slide seminar - ii pathology of renal transplant

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International CME on Renal Pathology, Department of Pathology , SGPGI, Lucknow, INDIA

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14th - 16th March, 2005Coordinator: R.K. Gupta

Professor & Head

Department of Pathology

SGPGIMS, Lucknow, India


Sanjay Gandhi Postgraduate

Institute of Medical Sciences

Lucknow- 226014, INDIA

US Coordinator: Surya V. Seshan

Professor of Pathology

Chief, Renal Pathology

Weill Medical College of Cornell University

New York, NY

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Go toCaseIndex Slide Seminar - II

Pathology of Renal Transplant

Lorraine RacusenProf. of Pathology

Johns Hopkins Medical School

Baltimore, MD

R.K. Gupta Prof & Head


SGPGIMS, Lucknow

India

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Go toCaseIndex Slide Seminar- II Pathology of Renal Transplant

L Racusen & RK Gupta

• Case 1: 38 years male, 2 yrs post renal transplant biopsy

• Case 2: 65 years female, 9 days post renal transplant biopsy

• Case 3: 34 years female, 3.2 years post renal transplant with H/O UTI &…

• Case 4: 58 yrs male, 6 month post-transplant with colonic perforation

• Case 5: 31 Yrs male, 4 yrs post-transplant with duodenojejunal mass

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Case 1

• 38 year old man status post renal transplant 2-3 years before biopsy.

• Original disease was Alport’s syndrome, complicated by hypertension.

• Presented with palpitations, and was found to have a creatinine of 4.9 mg%. With hydration, his creatinine only fell to 4.1 mg%.

• He was biopsied to rule out rejection and other processes in the allograft, and to assess for chronic changes.

• There are a variety of processes in this allograft – please identify.

• What is the prognosis in the short-term? The long-term? • What special concern is there in a transplant patient with this

underlying disease?

Slide Seminar- II: Pathology of Renal Transplant - Case 1

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DISCUSSION International CME on Renal Pathology, Department of Pathology , SGPGI, Lucknow, INDIA

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Case 1

Diagnosis Acute vascular rejection, Banff Grade

2A, with severe tubulo-interstitial inflammation with C4d positivity


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Case 1• The biopsy reveals acute rejection, with mild intimal arteritis

(v1), Banff type 2A, with a severe tubulointerstitial component (i3, t3). Focal leukocyte margination is noted in glomeruli and peritubular capillaries, mononuclear with occasional neutrophils. Though difficult to assess, chronic changes are significant (ci2-3, ct2-3).

• Immunofluorescence reveals diffuse though mild linear capillary staining for C4d – R/O anti-donor antibody.

• The patient had been previously treated with OKT3, and had developed anti-OKT3 antibodies, so he was treated with thymoglobulin. There was poor response to therapy, and the patient returned to dialysis within months with a failed allograft.


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• In the setting of Banff type 2 rejection, a severe tubulointerstitial component predicts relative resistance to treatment short-term; the same study also demonstrated worse outcome with type 2B than with type 2A rejection, reinforcing the importance of making this distinction on allograft biopsy.

• The staining for C4d is diffuse, but only mild, with staining done on frozen tissue using the monoclonal antibody for C4d; the requirement for a positive reading using this technique is for strong staining, so this should be interpreted as below threshold. However, anti-donor antibody should be sought, to rule out an antibody-mediated component. The quite extensive chronic changes portend a poorer long-term (and in this case short-term!) outcome.


Case 1

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References:1. Haas M, Kraus ES, Samaniego-Picota M, et al, Acute renal

allograft rejection with intimal arteritis: histologic predictors of response to therapy and graft survival. Kidney Int 61:1516-26, 2002

2. Racusen LC, Solez K, Colvin RB, et al, The Banff 97 working classification of renal allograft pathology. Kidney Int 55:713-723, 1999

3. Racusen LC, Solez K, Colvin R. Fibrosis and atrophy in the renal allograft – Interim report and new directions. Am J Transplant 2:203-6, 2002

4. Racusen LC, Halloran PF, Solez K. Banff 2003 meeting report: new diagnostic insights and standards. Am J Transplant 4:1562-6, 2004

Case 1


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• 65 year old female had a history of chronic interstitial nephritis and was on dialysis.

• She received a living related renal transplant from her daughter 9 days prior to biopsy.

• The patient has developed a rise in creatinine after improving function post-operatively.

• A biopsy is performed to rule out rejection. What is you diagnosis? Indicate possible underlying etiologies.

Case 2Slide Seminar- II: Pathology of Renal Transplant - Case 2

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DiagnosisAcute vascular rejection, Banff Grade 2B,

with no tubulo-interstitial inflammationExtensive tubulo-toxic change

Case 2


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Case 2• The biopsy reveals acute rejection, vascular type, with

moderate-to-severe intimal arteries (v2), Banff type 2B, with no significant tubulointerstitial component (i0, t0).

• A total of 4 small arteries have intimal arteritis, of varying severity.

• There is significant and extensive isometric vacuolization of tubular cells – R/O drug toxicity.

• No chronic changes are seen. • There is minimal C4d staining in peritubular capillaries.• She was begun on steroids and thymoglobulin for the

rejection; the dose of thymoglobulin had to be decreased due to pancytopenia.

• Creatinine fell to 0.9 mg%, then stabilized at 1-1.3 mg%.


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Reference:1. Racusen LC, Solez K, Colvin RB, et al, The Banff 97

working classification of renal allograft pathology. Kidney Int 55:713-723, 1999


Case 2

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Slide Seminar – I : Pathology of Glomerular Diseases - Case 2

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• 34 year old female S/P deceased donor renal transplant 3.2 years prior to biopsy. The cause of end-stage renal disease is unknown.

• She now presents with a rise in creatnine from 1.9 to 2.9 mg%. She has multiple leukocytes in the urine, and history of recent urinary tract infection.

• There is some concern that the patient has been non-compliant with her medications. Indicate your diagnosis/diagnoses.


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Case 3

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Diagnosis Acute cellular rejection, Type IB, with

focal acute pyelonephritisMembranous glomerulonephritis

Case 3


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Case 3• The biopsy reveals acute cell-mediated rejection, moderate-to-severe

tubulointerstitial type, Banff type IB, with focally severe tubulitis (t3). In addition, there was an area in the cortex with numerous peritubular and intratubular neutrophils, consistent with bacterial infection. In addition, glomeruli show mild increase in mesangial matrix, with very mild glomerulitis (g0-1). While difficult to assess, there appear to be mild-to-moderate chronic changes (ci1-2, ct1-2).

• Immunofluorescence studies reveal no C4d staining in peritubular capillaries. However, there is diffuse granular capillary staining for IgG (2-3+), IgM (trace-1+), C3 (1+) and kappa and lambda light chains (2-3+), and C4d (2-3+).

• Electron Microscopy reveals subepithelial dense deposits, confirming a diagnosis of early membranous glomerulopathy. Presumably this is a de novo disease, thought the cause of the patient’s end-stage renal disease is unclear.

• Membranous glomerulopathy in the allograft may impinge on graft survival, but not invariably.

• Pyelonephritis in grafts is not rare – if occurring within the first 3 months, it impacts on graft survival.


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References: 1. Racusen LC, et al, Banff 97 (see above)

2. Denton MD, Singh AK. Recurrent and de novo glomerulonephritis in the renal allograft. Semin Nephrol 20:164-75. 2000

3. Hariharan S. Long-term kidney transplant survival. Am J Kidney Dis 38:S44-50, 2001

4. Seikaly MG. Recurrence of primary disease in children after renal transplantation. Ped Transplant 8:113, 2004

5. Giral et al, Acute graft pyelonephrits and long-term kidney graft outcome. Kidney Int 61:1880, 2002


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• 59 Yrs/ Male• Received live related renal allograft 6 months back• Had H/O cyclosporine toxicity and acute cellular rejection• Presented with facial swelling, raised S. creatinine, UTI and

sinusitis • Cald well luck surgery performed• Post operative patient developed acute abdominal pain,• X-ray abdomen showed gas under diaphragm and a

diagnosis of intestinal perforation was made• Exploratory laprotomy done and colonic perforation repaired• Tissue from maxillary sinus and Colonic resection margins for

histopathology

Case 4


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Maxillary Sinus

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Maxillary Sinus


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Maxillary Sinus

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Colonic Biopsy


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Case 4

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Case 4

Diagnosis: Post Renal Transplant Mucormycosis

- Maxillary Sinus and Colon


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Microscopy:• Many broad aseptate fungal hyphae• Non-parallel walls• Angioinavsion• Surrounded by multinucleated histiocytic giant cells

Follow-up• Patient died due to septicemia after second surgery

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Mucor:Ubiquitous aerobic saprophytic opportunistic fungus of low virulence, however, initiating aggressive and fatal infection in immunocompromised individuals.

Classification:Order: MucoralesClass: ZygomycetesGenera: Mucor, Rhizopus, Absidia.

Morphology:Broad, twisted, aseptate ribbon like hyphae, branching at right angles, size: 5 - 25 micron

Special stains: PAS, GSM and CSM


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• Fungal infection is an uncommon complication after renal transplantation

• Mucormycosis is rare fungal infection in immuno-suppressed patient (Approx 4% in post renal Tx)

• Common clinical presentations- Cerebral, sino-pulmonary, GIT, Kidney, disseminated and cutaneous

• Local area necrosis and angioinvasion• Fatal out come in majority of cases• A high index of suspicion, leading to early diagnosis and

initiation of antifungal treatment, in addition to early surgery, are keys to a more favorable outcome.


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References:1. Chkhotua A, Yussim A, Tovar A, etal Mucormycosis of

the renal allograft: case report and review of the literature. Transpl Int. 2001 Dec;14(6):438-41.

2. Jha V, Chugh KS. Posttransplant infections in the tropical countries. Artif. Organs 2002: 26 (9): 770- 7.

3. Reis MA, Costa RS, Ferraz AS. Causes of death in renal transplant recipients: a study of 102 autopsies from 1968 to 1991. J R Soc Med. 1995 Jan;88(1):24-7.

4. Bakshi NA, Volk EE. Pulmonary mucormycosis diagnosed by fine needle aspiration cytology. A case report.Acta Cytol. 2001 May-Jun;45(3):411-4.


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• 31 Yrs/ Male• Received live related renal allograft 4 years back• Presented with gastric outlet obstruction• Upper GI endoscopy revealed narrowing of duodeno-

jejunal junction• CT scan showed mass in D3 and D4 and proximal

jejunum• Operative findings - large well encapsulated mass in DJ

region• Resected loop of jejunum with mass for histopathology


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Case 5

Gross: • A large irregular greyish white fleshy and friable mass

with areas of haemorrhage, measuring 11x8x4cm involving 9 cm length of the jejunum.

• Mesentric fat showed haemorrhage with whitish areas.• No lymph nodes were found.


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Go toCaseIndex Slide Seminar- II : Pathology of Renal Transplant - Case 5

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Case 5

Diagnosis :Post Transplant Monomorphic Diffuse

Large B- Cell Lymphoma - Jejunum


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Case 5

• Ulcerated mucosa with dense diffuse infiltration by predominantly intermediate sized atypical lymphoid cells displaying round to irregular nuclear contours with clumped chromatin, inconspicuous nucleoli and scant to moderate amount of cytoplasm.

• Tumor was extensively present in the lamina propria• Tumor was infiltrating transmurally upto the serosa. • At places large atypical lymphoid cells with bizarre

hyperchromatic nuclei and focal lymphoplasmacytoid cells were also seen.

• Brisk mitotic activity present


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CD 20 CD 3CD 30


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CD 20 CD 3


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CD 30


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Case 5Post Transplant Lymphoproliferative Disorder (PTLD) • Heterogenous group of lymphoid proliferations.• Occuring after solid organ and bone marrow

transplantation.• Variable clinical and histopathological spectrum.• Scarce data on live related renal allograft recipients.Incidence:• Depends upon the intensity and duration of

immunosuppression.• 0.5 to 2.55 % in renal transplant recipients.• 2.2-10 % heart, lung and heart-lung transplant

recipient.


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Classifications of PTLD • Frizzerra et al 1981• Shapiro et al 1988• Nalesnik et al 1989• Knowels et al 1995• Society for Haematopathologist workshop

1997


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Society for Haematopathologist workshop (1997)

Early Lesions Reactive plasmacytic hyperplasias Infectious mononucleosis - like

PTLD PolymorphicPTLD Monomorphic

B-Cell Diffuse large cell lymphomas centroblastic / immunoblastic Burkitts / Burkitts like lymphoma T-cell lymphomas : Peripheral T-Cell lymphomas Anaplastic large cell lymphomas (T or null)

Others

Plasmacytoma like, T-cell rich / Hodgkins disease like B cell PTLD


Case 5

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Clinicopathological GroupsMinnesota group 1992

Early onset PTLD Late onset PTLD

young patients older patients

6 to 12 months 38 to 146 months

Polymorphic Monomorphic

Polyclonal Monoclonal

EBV positive EBV negative

Negative for oncogenes c-myc, ras, p53

Rx Immunosuppression Antiviral therapy

Chemotherapy


Case 5

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References:1. Nalesnik MA, Jaffe R, Starlz TE, Demetris AJ, Porter K, Burnham JA etal. The

pathology of posttransplant lymphoproliferative disorder occurring in the setting of cyclosporine A- prednisolone immunosuppression. Am J of Pathol 1988; 133(1): 173-92.

2. Harris NL, Jafe ES, Stein H, et al. A revised European-American classification of lymphoid neoplasms. A proposal from the international lymphoma study group. Blood 1994; 84: 1361-92.

3. Swerdlow SH. Classification of post transplant lymphoproliferative disorders: from the past to the present. Semin Diag Pathol 1997; 14(1): 2-7.

4. Bates WD, Gray DW, Dada MA, Chetty R, Gatter KC, Davies DR etal. Lymphoproliferative disorders in Oxford renal transplant patients. J Clin Pathol 2003; 56(6): 439-46.

5. Opelz G, Dohler B. Lymhpoma after solid organ transplantation: a collaborative transplant study report. Am J Transplant 2004; 4: 222-30.

6. Maniyur R, Anant K, Aneesh S, Vinita E, Manoj J, Rakesh P. Posttransplant epididymal lymphoma: an aggressive variant. Transplantation 2003; 75(2): 246-7.


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slide seminar - ii pathology of renal transplant

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