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Renal Pathology
Tantalizing Transplant Topics
Wednesday, March 2, 2005 - 7:30 PM
Convention Center, Room 007 A-D
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Moderator:
Agnes Fogo
Vanderbilt University Medical Center
Nashville, TN
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Click on each slide thumbnail image for an enlarged view
Submitted by:
Volker Nickeleit
University of North Carolina
Chapel Hill, NC
The patient is a 39-year-old African American male who had developed end stage renal disease
(presumably secondary to hypertension). He had been on hemodialysis for more than 5 years.
In August 2004 the patient received a renal transplant of cadaveric origin. A zero-hour implantation
biopsy only revealed unremarkable medullary parenchyma. The graft functioned reasonably well post
surgery (baseline serum creatinine reading 10 days post transplantation: 1.6 mg/dl). The patient was
enrolled into a "blinded drug trial protocol" with baseline immunosuppression consisting of
cysclosporine, prednisone and a study drug (either mycophenolate mofetil or FTY720). During the first 2
months after surgery the patient experienced a complicated clinical course with wound dehiscence and
infection requiring surgical intervention and antibiotic therapy.
Laboratory Results
Serum creatinine:
| 8/04 | 1.6 mg/dl |
| 9/04 | 2.3 mg/dl |
| 10/04 | 2.6 mg/dl |
| 11/04 | 2.3 mg/dl |
Urine analysis:
| No hematuria or proteinuria |
| Urine cytology | 8/04
9/04
10/04 | no decoy cells
no decoy cells
between 40 and 100 decoy cells / 10 high power fields |
| Urine PCR | 10/04 | 200.000.000 BK-virus copies/ml |
Blood:
| Serum PCR | 8/04 - 11/04
10/04 | no detection of CMV or EBV
600 BK-virus copies / ml serum |
Unsuccessful biopsy attempts end of October; diagnostic graft biopsy 11/18/2004.
Submitted by:
Lorraine C. Racusen
Johns Hopkins School of Medicine
Baltimore, MD
The patient is an 18 year old male 11 months status post his second kidney transplant. He had
developed end-stage renal disease by the age of 12 due to chronic tubulo-interstitial disease of unknown
etiology. After about a year on peritoneal dialysis, the patient had received an initial living
unrelated transplant from an altruistic donor. The graft was a 3-antigen match; the patient was CMV and
EBV negative. The donor was CMV positive, and appropriate prophylaxis was given. A biopsy was performed
5 days post transplant for deterioration of renal function, and revealed focal thrombotic microangiopathy
(TMA), with very focal infarction. Because of concern about possible tacrolimus toxicity, he was
converted to Cellcept and prednisone, and eventually to cyclosporine. He subsequently had 2
biopsy-documented episodes of acute rejection, perhaps due to non-compliance, at 1 month and 13 months
post transplant. Both rejections were mild vascular type, Banff type 2A, with a significant
tubulo-interstitial component; immuno-staining for C4d was not being done at that time. He was treated
with OKT3 and ATGAM for these rejection episodes. Chronic allograft dysfunction and fibrosis evolved in
the graft, and he returned to dialysis. Due to recurrent fevers, rejection, and persistent requirement
for immunosuppression, he underwent graft nephrectomy approximately 2.7 years post-transplant.
Histological examination revealed acute and chronic rejection, with focal transmural arteritis and
extensive fibrosis in vessels and parenchyma; no viral inclusions were detected.
The second allograft was a 6 antigen match from a deceased donor. He had thymoglobulin induction
to avoid steroid use (he had avascular necrosis with involvement of right femoral head) and to avoid
calcineurin inhibitors. He had initial good urine output, but only slow decline in serum creatinine. He
developed fevers, migratory arthralgias, and decreased platelets and hemoglobin – testing for anti-donor
antibody was repeatedly negative. At 12 days post-transplant, a biopsy revealed acute rejection, Banff
type 2A, with diffuse capillary staining for C4d. He remained antibody negative, and he was treated with
OKT3, with return of brisk urine output and fall in creatinine to 1.3 mg%. He was discharged on
Rapamycin and Cellcept.
In the subsequent few months, he had a persistent lymphocele around the kidney, and required
placement of drains and a nephrostomy tube. A biopsy at 4 months revealed infiltrates suspicious for
rejection, with mild capillary margination and diffuse capillary staining for C4d (1-2+); antibody
screens remained negative. At 6.3 months post transplant, he presented with fever, abdominal pain,
increased drain output and graft tenderness. Open renal biopsy revealed acute rejection, Banff type 2B,
superimposed on chronic rejection. Neutrophil margination was noted in capillaries, with "fairly
diffuse" staining for C4d (1-2+). Approximately 9 months post transplant, he was hospitalized to place a
JP drain in the perinephric lymphocele; culture of fluid revealed VRE, treated with antibiotics. Renal
biopsy revealed acute rejection, Banff type 2A, with moderate evolving chronic changes and neutrophils in
glomerular and peritubular capillaries – R/O anti-donor antibody; screens for anti-donor antibody
remained negative. The patient had been chronically hypertensive on multiple medications. He was
switched from Rapamycin to cyclopsporine, due to marrow suppression. At 11 months post-transplant, he
developed a lung infiltrate and required ventilator support. His immunosuppression was stopped, and he
developed a clinical acute rejection. Allograft nephrectomy was performed.
Submitted by:
Robert B. Colvin
Massachusetts General Hospital
Boston, MA
Present Illness: 57 y.o. white woman had a transplant 10 years ago from a
cadaveric donor. She experienced no episodes of rejection. Beginning 3 years ago pregressive renal
dysfunction developed with creatinines 1.9-2.9 mg/dl and with the new onset of 3+ proteinuria. A recent
urine protein was 1.2 grams/24 hours. Has been maintained on cyclosporine (225 mg/d), azathioprine (75
mg/d) and prednisone 5 mg/d). Has difficult to control hypertension (on Atenolol and Losartan) and
hyperlipidemia. History of glomerulonephritis at age 19 (no further information). Physical: BP 145/89. Labs: Blood cyclosporine 239
ng/ml., Cr 7.5 mg/dl., albumin 3.3 gm/dl.
Past Medical History: No history of diabetes mellitus, IV drug abuse or
infections. Splenectomy post- trauma at age 38 and partial thyroidectomy for a benign thyroid nodule 2
years previously.
She was put on hemodialysis. Two months later she received a living unrelated kidney transplant.
The sample for review is a nephrectomy performed as part of the transplant procedure (PAS stain, photos
of EM and IF).
Submitted by:
M. Barry Stokes
Columbia Presbyterian Medical Center
New York, NY
A 60 year-old Caucasian female developed chronic renal failure from focal segmental
glomerulosclerosis and received a living-related renal allograft from her 28-year-old son. She presented
initially at age 48 with nephrotic syndrome and mild renal insufficiency (serum creatinine 1.5 mg/dL) and
was treated with prednisone, with partial remission of proteinuria. Renal function continued to decline
over the next 10 years, leading to hemodialysis two years previously.
Her past medical history was significant for hypertension for 25 years, hypothyroidism, and
FK506-induced diabetes mellitus. Her operative course was unremarkable. Post-operative ultrasound
showed good arterial and venous flow and no evidence of obstruction. She was discharged seven days
post-operatively with a serum creatinine of 1mg/dL. Her immunosuppressive regimen consisted of FK506,
mycophenolate mofetil, and prednisone.
Four weeks post-transplant, the patient developed 3+ lower extremity edema. Urinalysis revealed 4+
protein with no RBCs and no WBCs. 24-hour urine collection contained 4.5grams protein. Laboratory values
were notable for serum albumin of 3.6 g/dL. Serum creatinine was 1.0 mg/dL. FK506 levels were within
therapeutic range. A renal ultrasound was negative for obstruction. A renal biopsy was performed.
Immunofluorescence showed no staining of peritubular capillaries for C4d and no glomerular staining for
IgG, IgM, IgA, C3, or C1.
Submitted by:
Charles E. Alpers
University of Washington Medical Center
Seattle, WA
The patient is a 60 year-old female who received a 2-antigen match kidney transplant from a 36
year-old living unrelated donor.
The patient's original disease was established by renal biopsy 20 years prior to transplantation. Her
renal presentation was that of an asymptomatic low serum albumin and subnephrotic proteinuria detected
during an evaluation for pneumonia at that time. The patient was also found to have an elevated serum
creatinine of 2.5 mg/dl. Laboratory workup at that time was unrevealing, and a renal biopsy established
a diagnosis of membranous nephropathy based on characteristic immunofluorescence and electron microscopic
findings. Slowly progressive renal insufficiency ensued over two decades, without development of
nephrotic syndrome and without treatment directed to the membranous nephropathy, leading to ESRD and
transplantation. The only significant concurrent medical disease was hypertension, controlled with
multidrug regimens. Noteworthy aspects of her clinical presentation were an intermittently positive ANA
serology and a family history that included a brother with an elevated serum creatinine, a niece with
systemic lupus, and one child (out of five) with an episode of "nephritis" at age 5 that resolved with
steroid therapy and did not recur.
At the time of transplantation, the patient was EBV, IgG positive but EBNA and CMV negative. The
donor was EBV positive and CMV negative. Induction immunosuppression utilized steroids and
thymoglobulin, with sequential introduction of mycophenolate and neoral cyclosporine. The patient had
immediate graft function following transplantation, with a serum creatinine falling to 0.3 mg/dl on the
day of transplantation and maintained between 0.8 and 1.0 mg/dl in the months thereafter.
Her post-transplant course was initially unremarkable, complicated only by mild fluctuations in blood
pressure, and she was maintained on a triple immunosuppression regimen of prednisone, cyclosporine, and
mycophenolate. Three evaluations in the first year following transplantation failed to detect
significant proteinuria. Approximately one year post-transplant she noted weight gain. She had a
measured 24-hour urinary protein excretion of 2.0 gm. Her serum creatinine remained in the 1.1 mg/dl
range. The renal biopsy available to you was performed 14 months following transplantation to evaluate
the basis for her increasing proteinuria.
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