Examkin

Question

Difficulty: MediumImmunologic and Inflammatory Processes

A 38-year-old man is evaluated in the nephrology clinic for a gradual increase in serum creatinine over the past two weeks. He underwent a deceased-donor renal transplantation 8 months ago for end-stage renal disease secondary to IgA nephropathy. His current medications include tacrolimus, mycophenolate mofetil, and prednisone. His blood pressure is 148/92 mmHg. Physical examination is unremarkable, and the patient reports no fever or dysuria. Laboratory studies show a serum creatinine of 2.6 mg/dL, an increase from his baseline of 1.3 mg/dL. A renal ultrasound reveals normal allograft size with no hydronephrosis and normal resistive indices. A renal allograft biopsy is performed. Immunofluorescence staining of the biopsy specimen reveals diffuse, strong linear deposition of C4d along the peritubular capillaries. Which of the following is the most likely initiating immunopathologic event responsible for this patient's current allograft dysfunction?

  1. Binding of newly formed recipient immunoglobulins to donor human leukocyte antigensAnswer
  2. B
    Infiltration of the tubulointerstitium and tubules by recipient CD8-positive lymphocytes
  3. C
    Rapid microvascular thrombosis mediated by preformed recipient anti-ABO antibodies
  4. D
    Nodular arteriolar hyalinosis driven by calcineurin inhibitor-induced vasoconstriction
  5. E
    Fibrin deposition and platelet aggregation driven by widespread activation of the coagulation cascade

Answer

The correct answer is the binding of newly formed recipient immunoglobulins to donor human leukocyte antigens.
The correct answer identifies the fundamental pathophysiology of acute antibody-mediated rejection (AMR). AMR is caused by the development of *de novo* donor-specific antibodies (DSAs) in the recipient, which bind to donor human leukocyte antigens (HLAs) on the graft endothelium. This antigen-antibody complex powerfully activates the classical complement cascade, leading to the cleavage of C4 and the covalent binding of the inactive C4d fragment to the local endothelial surface. Therefore, diffuse peritubular capillary C4d staining is considered the hallmark diagnostic signature of AMR.

Step-by-Step Solution

1
Analyze the clinical presentation and timeline.
The patient is 8 months post-renal transplant and presents with acute allograft dysfunction (elevated creatinine).
Establishing the timeline helps rule out hyperacute rejection (minutes to hours) and makes acute or chronic processes more likely.
2
Interpret the specific diagnostic biopsy finding.
The biopsy shows diffuse linear deposition of C4d along peritubular capillaries.
C4d is a degradation product of the classical complement pathway. Its presence on the endothelium is a specific marker for antibody-antigen interaction in the transplanted organ.
3
Correlate the biopsy finding with the immunopathologic mechanism.
C4d positivity indicates Acute Antibody-Mediated Rejection (AMR), which is caused by the recipient forming donor-specific antibodies (DSAs) against the donor's HLA molecules.
Identifying the correct mechanism is required to select the targeted option differentiating it from T-cell-mediated cellular rejection or drug toxicity.

Key Concept

Acute Antibody-Mediated Rejection (AMR) pathophysiology
Rate this question

Topics

Immunologic and Inflammatory Processes

More questions from this topic