electron-dense
deposits. There were small to medium-sized mesangial elec-
tron-dense deposits (Fig 3). Glomerular epithelial cells
showed mild (10%) foot process effacement. Endothelial
cells were unremarkable without reticular aggregates, and
the tubular basement membranes did not show deposits. The
final diagnoses were mild acute cellular rejection and, in
addition, mesangial deposits of C3 and C1q suggestive of
early recurrent lupus nephritis.
Renal Biopsy Findings
A native kidney biopsy performed in December 1998
showed typical diffuse proliferative lupus nephritis, with
moderate activity and chronicity. There were 20 glomeruli
sampled, about a third of them obsolescent. The remaining
glomeruli showed moderate irregular proliferative and scle-
The nephrectomy specimen showed extensive areas of
Fig 1. Day 6 renal biopsy
with mild interstitial lympho-
cytic infiltrate with focal tu-
bulitis indicative of acute cel-
lular rejection (Jones’ silver
stain, original magnification
؋500).

1244
REVELO ET AL
Fig 2. Day 6 renal biopsy
with 1؉ granular mesangial
C3 staining. (Antisera for C3,
original magnification ؋500.)
cortical necrosis involving approximately 40% of the kidney
parenchyma. There was intimal arteritis of interlobular and
large arteries diagnostic of acute vascular rejection (Fig 4).
There was no fibrinoid necrosis, but neutrophils were pres-
ent within the intima, and occasional glomeruli showed
polymorphonuclear neutrophils cells within capillary loops.
In addition, the interstitium showed lymphoplasmacytic in-
filtrate with frequent tubulitis indicative of acute tubulointer-
stitial rejection. IF showed predominant mesangial staining
with C3 (trace to 1ϩ), C1q (1ϩ) and very trace mesangial
staining with IgG and polyvalent antisera. EM studies showed
rare mesangial electron-dense deposits, without reticular
aggregates. The diagnoses were acute vascular and cellular
rejection with extensive cortical necrosis, and mesangial
deposits of IgG, C3, and C1q, indicative of recurrent lupus
nephritis.
Final Diagnosis
The final diagnosis was acute vascular and cellular rejec-
tion and recurrent lupus nephritis.
Clinical Follow-Up
The day after nephrectomy, the hematocrit dropped to
13% and the patient had increasing oxygen requirement,
necessitating transfusion. On the second day after nephrec-
tomy, an abdominal computed tomography scan showed a
large retroperitoneal hematoma, which was evacuated. The
Fig 3. Day 6 renal biopsy
with electron-dense mesan-
gial deposits. (Transmission
electron microscopy, origi-
nal magnificaiton ؋25,550).

SLE AND ALLOGRAFT FAILURE
1245
Fig 4. Day 11 transplant
nephrectomy specimen illus-
trates intimal arteritis with
rare neutrophils and swollen
endothelium. (Jones’ silver
stain, original magnification
؋500.)
patient stabilized and the rest of her hospital course was
uneventful. She was discharged on postnephrectomy day 8
on dialysis.
728 transplants, an incidence of recurrence of
2.7%.4-8 However, recent studies showed a higher
incidence of recurrence of LN.9,10 In our series of
46 SLE patients who received transplants, a 24%
recurrence rate was observed, with one case of
loss of the graft due to recurrence.9 Stone et al10
reported 8.5% recurrence in a series of 97 pa-
tients who were followed-up for an average of
62.6 months. Three of these patients with recur-
rence presented serological evidence of active
lupus, and in four cases, the recurrence of LN
contributed to graft loss.
The timing of recurrence of LN is variable
among the studies. This most likely only is a
reflection of the time when graft biopsies were
performed for other clinical indications, such as
suspected acute rejection. No studies with proto-
cols for serial elective biopsies in transplanted
lupus patients have been performed that could
determine the exact timing of recurrence of LN.
Our patient’s course illustrates the possibility of
very early development of new immune com-
plexes in the graft, within days of transplant.
This second biopsy was performed based on a
clinical suspicion of acute rejection, confirmed
by biopsy, although the patient did not present
clinical evidence of lupus nephritis, such as he-
maturia or proteinuria. Of note, LM alone did not
permit recognition of recurrent LN in this biopsy,
whereas the demonstration of immune com-
plexes by IF and EM gave unquestionable evi-
dence of recurrence of an immune complex–
DISCUSSION
Recurrence of the primary disease in the kid-
ney allograft has been estimated to account for
less than 2% to 4% of all allograft failure.1 The
incidence of recurrence varies by disease, the
most frequent being focal segmental glomerulo-
sclerosis and membranoproliferative glomerulo-
nephritis.1-3 Although the recurrence of lupus
nephritis (LN) has been reported in the allograft,
there are conflicting data about its incidence. For
several reasons, the exact incidence of recur-
rence of LN is difficult to establish. These in-
clude underreporting of recurrence, insufficient
follow-up to detect all recurrences, and the diffi-
culty in distinguishing recurrent LN from other
causes of impaired graft function such as acute
rejection or chronic transplant nephropathy in
the absence of the allograft biopsy, or even with
biopsy if only LM examination is done. There-
fore, renal biopsy remains the only accurate
method for the diagnosis of recurrent disease in
the kidney allograft. It is likely that such cases of
subclinical recurrence would be detected more
frequently if IF and EM studies were applied
systematically.
Several studies have suggested that LN has
very low rates of recurrence. In a review of
several studies, including case reports, 20 defi-
nite cases of recurrence of LN were observed in

1246
REVELO ET AL
mediated process, namely lupus nephritis. Our
patient’s biopsy also showed evolution of the
deposits in LN with early C3 and C1q and IgG
detected later. Stone et al10 described an even
earlier case of recurrence of LN on postoperative
day 5. This donor was a 16-year-old boy with no
known underlying illnesses who died of acciden-
tal causes. By LM, the biopsy showed mild
increases in mesangial matrix and mesangial
cells. The IF showed deposits of IgG, IgA, C3,
and C1q, and by EM, mesangial electron-dense
deposits were shown, and no reticular aggregates
were described.
To minimize the risk of recurrence of LN in
the graft, a 3-month interval from onset of end-
stage renal disease (ESRD) treatment until trans-
plantation in SLE patients has been suggested.11-13
This recommendation is based on the observed
loss of clinical and serological activity of SLE
that often precedes ESRD. This activity is not
affected by either the mode of dialysis treatment
or by kidney transplantation.4,7 Several mecha-
nisms have been suggested for this burn-out
phenomenon, including impaired cellular and
humoral responses caused by uremia and per-
haps the natural progression of the disease to-
ward diminished activity over time.4,5 However,
serological parameters seem to be unreliable
predictors of either recurrence or outcome after
transplantation.7
The most important cause of early graft loss in
lupus patients appears to be acute rejection. In a
series of 69 transplanted lupus patients, the rela-
tive risk of acute rejection in the first posttrans-
plantation year was 1.7 compared with the con-
trol group.14 This may be partly related to the
higher incidence of preformed antibodies in lu-
pus patients. The titer of preformed antibodies
correlates inversely with graft survival, presum-
ably because of an increase in the likelihood of
rejection in patients with higher levels of pre-
formed antibodies.5,10 In this patient, the demon-
stration of high levels of antibodies to donor
antigen correlated with graft loss caused by se-
vere acute vascular rejection.
series,9 only 3 of 11 patients with recurrent LN
showed proliferative changes by LM. Mesangial
deposits were the most frequent manifestation of
recurrent LN present in five patients, and a
membranous LN was present in three patients.
Recurrent LN may have the same pattern as the
original disease, although several cases of trans-
formation of the histological lesions have been
reported.8,15,16 Fernandez et al16 reported a pa-
tient with a cadaveric transplant for diffuse prolif-
erative LN that in the allograft recurred initially
as a membranous LN pattern 2 years after trans-
plantation. A subsequent biopsy approximately 6
months later showed transformation to diffuse
proliferative LN. Transformations of diffuse pro-
liferative pattern to focal proliferative pattern, or
from membranous to diffuse proliferative LN,
also have been reported.15 Thus, patients may
have recurrence of LN with either milder or more
severe forms than their original disease.
Overall, the recurrence of LN is rarely respon-
sible for graft failure, as is the case for most
recurrent glomerular diseases.1,3,17 A notable ex-
ception to this generalization is recurrent focal
segmental glomerulosclerosis, which doubles the
risk of allograft failure.1 The graft loss with
recurrent LN may reflect lessened disease activ-
ity and/or the effect of immunosuppression.5,7
In summary, this case shows the value of
baseline donor biopsies in definitively excluding
preexistent diseases in the graft and the value of
complete morphological studies with LM, IF,
and EM in selected transplant biopsies. Although
recurrence of immune complex diseases in the
transplant is rare, it may affect graft outcome.1
Undoubtedly, there are many examples of sub-
clinical recurrences that are never detected or
specifically diagnosed because experimental sur-
vey serial biopsies are not performed. Screening
in clinically indicated renal biopsy specimens for
recurrent or de novo immune complex diseases
with IF allows early detection of potentially
important disease processes affecting the graft.18
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SLE AND ALLOGRAFT FAILURE
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