Transplant pathologists play an essential role in organ transplantation by evaluating biopsies of failing organs, matching donor and recipient tissues, assessing donor organ viability, and monitoring for rejection or complications through histopathological examination of biopsies. Key tasks include initial patient evaluation, blood and tissue typing to ensure compatibility, evaluating donor organs, and monitoring allografts over time with protocol biopsies to diagnose issues like acute or chronic rejection, infection, drug toxicity, or disease recurrence. The pathologist aims to ensure transplant success and identify any issues requiring clinical intervention.

1. Transplant Pathology of Heart,
Lungs, Kidney, Liver.
Dr. Evith Pereira
Moderator : Dr. P. Patro

2. Transplantation
• The process of transferring cells, tissues or
organs called a graft, from one individual and
placing them into a (usually) different
individual.

3. Classification of grafts
• Anatomical site of origin-
- orthotopic
- heterotopic
• Genetic relation between donor and recipient-
- autograft
- isograft
- allograft
- xenograft
• Living or non-living
• Fresh or stored

4. Based on genetic relationship

5. Need for transplantation

6. KIDNEY
ESRD GFR less than 15ml/L
MALIGNANCY
HYPERTENSION
DIABETES MELLITUS
GENETIC DISEASES- polycystic kidney diseases
METABOLIC DISORDERS
AUTO IMMUNE CONDITIONS- lupus ,good
pastures syndrome
CRF

7. LIVER
END STAGE LIVER DISEASE
CHRONIC LIVER FAILURE
ACUTE FULMINANT LIVER FAILURE
PRIMARY HEPATIC MALIGNANCY
INBORN ERRORS OF METABOLISM

8. HEART

9. LUNG

10. Cells of Immune system –
TCR complex & other molecules involved in T- cell
activation
T cell

11. Cells of Immune system –
B cell

12. Major Histocompatibility Complex
(MHC)
• Set of cell surface molecule encoded by a large gene
family, control a major part of immune system.
• Major function of MHC- bind to peptide fragments
derived from foreign antigen and display them on
cell surface for recognition by appropriate T cell.
• MHC determines the compatibility between donor
and recipient for organ transplantation.
• In humans MHC region- 6th Chromosome.

13. Major Histocompatibility molecules(HLA Complex)

14. Characteristics of MHC
• Most polymorphic genes present in the genome
• Genes are expressed codominantly
• Responsible for strong rejection
• MHC class I molecules - almost all nucleated cells
• MHC class II molecules – APCs, B cells,
Macrophages

15. Antigen processing and display by MHC Molecule

16. Rejection
Immunological phenomenon associated with
inflammatory reaction leading to the failure of
graft.
Allograft rejection
• Alloantigens
- major antigens - MHC
- minor antigens
• Alloreactive cells
- lymphocytes
- antibodies

17. Rejection mainly involves
• First set rejection
• Second set rejection

18. Allograft rejection

19. Mechanism of Rejection
• Sensitization stage-
- direct pathway
- indirect pathway
• Effector stage

20. DIRECT PATHWAY
T Cell recognizes unprocessed allogenic MHC molecule
on graft APCs. (Passenger Leukocyte Hypothesis)

21. INDIRECT PATHWAY

22. EFFECTOR PHASE

23. TYPES OF GRAFT REJECTION
• Hyperacute rejection
• Acute rejection
• Chronic rejection

24. Hyperacute Rejection
• Occurs within minutes of transplantation
• Pre-existing IgM antibodies against
– ABO blood group antigens
– Class I MHC molecules .

25. Steps in hyperacute rejection

26. Acute Rejection
• Occurs within days or weeks after transplantation.
• Mediated by IgG antibodies
1- Acute cellular rejection – T cell mediated
• Activated CD4+ T cells -> Cytokines secretion -> Inflammation in
graft.
• Increased vascular permeability, local accumulation of mononuclear
cells and graft injury by the activated macrophages.
2- Acute antibody-mediated rejection
• Mediated by antidonor antibodies produced after transplantation.
• Microvascular endothelitis, interstitial inflammation, parenchymal
cell damage

27. Chronic Rejection
• Occurs over months to years
• Accelerated arteriosclerosis
• Fibrosis with loss of normal organ structures

28. Non rejection complications
• Transport injury
• Drug toxicity
• Infection
• Malignancy
• Recurrence of disease

29. Role of pathologist and biopsy
• Initial patient evaluation – failing organ
• Blood matching and histocompatibility,
assessing of donor organ
• Monitoring rejection- Protocol biopsies

30. Kidney
• Most common solid organ
• End stage renal disease- DM
• Evaluation : FNAC/ Urine analysis/ Biopsy.
Hyper acute rejection
- Fibrin and antibodies, PMN’s, Haemorrhage, Cortical
necrosis.
Hyperacute rejection
of kidney allograft-
platelet and fibrin
thrombi, neutrophil
infiltration, severe
ischemic injury in a
glomerulus.

31. Acute rejection:
Rapid decline in urine output, rise in Serum Creatinine,
Tenderness and edema of graft
Acute antibody-mediated (humoral) rejection-
inflammation in peritubular
capillaries(capillaritis)
Immunoperoxidase stain- C4d deposition
in peritubular capillaries and a
glomerulus

32. Acute T cell–mediated (cellular) rejection:
Tubulointerstitial pattern
(Common)Inflammatory cells in
the interstitium and between
epithelial cells of the tubules
(tubulitis)
Vascular pattern- Rejection
vasculitis, with inflammatory cells
attacking and undermining the
endothelium (endotheliitis)

33. Chronic rejection:
Gradual and progressive decline of renal function in
absence of specific cause that develops over months to
years after transplantation.
• Pathogenesis unclear
Chronic rejection is dominated by vascular changes –
1. Intimal thickening with inflammation.
2. Glomerulopathy with duplication of the basement membrane.
3. Peritubular capillaritis with multilayering of peritubular capillary
basement membranes.
• Interstitial fibrosis and tubular atrophy with loss of renal
parenchyma -secondary to the vascular lesions.
• Interstitial mononuclear cell infiltrates, including NK
cells and plasma cells.

34. Chronic rejection:
Glomerulus-inflammatory cells
within the capillary loops
(glomeruliitis), accumulation of
mesangial matrix, and duplication
of the capillary basement
membrane.
Interstitial fibrosis and tubular
atrophy. (trichrome stain),
contrasted with the normal
kidney.
Artery-prominent arteriosclerosis

35. Banff classification for rejection

36. Non rejection complications:
• Cyclosporin A nephrotoxicity
• Recurrent renal disease
• De novo glomerulonephritis
• Infection.

37. Liver transplantation
Hyperacute rejection:
• Uncommon – size & functional
reserve and sinusoidal architecture
limits ischemia in focal thrombosis.
• Occurs- preexisting antibodies.
• HPE
- Arteritis, neutrophilic infiltrate
with zonal or diffuse necrosis.

38. Acute rejection:
Reversible form of cell
mediated rejection.
Clinical features – fever, change
in mental status, decreased
bile output and abnormal
hepatic enzymes
Diagnostic triad:
portal inflammatory lymphoid
infiltrate, bile duct damage,
endothelitis.
Lymphocytes, eosinophils,
occasionally PMNs but no Plasma
cells
Liver transplantation
Transplanted liver with acute
cellular rejection. Mixed
inflammatory cell infiltration in
portal tracts, bile duct damage,
and endotheliitis.

39. Liver rejection grading-
University of Minnesota grading system:
Diagnosis Histologic features
Non diagnostic of
rejection
Lymphocyte or mixed portal infiltrate,
<50% damaged bile ducts, no endothelitis
Acute rejection grade 1 As above with endothelitis
Acute rejection grade 2 Lymphocyte or mixed portal infiltrate,
>50% damaged bile ducts, with/without
endothelitis
Acute rejection grade 3 Acute rejection plus arteritis, paucity of
bile ducts, or central hepatocellular
ballooning with confluent dropout of
hepatocytes.

40. Chronic rejection:
- Irreversible
- 6 -20%. Cases.
Synonyms- Ductopenic rejection & Vanishing bile duct
syndrome
Two histological pattern-
1-Chronic vascular rejection –
obliterated endarteritis – ischemic damage – liver failure
Risk factors – prior rejection, CMV, MHC matching at class I
with mismatch of class II
- Gradual liver failure – increased biliary enzymes and bilirubin
and decrease proteins
- Biopsy – central ischemic changes associated with loss of
interlobular bile ducts.
Liver transplantation-

41. 2-Pure Vanishing bile duct syndrome/ progressive
rejection with paucity of ducts:
• Near total loss of ducts without ischemic changes.
• C/F- Elevated bilirubin, minimal elevation of enzymes
and no effect on protein synthesis.
• Reversible even though chronic
CHRONIC REJECTION

42. Liver transplantation-
Non rejection complications:
• Reperfusion injury
• Infections- Hep B,C
• Drugs-Cyclosporin A
• Recurrence- HCC.
Reperfusion injury in liver allograft-
severe cholestasis and balloning
affecting perivenular & mid zonal
hepatocytes

43. Time period Common diagnosis Less likely diagnosis
First week Vascular anastomoses
Acute rejection
Primary graft failure
Hyperacute reaction
Drug reaction
Opportunistic
infection
1week to 2
months
Acute rejection
Opportunistic infection
Drug reaction
Biliary anastomoses
Chronic vascular
rejection
Vanishing bile duct
syndrome
2 months and
beyond
Chronic vascular rejection
Vanishing bile duct
syndrome
Recurrence of original
disease
Hepatitis B or C
Acute rejection
Drug reaction
Opportunistic
infection
Technical problems
Differential diagnosis of liver dysfunction post
transplantation

44. HEART TRANSPLANTATION
• Less complicated
• Protocol biopsies
Acute rejection
• Cell mediated(Common). Reversible
• Subtle cardiac enlargement, ECG changes, decreased ejection
fraction to cardiac failure
• Interstitial infiltrate of lymphocytes, with/without myocyte
damage or necrosis .

45. HEART TRANSPLANTATION
Acute humoral rejection:
• High death rate.
HPE-
• Cellular infiltrate absent in endomyocardium.
• Endothelial swelling and edema
• Immunofluorescence - Immunoglobulins on
endothelial surface (Diagnostic).

46. Acute cardiac rejection grading system
Grade Description
0 No rejection
1A Focal(perivascular/interstitial) infiltrate without necrosis
1B Diffuse but sparse infiltrate without necrosis
2 One focus with aggressive infiltration or focal myocyte
damage or both
3A Multifocal aggressive infiltration or focal myocyte
damage or both
3B Diffuse inflammatory process with necrosis
4 Diffuse aggressive polymorphous infiltrate with myocyte
necrosis, edema or haemorrhage or all signs

47. HEART TRANSPLANTATION
Chronic rejection:
Insidious process
• Concentric narrowing of coronary arteries.
• Intima – foamy histiocytes, smooth muscle cells, fibroblasts
• Arteriopathy- Concentric, continuous, rapid development &
involve small branches – r/o atherosclerosis
• Asymptomatic until sudden death due to ischemia.

48. Technical problems: Related to biopsy interpretation
• Same biopsy site – Ventricular septum near apex of
right ventricle – fibrosis and lymphocytic infiltration.
• Perioperative ischemic events – small areas of necrosis,
granulation change.
• Quilty effect – dense subendocardial accumulation of
small lymphocytes with interspersed thickened blood
vessels – Cyclosporin A

49. LUNG TRANSPLANTATION
Hyperacute rejection: within 48 hours.
Previous sensitization
• Gross- Congestion and edema, copious
frothy blood stained fluid.
• Biopsy – congestion, edema,
haemorrhage, thrombosis,
neutrophils, alveolar damage.
Immunofluorescence –
IgG in vessel wall
Neutrophils engorge the blood vessels and
enters in to alveolar interstitium and lumen

50. LUNG TRANSPLANTATION
Acute rejection:
40-75% cases
C/F- Fever, dyspnea, cough.
X-Ray- lung infiltrate/pleuropulmonary
opacification
HPE-
Prerequisite for biopsy (presence of vessels)
Perivascular infiltrate extending to adjacent
interstitium.
Endothelitis and peribronchial inflammation

51. Perivascular infiltrate extending to adjacent interstitium.
Acute lung rejection:

52. Acute pulmonary rejection grading system
• Grade 0 – no significant abnormality
• Grade 1 – minimal (difficult to find perivenular
mononuclear infiltrate)
• Grade 2 – Mild (easily found perivenular,
predominantly mononuclear infiltrate)
• Grade 3 – moderate (easily found perivenular
infiltrate with interstitial infiltrate)
• Grade 4- Severe (as grade 3 with alveolar injury, fibrin
exudates, membranes)

53. Chronic rejection:
• Incidence- 25 – 70%
• Progressive shortness of breath.
• HPE-
• Bronchiolitis obliterans- Partial or complete occlusion
of small airways by fibrosis, with or without active
inflammation
• Patchy, difficult to diagnose via transbronchial biopsy.
• Long-standing-Bronchiectasis, pulmonary fibrosis.
LUNG TRANSPLANTATION

54. LUNG TRANSPLANTATION
Chronic rejection
Occlusion of small airways by fibrosis (Bronchiolitis obliterans)

55. LUNG TRANSPLANTATION
Technical problems –
Reimplantation response – Decreased pulmonary function
with impaired ventilation, decreased compliance and edema.
(reperfusion injury)
Biopsy – dilated lymphatics, edema neutrophilic infiltration
Infections – P. carinii pneumonia, CMV, HSV, EBV, Fungi.
Recurrence of disease

56. PREVENTION OF GRAFT REJECTION
Histocompatibility testing
Post-operative immunosuppressive therapy

57. Histocompatibility testing
• ABO typing
• HLA typing: determination of HLA phenotype
of donor & recipient

58. • Typing methods-
1. Tissue typing-
- Microlymphocytotoxicity test
- Mixed lymphocyte reaction
2. Cross matching
3. Molecular methods-
- PCR - SBT
- SSP - SSOP
4. Detection of preformed antibodies
- ELISA
- Flow cytometry
58

59. SUMMARY
• Role of pathologist-
• Biopsy of failing organ.
• Matching of blood types and histocompatibility
of graft.
• Verify viability of tissue while transplantation.
• Histopathological evaluation- Monitoring
rejection, complication (Infection, drug toxicity,
disease recurrence).

60. THANK YOU