Kidney nontumor
Diseases of renal allograft
Acute / chronic cellular rejection

Editor-in-Chief: Debra Zynger, M.D.

Topic Completed: 24 July 2018

Revised: 28 December 2018

Copyright: (c) 2018, PathologyOutlines.com, Inc.

PubMed Search: Kidney (acute OR chronic) cellular rejection[TI]

Related topics: Banff classification of rejection
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Page views in 2019 to date: 300
Cite this page: Sağlam A. Acute / chronic cellular rejection. PathologyOutlines.com website. http://www.pathologyoutlines.com/topic/kidneyacutechroniccellularrejection.html. Accessed February 17th, 2019.
Definition / general
  • Alloimmune reaction to major histocompatibility complex (MHC) and non-MHC donor alloantigens resulting in damage to the kidney allograft
  • Mediated by T cells and hence referred to as T cell mediated rejection (TCMR) in the Banff 2017 classification (Am J Transplant 2018;18:293)
  • 2 major subcategories:
    • Acute T cell mediated rejection: characterized by an acute immunologic reaction
    • Chronic active T cell mediated rejection: chronic renal injury due to persistent / recurrent TCMR
Essential features
  • Presence of interstitial inflammatory infiltrate characterized by tubulitis
  • Coded by the "i" and "t" Banff scores (see Grading below)
  • Inflammatory infiltrate should comprise at least 25% of the cortical parenchyma (i2 and above)
  • Tubulitis should be ≥ 5 inflammatory cells per tubular cross section (t2 and above)
  • Intimal arteritis or vasculitis may also be present (can sometimes be the sole component)
    • This lesion can be caused by T cell mediated rejection (TCMR), active antibody mediated rejection or both
Terminology
  • Acute T cell mediated rejection: also referred to as acute cellular rejection, acute interstitial rejection, acute tubulointerstitial rejection
  • Chronic active T cell mediated rejection: also referred to as chronic cellular rejection
ICD coding
Epidemiology
  • With currently used combination therapies, one year acute rejection rates have decreased to 10 - 15%
Pathophysiology
  • T cells are sensitized and react against donor antigens expressed on antigen presenting cells and donor cells; delayed type hypersensitivity is also involved (Clin Biochem 2016;49:320, Nephron 2016;132:227)
  • Macrophages and granulocytes are frequently recruited and also mediate tissue injury
Clinical features
  • Acute T cell mediated rejection (TCMR):
    • Usually seen during the first month after transplantation or later as immune suppression decreases due to noncompliance, adjustment of medication by physicians (as complications present), gastrointestinal diseases, metabolic diseases, etc.
    • Presents with acute renal failure or oliguria; may also be asymptomatic (diagnosed on protocol biopsies)
  • Chronic active TCMR: chronic renal failure with or without proteinuria; may also be asymptomatic (diagnosed on protocol biopsies)
Grading
Banff grading (modified from the latest Banff revision, Am J Transplant 2018;18:293):

  • Suspicious / borderline for acute T cell mediated rejection (TCMR):
    • Tubulitis (t > 0) with interstitial inflammation comprising ≤ 25% of the nonscarred cortex (i0 or i1)
    • Interstitial inflammation comprising > 25% of the nonscarred cortex (i2 or i3) with mild tubulitis (t1, pertaining to 1 - 4 inflammatory cells per tubular cross section)

  • Acute TCMR:
    • Grade IA: interstitial inflammation involving > 25% of nonscarred cortex (i2 or i3) with moderate tubulitis (t2) of at least one tubule, excluding atrophic tubules
    • Grade IB: interstitial inflammation involving > 25% of nonscarred cortex (i2 or i3) with severe tubulitis (t3) of at least one tubule, excluding atrophic tubules
    • Grade IIA: mild to moderate intimal arteritis (v1) ± interstitial inflammation or tubulitis
    • Grade IIB: severe intimal arteritis (v2) ± interstitial inflammation or tubulitis
    • Grade III: transmural arteritis or arterial fibrinoid necrosis of medial smooth muscle (v3) ± interstitial inflammation or tubulitis

  • Chronic active TCMR:
    • Grade IA: interstitial inflammation involving > 25% of the total cortex (ti2 or ti3) and > 25% of the scarred cortex (i-IFTA2 or i-IFTA3) with moderate tubulitis (t2) of at least one tubule, excluding severely atrophic tubules; other known causes of i-IFTA should be ruled out
    • Grade IB: interstitial inflammation involving > 25% of the total cortex (ti2 or ti3) and > 25% of the scarred cortex (i-IFTA2 or i-IFTA3) with severe tubulitis (t3) of at least one tubule, excluding severely atrophic tubules; other known causes of i-IFTA should be ruled out
    • Grade II: chronic allograft arteriopathy

  • Banff "i" interstitial inflammation scoring (Am J Transplant 2008;8:753, Zhou: Silva's Diagnostic Renal Pathology, 2nd Edition, 2017):
    • i0: < 10% of nonfibrotic cortex
    • i1: 10 - 25% of nonfibrotic cortex
    • i2: 26 - 50% of nonfibrotic cortex
    • i3: > 50% of nonfibrotic cortex

  • Banff "t" tubulitis scoring:
    • t0: no mononuclear cells in tubules
    • t1: 1 - 4 cells/tubular cross section
    • t2: 5 - 10 cells/tubular cross section
    • t3: > 10 cells/tubular cross section
Diagnosis
  • Established via indication or protocol biopsies
Laboratory
  • Acute T cell mediated rejection (TCMR): acute increase in serum creatinine levels
  • Chronic active TCMR: chronic increase in serum creatinine levels, proteinuria may develop eventually
Radiology description
Prognostic factors
  • Vascular rejection is associated with a poor long term outcome and is generally resistant to antirejection therapy (Kidney Int 2002;61:1516)
  • Eosinophils and plasma cells within the inflammatory infiltrate is associated with poor long term outcome and resistance to antirejection therapy
Case reports
Treatment
  • Pulse steroid therapy for grade I acute T cell mediated rejection (TCMR) (Talanta 2014;130:542)
  • Anti-T cell agents for grade II acute TCMR
  • Grade III acute TCMR is resistant to therapy
Gross description
  • Acute T cell mediated rejection (TCMR): kidney is swollen, cortex is pale and shiny; hemorrhage and necrosis may be present in severe cases with vascular involvement
  • Chronic active TCMR: kidney may be shrunken with surface depressions due to scarring of the underlying parenchyma; corticomedullary junction is blurred
Gross images

Images hosted on PathOut server:

Contributed by Arzu Sağlam, M.D.

Acute cellular and humoral type III rejection

Chronic active TCMR

Microscopic (histologic) description
  • Acute T cell mediated rejection (TCMR):
    • Interstitial edema and inflammatory infiltrate involving at least 25% of the nonscarred cortex; graded according to severity ("i" score ≥ 2)
    • Presence of tubulitis: inflammatory cells within and among tubular epithelial cells within the confines of the basement membrane; is graded according to severity ("t" score ≥ 2)
    • Lesser degrees of inflammation (< 25% of the nonscarred cortex - i0 or i1) or inflammation involving ≥ 25% of the nonscarred cortex ("i" score ≥ 2) but accompanied by only mild tubulitis (t0 or t1 - up to 4 inflammatory cells / tubular cross section) is considered suspicious / borderline for acute TCMR
    • Inflammatory population is mainly mononuclear - T cells and macrophages, CD4+ T cells dominate
    • Eosinophils and plasma cells may also be present, especially in severe cases and more commonly if acute TCMR develops late (after the first year of transplantation)
    • Glomeruli usually spared; however, in cases with accompanying vascular involvement, endothelial swelling and mesangiolysis may be present - acute allograft glomerulopathy
    • Vascular involvement (type II and III): inflammation of the arterial or arteriolar wall, intimal infiltration (intimal arteritis, endarteritis, endothelialitis) or transmural infiltration by lymphocytes and macrophages, with or without accompanying fibrinoid necrosis; note that these vascular lesions can also be a part of active antibody mediated (humoral) rejection and are not a defining feature (unlike tubulitis)
  • Chronic active TCMR:
    • Areas of tubular atrophy and interstitial fibrosis with mononuclear inflammatory infiltrate and tubulitis; this morphology is referred to as i-IFTA (inflammation in areas of interstitial fibrosis / tubular atrophy) (Am J Transplant 2018;18:364, Am J Transplant 2018;18:377)
    • Transplant arteriopathy: intimal fibrosis together with mononuclear cells and foam cells in the intima
    • Glomeruli may show focal segmental and global sclerosis
    • Other causes of i-IFTA (such as BK virus nephropathy, chronic pyelonephritis, antibody mediated rejection, recurrent glomerulonephritis) should be ruled out because i-IFTA is a nonspecific lesion
Microscopic (histologic) images

Images hosted on PathOut server:

Contributed by Arzu Sağlam, M.D.

Low power demonstrates prominent inflammatory infiltrate in the tubulointerstitial space; image on right has infiltrate rich in macrophages

Areas of tubulitis; note inflammatory cells within tubuli


Tubulitis: note inflammatory cells in tubuli - silver stain

Tubulitis: note inflammatory cells in tubuli - PAS stain


Left: an intraluminal lymphocyte in close contact with activated endothelium (endothelial cells are swollen); this and interstitial hemorrhage (right) should prompt one to thoroughly search for endothelialitis

Intimal arteritis: note lymphocytes and macrophages beneath the endothelium


Part 1: transmural arteritis and fibrinoid necrosis

Part 2: this case also had accompanying acute AMR and acute allograft glomerulopathy characterized by mesangiolysis, widening of the subendothelial space due to edema, better appreciated with the silver stain


Nephrectomy specimen of a patient with chronic active TCMR; note that inflammation and tubulitis are confined to areas of tubular atrophy

Transplant arteriopathy lesions in the nephrectomy specimen, intimal thickening, lymphocytic infiltration and intimal foam cells are present; note also recanalization of the lumen in image on right

Special stains
  • PAS, Jones methenamine silver and periodic acid silver methenamine stains are very useful for identifying tubulitis by highlighting the basement membrane and stromal epithelial interface
  • Silver and trichrome stains are useful for identifying fibrinoid necrosis
Molecular / cytogenetics description
  • Genome wide expression studies in kidney transplants have identified certain sets of genes / transcripts which correlate with T cell mediated rejection (TCMR) (BMC Nephrol 2015;16:132)
    • Top molecules involved with T cell effector mechanisms: granzyme, perforin
    • Top molecules involved with γ interferon effects: CXCL9, CXCL10, CXCL11
    • Top molecules involved with effector / inflammatory cell recruitment: CCL5, PSMB9
  • Molecular phenotype for TCMR however is not present amongst the criteria for TCMR in the most recent Banff classification
Differential diagnosis
  • Acute T cell mediated rejection (TCMR):
    • Acute allergic / drug induced tubulointerstitial nephritis: tubulitis may be less prominent, eosinophils may be more prominent but differentiation from acute TCMR is not possible on morphologic grounds
    • Active antibody mediated rejection (active AMR): inflammatory infiltrate mostly confined to lumen of peritubular capillaries, signs of microvascular endothelial cell injury (peritubular capillaritis, glomerulitis, thrombotic microangiopathy) and peritubular C4d positivity (immunofluorescence or immunohistochemistry) are present; active AMR frequently accompanies acute TCMR
    • Acute pyelonephritis: usually patchy inflammatory infiltrate with predominance of polymorphonuclear leucocytes, neutrophilic tubulitis and neutrophil casts within tubular lumen
    • Polyomavirus infection: usually patchy inflammatory infiltrate, viral cytopathic changes in tubular epithelial cells and positive polyomavirus immunostain (should be performed on every allograft renal biopsy specimen)
    • Posttransplant lymphoproliferative disease (PTLD): is mainly of differential diagnostic concern in cases of PTLD where inflammatory infiltrate is polymorphic; however, the presence of transformed atypical large B lymphocytes within the infiltrate is a clue to diagnosis; stains to detect EBV will help in the differential
  • Chronic active TCMR:
Board review question #1
Which of the following regarding arteritis lesions in allograft transplant biopsies is correct?

  1. Are always characterized by fibrinoid necrosis
  2. Are associated with a good prognosis
  3. Are only associated with chronic rejection
  4. Can be seen in both T cell mediated and antibody mediated rejections
  5. Indicate mild rejection
Board review answer #1
D. Can be seen in both T cell mediated and antibody mediated rejections

Comment Here
Board review question #2
32 year old renal transplant patient wished to become pregnant. Her medication was adjusted accordingly. Within 2 months, her creatinine levels increased from 0.67 to 4.28 mg/dl. The biopsy sample displayed the finding shown below. What is the most probable diagnosis?
  1. Acute pyelonephritis
  2. Acute T cell mediated rejection
  3. Chronic active antibody mediated rejection
  4. Chronic active T cell mediated rejection
  5. Posttransplant lymphoproliferative disorder
Board review answer #2
B. Acute T cell mediated rejection