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Renal Pathology
Tuesday, March 23, 7:30 PM
Maryland
Clinical histories are printed below.
Click on the case numbers for text and references of each case.
Click on each slide thumbnail image for an enlarged view
Challenging Renal Transplant Biopsies
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Moderator:
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MARK HAAS
Cedars-Sinai Medical Center
Los Angeles, CA
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Disclosure:
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In accordance with ACCME guidelines regarding disclosure, the USCAP policy requires that faculty members who have a significant financial or other relationship with a commercial company, entity, or service (which will be discussed in this Symposium) must disclose this to attendees. The Academy also requires that speakers disclose any products that are not labeled for the use under discussion. The speakers listed below have indicated they have nothing to disclose.
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Panelists:
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IAN W. GIBSON, University of Manitoba, Winnipeg, Manitoba, Canada
INGEBORG BAJEMA, Leiden University Medical Center, Leiden, Netherlands
CYNTHIA C. NAST, Cedars-Sinai Medical Center, Los Angeles, CA
SERENA M. BAGNASCO, Johns Hopkins University School of Medicine, Baltimore, MD
LILLIAN W. GABER, The Methodist Hospital, Houston, TX
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Clinical histories are displayed below.
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for Text and References
Submitted by: Cynthia C. Nast, Cedars-Sinai Medical Center, Los Angeles, CA
History of Present Illness: 53 year old Filipino female with end stage renal disease thought to be secondary to long standing severe hypertension. She underwent a deceased donor transplant (39 hours cold ischemia time) and induction therapy included steroids, thymoglobulin and mycophenolate. On POD #6 she was steroid-free, and tacrolimus was begun on POD#10, with subtherapeutic levels until POD#15 at which time the serum creatinine declined from a peak of 5.2 mg/dl to 1.8 mg/dl. Five days later the serum creatinine increased to 2.7 mg/dl at which time she also experienced hypotension and had a urinary tract infection for which IV vancomycin was administered.
Past Medical History: Severe hypertension as noted above with coronary artery disease. Remote history of tuberculosis.
Medications: mycophenolate, tacrolimus, septra nightly, cipro, vancomycin, valcyte, sporanox, magnesium oxide, labetolol, diltiazem, catapres, minoxidil, hydralazine,
Review of Systems: Noncontributory.
Physical Exam: BP: 130/63 T: 97.8 HR: 62 RR: 16
Chest: clear
Heart: regular rate, loud murmur
Abd: nontender, well-healed incision, no herniation.
Ext: 1-2+ bilateral lower extremity edema. Foley catheter draining clear urine
Neuro: Alert and oriented
Case 1 - Figure 1
The large artery wall is unremarkable. Tubular cells focally are flattened with dilated lumina but no inflammation.
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Case 1 - Figure 2
The glomerulus is hypercellular but the tubulo-interstitium and artery have no inflammation.
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Case 1 - Figure 3
Glomerular capillaries often are obliterated with inflammatory cells. There is no inflammation in the small artery or the walls of tubules.
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Case 1 - Figure 4
Higher magnification of a glomerulus demonstrating many mononuclear leukocytes within capillary lumina. Capillary walls are predominantly single contoured.
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Case 1 - Figure 5
There are lymphocytes, monocytes and few neutrophils in glomerular capillaries.
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Case 1 - Figure 6
There is no tubulo-interstitial, peritubular capillary or vascular inflammation. Few tubular cells show loss of cytoplasmic volume with mild luminal dilatation.
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Case 1 - Figure 7
Tubular epithelial cells are flattened and show acute injury.
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Case 1 - Figure 8
Granular to confluent granular IgM within arterial walls.
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Case 1 - Figure 9
Glomerular capillary walls with subendothelial flocculent material, swollen endothelium, and early deposition of new basement membrane material in the subendothelial area (double contour formation).
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Case 1 - Figure 10
Multilayered peritubular capillary basement membrane.
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Case 1 - Figure 11
C4d immunostain is negative.
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Case 1 - Figure 12
Glomerulus with segmental podocyte hypertrophy,and cytoplasmic vacuoles and protein reabsorption droplets near the tubular pole.
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Case 1 - Figure 12a
There is moderate glomerular inflammation primarily with mononuclear leukocytes. Note the arteriole has no abnormalities.
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Case 1 - Figure 13
Thre is necrosis of tubular epithelial cells with a mitotic figure showing regeneration.
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Case 1 - Figure 14
Arteriole with fibrin in the walls.
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Case 1 - Figure 15
Glomerular capillary showing swollen endothelial cell cytoplasm, subendothelial lucency and new subendothelial basement membrane material.
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for Text and References
Submitted by: Serena M. Bagnasco, Johns Hopkins University School of Medicine, Baltimore, MD
At the time of biopsy the patient was a 72 year old white male with past medical history of hypertension, and achalasia, found to have renal failure with serum creatinine 9 mg/dl, during hospitalization for chest pain.
A native kidney biopsy showed “Necrotizing crescentic GN, c/w anti-GBM disease”
with positive anti-GBM titer: 7.7 U/ml (NV:<3 U/ml).
He underwent transplant from deceased donor followed by DGF with slow serum creatinine stabilization to baseline ~1.3 mg/dl.
The post transplant course included:
Repair of anterior wall hernia, and recurrent esophageal stricture.
2.7 years post transplant: a severe stenosis of right and left coronary arteries was diagnosed, and was followed by CABG x3.
2 weeks post CABG he developed internal jugular vein thrombosis (started on anticoagulant), pleural effusions, had an episode of altered mental status, and his serum creatinine increased up to 2.6-3 mg/dl.
~1.5 months post CABG his creatinine had reached 7 mg/dl, he was hospitalized, and underwent bladder decompression with incomplete recovery of renal function, and serum creatinine of 4.9 mg/ml at discharge.
~2.9 years post transplant , due to persistence of elevated serum creatinine a graft biopsy was performed.
Laboratory tests at time of biopsy, serology was pending:
Na 134 mEq/L
K 5.4 mEq/L
CO2 20 mEq/L
Glucose 104 mg/dl
BUN 70 mg/dl
Creat 5.3 mg/dl
Ca 8.8 mg/dl
Tot Prot 5.3 g/dl
Albumin 2.8 g/dl
Total Bilirubin 0.3 mg/dl
Alk. Phosp. 36 U/L
Asp. Amino Transf. 8 U/L
Ala. Amino Transf. 9 U/L
AnionGap 14 U/L
WBC 13,100 c/cu mm
RBC 3.47 M/cu mm
Ht 29.9 %
Platelet 491 K/cu mm
ESR 58 mm/hr
IgA 236 mg/dl
C-R Prot 6.4 mg/dl
Tacrolimus 9.8 ng/dl
Medications at time of biopsy:
Prednisone 5 mg/day, Tacrolimus 3 mg/day, Zocor 10 mg/day, Darbepoetin alpha 25 mcg/7 days, Myfortic 360 mg x3/day, Norvasc 5 mg/day, Tamsulosin 0.8 mg/day
for Text and References
Submitted by: Ingeborg Bajema, Leiden University Medical Center, Leiden, Netherlands
This 60-year-old male was diagnosed with Wegener's Granulomatosis 8 years ago. A native renal biopsy at that time showed a pauci-immune crescentic glomerulonephritis. There were 20 glomeruli, one was globally sclerosed. All other glomeruli were affected by extracapillary proliferation, some contained fibrinoid necrosis. There was a moderate interstitial infiltrate. There was no extensive interstitial fibrosis or tubular atrophy. Despite extensive treatment with immunosuppressive therapy, the patient gradually developed renal insufficiency. Six years after the initial diagnosis, he received a postmortal renal transplant. The procedure was without complications. Because the patient was entered into a clinical trial, a protocolized renal transplant biopsy was taken 12 days after transplantation. This showed 13 glomeruli of which one was globally sclerosed, the others were without histopathological abnormalities. Tubuli showed signs of recovered ATN. There was minimal intimal fibrosis of large arteries. In three years time, his renal function slightly deteriorated (serum creatinine levels rose from 170 to 220 micromol/l). A renal biopsy was performed. The main clinical question was: Chronic allograft nephropathy?
At the time of his second renal transplant biopsy, 3 years after transplantion, the following laboratory data were available for the renal pathologist: MDRD 25 Proteinuria: 0.7 grams/24 hours Edema: 1+ Urine sediment: no abnormalities Serum cholesterol: 4.93
Case 3 - Figure 5
TX2_C4d: C4d staining is minimally positive in the second biopsy |
Case 3 - Figure 6
TX2_hyalinosis: arteriolar hyalinosis in the second renal biopsy |
Case 3 - Figure 7
TX2_IFTA: interstitial fibrosis and tubular atrophy in the second biopsy |
for Text and References
Submitted by: Ian W. Gibson, University of Manitoba, Winnipeg, Manitoba, Canada
A 54-year old male undergoing peritoneal dialysis for end-stage renal disease due to hereditary nephritis, received a kidney transplant from a living unrelated donor. The donor was a 2-antigen match (1A, 1DR) and the crossmatch was negative using flow cytometry. Both donor and recipient were CMV positive. The recipient was treated with prednisone, mycophenolate (1 g bid), and tacrolimus, with the last of these being started one week prior to transplantation; he did not receive induction/anti-lymphocyte antibody therapy. The transplant surgery was uncomplicated, and renal function was immediate; no dialysis was required post-transplant, and the patient's serum creatinine dropped to 156 umol/L (1.76 mg/dl) at one week.
Early post-transplant, the patient complained of odynophagia, and he underwent an upper GI endoscopy on post-transplant day 6, which revealed a ring of discrete ulcers in the lower esophagus, suggestive of viral esophagitis. Biopsies were taken, and the patient was started on valganciclovir 450 mg bid, following which his symptoms quickly improved. The esophageal biopsy showed ulcerated squamous mucosa with regenerative changes, negative for viral inclusions and fungal organisms. Viral cultures and immunocytochemical stains for HSV and CMV of the esophageal biopsy were both ultimately negative. The patient was maintained on valganciclovir at the same dose, in addition to his immunosuppression.
He was noted to have viral cytopathic changes (“decoy cells”) in his urine on routine monitoring at 12 days post-transplant, and these changes persisted. Weekly serum PCR for BK and JC viruses were negative throughout the post-transplant course. Serum for donor-specific antibodies was negative.
An ultrasound of his allograft, performed 2 weeks post-transplant due to persistently high serum creatinine (around 150-170 umol/L), was suggestive of renal artery stenosis. A conventional renal angiogram was then performed, which showed no stenosis.
Serum creatinine steadily increased to 190 umol/L (2.15 mg/dl). The patient was clinically well, and repeat ultrasound of the allograft was normal. Acute rejection was suspected, and the patient was given an oral dose of 200 mg of prednisone, followed by a taper. A renal allograft biopsy was performed three days later, at six weeks post-transplant (biopsy 1, Slide 1, Figures 1 - 10).
One week later, serum creatinine had risen to 283 umol/L (3.2 mg/dl), and a repeat renal allograft biopsy was performed at seven weeks post-transplant (biopsy 2, Slide 2, Figures 11 - 17).
Case 4 - Slide 1
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Case 4 - Slide 2
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Renal Allograft Biopsy no.1
Case 4 - Figure 1
Focal severe tubulointerstitial inflammation, peritubular capillaritis (Banff score ptc3), tubulitis and tubular epithelial injury (H&E). |
Case 4 - Figure 2
Severe tubulointerstitial inflammation, tubulitis (Banff score t3) and tubular epithelial injury with denuded tubular basement membrane (H&E). |
Case 4 - Figure 3
Severe tubulointerstitial inflammation, tubulitis (Banff score t3) and tubular epithelial injury, with tubular mitotic figure (H&E). |
Case 4 - Figure 4
Severe tubulointerstitial inflammation, tubulitis (Banff score t3) and tubular epithelial injury (H&E). |
Case 4 - Figure 5
Severe tubulointerstitial inflammation and edema, and focus of intimal arteritis with subendothelial mononuclear cell infiltration, Banff score v1 (H&E). |
Case 4 - Figure 6
Nodular area of granulomatous interstitial inflammation surrounding injured tubules (H&E). |
Case 4 - Figure 7
Dense interstitial infiltrate with activated lymphohistiocytic cells (H&E). |
Case 4 - Figure 8
Palisading epithelioid cell granuloma surrounding tubule with tubulitis, severe tubular necrosis and smudgy intranuclear inclusions (H&E). |
Case 4 - Figure 9
Tubule with enlarged hyperchromatic smudgy intranuclear inclusion bodies and tubular cell necrosis (H&E). |
Case 4 - Figure 10
Tubule with enlarged hyperchromatic smudgy intranuclear inclusion bodies (H&E). |
Case 4 - Figure 11
Positive tubular nuclear staining for adenovirus DNA (in situ hybridization performed by Dr P. Randhawa, University of Pittsburgh Medical Centre) |
Renal Allograft Biopsy no.2
Case 4 - Figure 5
Moderate acute transplant glomerulitis, with mononuclear cells and neutrophils, Banff score g2 (H&E). |
Case 4 - Figure 6
Moderate acute transplant glomerulitis, with mononuclear cells and neutrophils, Banff score g2 (PAMS). |
Case 4 - Figure 7
Severe peritubular capillaritis with predominantly mononuclear cells, Banff score ptc3 (H&E). |
for Text and References
Submitted by: Lillian W. Gaber, The Methodist Hospital, Houston, TX
A 63-year-old female, with past medical history of arthritis, elevated uric acid, anemia, HTN, anxiety and panic attacks was first seen in 1987, at age 40 for renal dysfunction ( Scr 1.7mg/dl), Proteinuria (700 mg/24 hr), and hematuria.
The patient had slow progression to end stage kidney disease. At the time when transplant work up was initiated in 2002 her 24 hour urine collection had 7.0 gm of protein.
She underwent a kidney transplant from a living unrelated donor in 2002. Post transplant Immune suppression consisted of prednisone, Cellcept and Neoral, which was later switched to Prograf in 2003.
Post transplant renal function was generally stable (baseline serum creatinine around 1.3 mg/dl). She had fluctuations in renal function attributed to calcineurin nephrotoxicity that responded to adjustments of immune suppression medications.
Proteinuria (urine protein/creatinine ratio of 1) was first detected in 2002, and slowly progressed over the following 7 years to nephrotic range proteinuria. The patient refused to undergo diagnostic renal biopsy.
Finally, the patient consented to a kidney biopsy to investigate nephrotic range proteinuria in 2009. The enal allograft biopsy was entirely submitted for light microscopy.
Pertinent Laboratory Data:
Serum creatinine: 1.8 mg/dl Creatinine clearance: 27.8 ml/min U p/c ration: 3.5 Serum albumin: 4.0 gm/dl Serum Cholesterol: 184 mg/dl
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