Acute Antibody-Mediated Rejection, Kidney



Acute Antibody-Mediated Rejection, Kidney


Lynn D. Cornell, MD





Key Facts


Etiology/Pathogenesis



  • DSA usually directed against HLA class I or II on endothelium



    • May be against ABO blood group antigens in ABO-incompatible grafts


Clinical Issues



  • Acute renal failure


  • Oliguria


  • Serum donor-specific antibody (DSA)


  • Worse allograft survival in acute AMR compared to C4d negative ACR


  • Increased risk of developing transplant glomerulopathy (chronic AMR) after acute AMR


Microscopic Pathology



  • Glomerulitis, neutrophils, monocytes, fibrin


  • Glomerular thrombi or mesangiolysis


  • Peritubular capillary neutrophils


  • Dilated peritubular capillaries


  • Diffuse, bright positive staining of peritubular capillaries for C4d


Top Differential Diagnoses



  • Acute cellular rejection


  • Pyelonephritis


  • Acute tubular necrosis


  • Accommodation



    • C4d deposition without histologic injury or graft dysfunction


    • Most likely seen in stable ABO-incompatible grafts






Glomerular intracapillary thrombi image are present in this ABO blood group-incompatible allograft. Dilated peritubular capillaries image containing marginated mononuclear cells and neutrophils are also seen.






Diffuse, bright staining of peritubular capillaries for C4d by immunofluorescence is shown. A positive C4d stain is defined as linear and diffuse PTC staining, usually taken as > 50%.


TERMINOLOGY


Abbreviations



  • Antibody-mediated rejection (AMR)


Synonyms



  • Acute humoral rejection (AHR)


ETIOLOGY/PATHOGENESIS


Donor-Specific Antibody (DSA)



  • DSA usually directed against HLA class I or II on endothelium



    • Blood group antigen in ABO-incompatible grafts


    • Other, unknown, non-MHC antigens on endothelium


  • DSA activates complement via classical pathway



    • C4d is inactive fragment of C4b of classical complement pathway


    • C4d is covalently bound at site of complement activation on endothelium


    • Complement-fixing DSA associated with greater acute graft injury


    • Terminal complement blockade with C5 inhibitor reduces early acute AMR in recipients with preformed DSA



      • Results provide evidence that most acute AMR is not only antibody mediated but also complement mediated


CLINICAL ISSUES


Epidemiology



  • Incidence



    • ˜ 25% of acute rejection episodes are due to antibody


  • Can occur any time post transplant



    • Presensitized patients at highest risk for acute AMR in 1st month post transplant


    • Some late acute AMR cases associated with immunosuppressive medication nonadherence (combined with acute cellular rejection)


Presentation



  • Acute renal failure


  • Oliguria


Laboratory Tests



  • Circulating donor-specific anti-HLA class I or II antibody in 88-95% of acute AMR with C4d deposition


  • Minority (5-10%) have undetectable DSA



    • May be due to non-HLA antibody


    • Possible antibody absorption by graft


  • High serum DSA levels in acute AMR



    • Can be measured by B- or T-cell flow crossmatch or by single-antigen bead tests


    • Serum DSA levels correlate with C4d immunofluorescence and severity of changes seen by light microscopy


Treatment



  • Plasmapheresis



    • Removes serum DSA from circulation


  • Increased immunosuppression



    • Anti-lymphocyte therapies


  • Intravenous immunoglobulin (IVIG)


  • Rituximab (anti-CD20)



    • Monoclonal antibody directed against B cells


    • Prevents B cell differentiation to plasma cells


    • Does not affect existing antibody-secreting plasma cells


  • Anti-plasma cell therapy (experimental)



    • Bortezomib



      • Proteasome inhibitor


      • Targets plasma cells actively producing immunoglobulin



      • Reduces serum DSA


      • May be combined with plasmapheresis to remove existing DSA


  • Complement inhibition (experimental)



    • Eculizumab (anti-C5)



      • Inhibits terminal complement pathway and prevents formation of membrane attack complex


      • Does not affect serum DSA level


      • Kidney biopsies show C4d(+) PTCs, as C4 is upstream of C5 in complement cascade


Prognosis



  • Worse allograft survival in acute AMR compared to C4d(-) acute cellular rejection (ACR)



    • ˜ 30% graft loss within 1 year vs. 4% graft loss for ACR


  • Increased risk of developing transplant glomerulopathy (chronic AMR)


  • Plasma cell-rich variant resistant to treatment; poor clinical outcome


MICROSCOPIC PATHOLOGY


Histologic Features



  • Glomeruli



    • Glomerulitis



      • Neutrophils


      • Monocytes


    • Enlarged/swollen endothelial cells



      • Mitotic figures sometimes seen


    • Fibrin or thrombi in capillary loops


    • Glomerular thrombi or mesangiolysis, particularly in ABO blood group-incompatible grafts


  • Peritubular capillaries (PTCs)



    • Dilated


    • Neutrophils and mononuclear cells, termed peritubular capillaritis



      • Peritubular capillaritis usually mild in early acute AHR


  • Arteries



    • Fibrinoid necrosis in minority of cases


    • Possible endothelialitis (typically an acute cellular rejection lesion)


  • Interstitium



    • Edema, sparse infiltrate


    • Hemorrhage occasionally


    • Plasma cell-rich variant of acute humoral rejection



      • Associated with edema, high interferon-γ, and increased plasma cells


  • Tubules



    • Acute tubular injury


    • Little or no tubulitis


    • Sometimes neutrophils in lumen


Banff Classification of AMR



  • Histologic patterns



    • Type I: Acute tubular injury, minimal inflammation


    • Type II: Peritubular capillary &/or glomerular capillary inflammation &/or thrombi


    • Type III: Arterial fibrinoid necrosis or transmural inflammation (v3 lesion)


  • In addition to these histologic patterns, biopsies should show diffuse peritubular capillary (PTC) C4d deposition and serologic evidence of DSA



    • C4d immunofluorescence intensity should be at least 1+


    • If only 1 of these 2 criteria (C4d, DSA) is present with histologic changes, then biopsy is “suspicious” for acute AMR


ANCILLARY TESTS


Immunohistochemistry



  • Diffuse PTC staining by immunohistochemistry (IHC)



    • IHC less sensitive than immunofluorescence (IF)


    • Circumferential peritubular capillary endothelial staining


    • Pitfall of IHC staining interpretation is serum staining for C4; may give false-positive result


Immunofluorescence



  • Diffuse, bright positive staining of PTCs for C4d




    • Small minority of probable acute AMR cases are C4d negative or very focal


    • Focal C4d (10-50%) less commonly has detectable DSA


    • C4d staining remains positive ˜ 5-7 days after removal of antibody from circulation


Electron Microscopy



  • Peritubular and glomerular capillary endothelial changes



    • Cell enlargement, loss of fenestrations, microvillous changes


    • Detachment from the basement membrane, lysis, apoptosis


DIFFERENTIAL DIAGNOSIS


Chronic AMR (CAMR)



  • CAMR biopsy features



    • Transplant glomerulopathy (TG)


    • Peritubular capillaropathy



      • PTC basement membrane multilamination


      • Best seen by electron microscopy


    • Transplant arteriopathy



      • Pattern may be due to chronic AMR or cellular rejection


      • “Accelerated arteriosclerosis” is another pattern of transplant arteriopathy due to CAMR and may be indistinguishable from arteriosclerosis due to hypertension


    • C4d may be negative or focally, multifocally, or diffusely positive


  • Mononuclear cells in capillaries; fewer neutrophils present



    • Peritubular capillaritis may be moderate to severe (Banff PTC score 2-3)


  • Usually a stable or slowly declining clinical course



    • Proteinuria often found in patients with TG


  • If acute renal insufficiency, acute AMR may occur together with features of CAMR



    • Diffuse C4d(+) PTCs


  • CAMR may be seen admixed with features of acute AMR and ACR, particularly later post transplant in patients with medication nonadherence


Acute Cellular Rejection



  • Tubulitis and interstitial inflammation


  • Endothelialitis


  • 20-30% of ACR cases are C4d positive, indicative of concurrent antibody-mediated rejection


Accommodation



  • C4d deposition without histologic evidence of graft injury and without graft dysfunction


  • Commonly seen in ABO blood group-incompatible grafts


Subclinical AMR

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Jul 9, 2016 | Posted by in PATHOLOGY & LABORATORY MEDICINE | Comments Off on Acute Antibody-Mediated Rejection, Kidney

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