HC39: Pathology of transplantation

Transplantation

A transplantation is successful if:

• There is no rejection
• There is a long graft survival

There are 2 types of rejection:

• Acute rejection: essentially a T-cell mediated response
  • Treated with for example cyclosporin → inhibits T-cell activation
  • Usually, the graft isn’t lost
• Chronic rejection: refers to scarring of the graft
  • Exact mechanism is unknown
  • Treatment is not available

T-cell mediated acute rejection

T-cell mediated acute rejection is a type of type IV hypersensitivity. This type of hypersensitivity reaction is important in:

• Graft rejection
• Lysis of virus infected cells
• Tumor immunity

CD8 T-cells kill antigen-bearing target cells → cytotoxic T-cells from the host try to kill the donor cells.

Transplantation patients often develop squamous cell carcinomas, a type of skin tumors. These are caused by the HPV virus which can be activated by immunosuppression.

Histopathology:

In case of acute rejection of the kidney, the following is visible:

• T-cells present in interstitial infiltrates → interstitial (inflammatory) infiltrate
• T-cells present in epithelium of tubes → tubulitis: interstitial rejection
• T-cells present in endothelium of vessels → endothelitis: vascular rejection

T-cells can be stained with a CD4 marker. In case of rejection, many CD4 positive T-cells will be visible by the tubuli → tubulitis. In case of vascular rejection, the lumen is filled with swollen endothelial cells with lymphocytes inside them.

Severity:

In the BENF classification, severity of acute rejection is graded from 0-3:

• 0: nil
• 1: mild
• 2: moderate
• 3: severe

This is applied as follows:

• T-cells present in interstitial infiltrates
  • i0-i3
  • Depends on the % of the interstitial area affected by the T-cells
• T-cells present in epithelium of tubes
  • t0-t3
  • Depends on the number of T-cells in a tube
• T-cells present in endothelium of vessels
  • v0-v3
  • Depends on the extent of inflammatory infiltrate and vascular changes in arteries

It isn’t necessary to know this by heart.

C4d:

C4d is a complement waste product, a footprint of classic pathway activation. C4d-positivity along the endothelium of peritubular capillaries signifies that immune complex formation has been active at the endothelial site. In this case, immune complexes of anti-donor antibodies + donor antigens are made. This signifies that some patients also have humoral rejection instead of only T-cell rejection.

Therapy for antibody-mediated rejection can consist of:

• Plasmaferesis
• Rituximab (anti-CD20)

Chronic rejection

Scarring is the most important cause of allograft loss. This is a chronic process of which the etiology is largely unknown. Beginning stages are present in 90% of protocol biopsies taken 1 year after the transplantation. There is no therapy.

Histomorphology:

Histomorphological features of chronic changes in the allograft show:

• Interstitial fibrosis
  • Collagen between the tubes
  • IFTA is a combination of interstitial fibrosis and tubular atrophy
• Tubular atrophy
  • Tubules become smaller
  • The basal membrane becomes irregular and thickened
• Glomerulosclerosis
• Chronic vasculopathy
  • Severe intimal thickening
  • No inflammation
  • Extremely narrow lumen of the vessel

Time zero biopsies:

Circa 1/3 of “time zero” renal transplant biopsies show no lesions. The other 2/3 show:

• Vessel changes
  • Atherosclerosis
  • Hyalinosis
• Glomerular changes
  • Glomerulosclerosis
  • Non-specific changes
• Renal disease
  • IgA nephropathy
    • In up to 11% of cases
    • Disappears after transplantation

Clinical background information

The main causes of end-stage renal failure are:

1. Hypertension
   • Through vascular changes
2. Diabetes mellitus
   • Diabetic nephropathy
3. Immune mediated renal disease
   • Many different diseases
   • Most frequently IgA nephropathy

Diabetes mellitus:

Irrespective of its causes, diabetes mellitus may give rise to many complications. Diabetic nephropathy develops in circa 30% of patients. Kidney involvement in diabetes is detrimental:

• Glomerular lesions are similar in type 1 and type 2 diabetes:
  • Glomerular basal membrane thickening
  • Mesangial expansion
  • Nodular lesion: Kimmelstiel Wilson lesion
• Vascular lesions: hyalinosis

A combined pancreas/kidney transplantation can form a cure for diabetes. The donor pancreas is attached to the recipient duodenum. After 1 year, the patient is cured of diabetes.

IgA nephropathy:

The cause of IgA nephropathy is unknown. It is characterized by deposits of IgA in glomeruli. Clinical findings are erythrocyte loss in urine. Eventually, IgA nephropathy leads to end-stage renal failure. It is not a reason to not do the transplant.

IgA nephropathy recurs in up to 60% of all grafts after a mean period of 5 years. The recurrent disease is similar to the original course of disease. It is not a benign condition → leads to graft loss. The prognosis is linked to the original histological aggressiveness.

Cyclosporin toxicity:

Hyalinosis is an example of cyclosporin toxicity. In this case, eosinophilic changes in the subendothelial layer of a small artery are visible. Early lesions show eosinophilic transformation of smooth muscle cells.

Vascular changes in diabetic nephropathy are also characterized by hyalinosis.

BK virus nephropathy:

BK stands for the initials of the first patient described with this virus. The BK virus is a polyomavirus present in most individuals. Under immunosuppression, it is reactivated. The subsequent T-cell response leads to tubulitis.

In the urine, decoy cells are visible. These are urothelial cells infected with the BK virus. Presence of the BK virus in the blood can be tested via PCR.

Possible therapy for BK virus nephropathy are:

• Temporarily decrease of immunosuppressants
• Anti-viral therapy

Risks of these treatments are development of acute rejection.