Renal Transplantation Pathology

Renal Transplant Basics - Matchmaking Kidneys

• Donor Types: Living (related/unrelated), Deceased (Donation after Brain Death - DBD; Donation after Circulatory Death - DCD).
• HLA System (Human Leukocyte Antigen):
  • Located on Chromosome 6p (Major Histocompatibility Complex - MHC).
  • HLA-A, HLA-B, HLA-DR are most critical for matching.
  • Goal: 0 antigen mismatch for best graft survival.
• Crossmatching (XM):
  • Tests recipient serum for pre-formed anti-donor antibodies (Donor Specific Antibodies - DSA).
  • Complement-Dependent Cytotoxicity (CDC) XM: Positive = generally an absolute contraindication.
  • Flow Cytometry XM: Higher sensitivity than CDC.
• Panel Reactive Antibody (PRA):
  • Measures recipient's sensitization to a panel of random HLA antigens.
  • ↑PRA indicates higher sensitization, making it harder to find a compatible donor.

⭐ A positive CDC (Complement-Dependent Cytotoxicity) crossmatch is generally an absolute contraindication to kidney transplantation due to the high risk of hyperacute rejection.

Allograft Rejection - Immune System Strikes

Kidney transplant rejection occurs when the recipient's immune system attacks the donor kidney. Classified by timing, mechanism, and morphology.

• Hyperacute Rejection:
  • Mins-hrs post-transplant.
  • Cause: Pre-formed anti-donor Abs (e.g., ABO, HLA). Type II HSR.
  • Patho: Diffuse thrombosis in graft vessels, fibrinoid necrosis. Irreversible.
• Acute Rejection:
  • Days to months (typically <6 months).
  • Acute Cellular Rejection (ACR): T-cell mediated (Type IV HSR).
    • Patho: Interstitial lymphocytic infiltrate, tubulitis (lymphocytes invading tubular epithelium), +/- endarteritis/endothelialitis (v-lesion).
  • Acute Antibody-Mediated Rejection (AMR): Donor-Specific Antibodies (DSA) against HLA or other antigens. Type II HSR.
    • Patho: Microvascular inflammation (glomerulitis, peritubular capillaritis), C4d deposition in PTCs, endothelial injury.
• Chronic Allograft Dysfunction/Rejection:
  • Months to years (>6 months). Immune (chronic AMR/ACR) & non-immune factors.
  • Patho: Interstitial fibrosis & tubular atrophy (IFTA), transplant glomerulopathy (TG - GBM duplication, mesangial expansion), vascular intimal fibrosis (arteriosclerosis). Progressive.

⭐ C4d deposition in peritubular capillaries (PTCs) is a key diagnostic marker for acute antibody-mediated rejection (AMR).

Key Pathologies Post-Transplant - Rogues' Gallery

• Calcineurin Inhibitor (CNI) Toxicity (Cyclosporine, Tacrolimus)
  • Acute: Toxic tubulopathy (isometric vacuolization), afferent arteriolar vasoconstriction, thrombotic microangiopathy (TMA).
  • Chronic: Arteriolar hyalinosis (nodular), tubular atrophy, striped interstitial fibrosis.
• BK Virus Nephropathy (BKVN)
  • Polyomavirus reactivation.
  • Tubular epithelial cells: enlarged nuclei, basophilic intranuclear inclusions (SV40 IHC+). "Decoy cells" in urine.
  • Interstitial nephritis, fibrosis if untreated.
  • 📌 "Decoy cells" in urine are a key indicator.
• Post-Transplant Lymphoproliferative Disorder (PTLD)
  • Mostly EBV-driven, especially early post-transplant.
  • Spectrum: polyclonal hyperplasia to monoclonal lymphoma (e.g., DLBCL).
  • Graft or systemic involvement.
• Recurrent Glomerular Diseases
  • FSGS (high risk, esp. collapsing), IgA nephropathy, MPGN, diabetic nephropathy.
  • Biopsy confirms recurrence.
• De Novo Glomerular Diseases
  • Transplant Glomerulopathy (TG): GBM duplication, endothelial injury (often chronic AMR feature).
  • Membranous nephropathy, collapsing glomerulopathy.

⭐ BKVN: allograft dysfunction; SV40 IHC+ on biopsy (viral inclusions) is diagnostic. Reduce immunosuppression.

Biopsy & Banff Score - Grading the Graft

• Allograft biopsy: Gold standard for diagnosing rejection and other graft injuries.
• Banff Classification: Standardized system scoring lesions to grade rejection.
  • Acute lesions: i (inflammation), t (tubulitis), v (arteritis), g (glomerulitis), ptc (peritubular capillaritis).
  • C4d deposition: Marker for antibody-mediated rejection (ABMR).
  • Chronic lesions: ci (fibrosis), ct (atrophy), cv (vascular thickening).
• Scores determine type (TCMR, ABMR) & grade of rejection.

⭐ DSA presence with C4d deposition & microvascular inflammation (g+ptc ≥ 2) strongly indicates active ABMR.

High‑Yield Points - ⚡ Biggest Takeaways

• Hyperacute rejection: Minutes/hours; pre-formed anti-donor antibodies (ABO/HLA); Type II HSR.
• Acute Cellular Rejection (ACR): Days/months; T-cell mediated; tubulitis & endothelialitis are key.
• Acute Antibody-Mediated Rejection (AMR): C4d deposition (PTCs), DSA, microvascular inflammation (glomerulitis, capillaritis).
• Chronic Allograft Nephropathy: Months/years; interstitial fibrosis, tubular atrophy, transplant glomerulopathy (GBM duplication).
• CNI toxicity: Arteriolar hyalinosis, isometric tubular vacuolization.
• BK Virus Nephropathy: Polyomavirus; intranuclear viral inclusions in tubules.
• PTLD: Often EBV-associated; B-cell proliferations, can become lymphoma.