College of American Pathologists

2010—November Case of the Month

Posted December 20, 2010


CAP Foundation November 2010 Online Case of the Month

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A 56-year-old woman with end-stage renal disease underwent renal transplant. The creatinine levels remained abnormal and despite immunosuppression adjustments, she finally required hemodialysis. Immunosuppression was discontinued and she developed fever. A transplant nephrectomy was performed after 6 weeks.

Archive Case and Diagnosis: This case first appeared as Performance Improvement Program in Surgical Pathology (PIP) 2007, Case 18 and is an acute cellular allograft rejection.

Criteria for Diagnosis and Comments: The sections of kidney show severe tubulitis, interstitial inflammation, and severe subintimal arteritis and thrombosis, correlating to Grade IIB acute cellular rejection. The interstitium is edematous with areas of hemorrhage, which, along with focal white cells infiltrating the arterial media (transmural arteritis), is suggestive of antibody-mediated rejection.

This nephrectomy specimen, taken from a patient whose anti-rejection therapy had been discontinued, shows a more severe, exaggerated form of rejection than is seen in the usual needle biopsy from an immunosuppressed patient.

All the pathologic changes fit under the diagnosis of acute cellular rejection. There are occasional leukocytes migrating through the arterial media, and the widespread interstitial hemorrhage suggests endothelial damage. However, neither finding is diagnostic of humoral rejection. In the absence of serologic evidence of anti-donor antibodies or immunopathologic demonstration of C4d in the peritubular capillaries, the best diagnosis remains acute cellular rejection. This kidney would evolve to chronic allograft nephropathy, but at this point, the interstitial and tubular changes are too acute.

The Banff Classification of Renal Allograft Pathology is a semi-quantitative system which guides current therapy for transplant patients. The classification was initially focused on acute cellular rejection, but since 2003, the diagnostic categories include 1) Normal; 2) Antibody-mediated rejection; 3) Borderline changes, “suspicious” for acute cellular rejection; 4) Acute/active cellular rejection; 5) Chronic/sclerosing allograft nephropathy; and 6) Other-- changes not considered to be due to rejection. Typically rejection is diagnosed on core biopsy, and an “adequate sample” requires two cores containing a minimum of seven glomeruli and two arteries.

The cardinal histologic features of acute/active cellular rejection are tubulitis and arteritis. In the absence of arteritis, a minimum threshold of tubulitis (greater than 4 mononuclear cells per tubular cross section) and interstitial inflammation (greater than 25% of the cortex) must be reached for a diagnosis of acute cellular rejection. Below that threshold is borderline rejection, which corresponds to at least 10% interstitial inflammation, foci of mild tubulitis (1 to 4 mononuclear cells per tubular cross section), and no intimal arteritis. Grade I acute cellular rejection is diagnosed with greater than 25% interstitial inflammation and moderate tubulitis (5 to 10 mononuclear cells per tubular cross section; Grade IA) or severe tubulitis (greater than 10 mononuclear cells per tubular cross section; Grade IB).

Banff classification of acute cellular rejection (ACR)
Borderline changes suspicious for ACR)-Less than 25% interstitial inflammation
-Mild tubulitis
-No intimal arteritis or arterial fibrinoid necrosis

Grade 1 ACR Tubulointerstitial type-Significant interstitial inflammation (>25% of non-fibrotic cortex)
-Moderate tubulitis (>4 lymphocytes/tubular cross section): grade 1A
-Severe tubulitis (>10 lymphocytes/tubular cross section): grade 1B

Grade 2 ACR, Vascular type -Intimal arteritis
<25% luminal occlusion: grade 2A
>25% luminal occlusion: grade 2B

Grade 3 ACRTransmural arteritis or fibrinoid necrosis

Intimal arteritis is a lymphocytic infiltration beneath the endothelium (as opposed to inflammation in the media with or without fibrinoid necrosis). Intimal arteritis itself is diagnostic of Grade II acute cellular rejection, characterized according to the most severely involved vessel as mild to moderate (Grade IIA) or severe (greater than 25% luminal area compromised in at least one cross-section; Grade IIB). Grade III acute cellular rejection is transmural arteritis and/or arterial fibrinoid change, which may also be seen in antibody-mediated rejection.

The criteria for antibody-mediated rejection are documented anti-donor antibody and immunopathologic demonstration of complement split product C4d deposition in peritubular capillaries along with acute tubular injury (Grade I); neutrophils or mononuclear cells in peritubular capillaries and/or glomeruli, and/or capillary thrombosis (Grade II); or transmural arteritis/fibrinoid change (Grade III). Often, cases will meet criteria for both acute cellular and antibody-mediated rejection, and should be reported as such. Antibody-mediated rejection may also occur in combination with chronic allograft nephropathy.

Chronic/sclerosing allograft nephropathy is a non-specific term for progressive renal allograft dysfunction due to causes that include chronic (immune) rejection, hypertension, cyclosporine toxicity, and chronic infection and/or reflux. The diagnosis is useful because while the majority of cases cannot be linked to a particular cause, it provides a morphologic correlate for the decreased function. It also implies that the changes are irreversible and represent fixed loss of function. Chronic allograft nephropathy is characterized by interstitial fibrosis and tubular atrophy, and is graded quantitatively—Grade I (mild; less than 25% of cortical area/tubules affected), Grade II (moderate; 26 to 50% affected), and Grade III (severe; greater than 50% affected). Changes indicating chronic rejection include intimal fibrosis with inflammatory cells, duplication of the glomerular basement membrane, and increase in mesangial matrix. Features of superimposed acute rejection may be seen.

Cyclosporine or tacrolimus toxicity and infections must be considered in the differential diagnosis for acute rejection. These are associated with tubular vacuolization, damage to glomerular capillaries and renal arterioles, and interstitial fibrosis. Chronic cyclosporine or tacrolimus toxicity is associated with nodular arteriolar hyaline change.

Bacterial infections are manifest by neutrophils in the interstitium and tubular lumina. Cytomegalovirus, polyomavirus, and adenovirus can also infect an allograft. Polyoma virus nephropathy (PVN) typically occurs several months after transplantation and can be divided into three stages. Stage A has only a few infected cells with minimal interstitial inflammation or fibrosis. Stage B is the active or florid stage with marked interstitial inflammation and tubular damage with mild or moderate fibrosis. The infiltrate is comprised of lymphocytes with variable number of plasma cells. Stage C is the late stage with severe interstitial fibrosis; inflammation and variable tubular damage. The tubular epithelial cells show characteristic amorphous basophilic viral inclusions in the nucleus and margination of nuclear chromatin. Other less common appearances include eosinophilic granular inclusion surrounded by a halo and a vesicular nucleus with irregularly clumped chromatin or nucleoli. The diagnosis can be easily confirmed with immunohistochemistry. Diagnosis of acute rejection in the setting of PVN is extremely difficult. Presence of tubulitis in areas away from viral inclusions, presence of endarteritis or C4d deposits in peritubular capillaries favor concomitant rejection.

An important entity to differentiate from the above infections and from rejection is post-transplant lymphoproliferative disorder (PTLD), which shows an aggressive mononuclear infiltrate expanding and displacing normal structures. The infiltrate in PTLD is comprised predominantly of Epstein-Barr virus (EBV) positive polyclonal B-cells, while the infiltrate in rejection is mostly T-cells, making immunohistochemistry for CD3 and CD20 and in situ hybridization for EBV a useful diagnostic adjunct. Therapy for PTLD involves reducing immunosuppression, which underscores the importance of differentiating rejection from other disease processes involving the allograft.

Supplementary Questions For each of the following, select the most likely diagnosis from the diagnostic set (an answer may be used once, more than once, or not at all).

Question Diagnostic Set
1. Which condition shows non-specific changes of interstitial fibrosis and tubular atrophy? A. Acute cellular allograft rejection
B. Acute tubular necrosis
C. Chronic allograft nephropathy
D. Cyclosporine/tacrolimus toxicity
E. Post-transplant lymphoproliferative disorder
2. Which condition is graded according to severity of tubulitis or arteritis? A. Acute cellular allograft rejection
B. Acute tubular necrosis
C. Chronic allograft nephropathy
D. Cyclosporine/tacrolimus toxicity
E. Post-transplant lymphoproliferative disorder
3. Which condition shows a predominantly B-cell infiltrate? A. Acute cellular allograft rejection
B. Acute tubular necrosis
C. Chronic allograft nephropathy
D. Cyclosporine/tacrolimus toxicity
E. Post-transplant lymphoproliferative disorder


  1. Collins AB, Schneeberger EE, Pascual MA, et al. Complement activation in acute humoral renal allograft rejection: diagnostic significance of C4d deposits in peritubular capillaries. J Am Soc Nephrol. 1999;10:2208-2214.
  2. Colvin, RB. Chronic allograft nephropathy. N Engl J Med. 2003;24:2288-2290.
  3. John R, Herzenberg AM. Our approach to a renal transplant biopsy. J Clin Pathol 2010;63:26-37.
  4. Racusen LC, Colvin RB, Solez K, et al. Antibody-mediated rejection criteria—an addition to the Banff 97 classification of renal allograft rejection. Am J Transplantation. 2003;3:708-714.
  5. Racusen LC, Solez K, Colvin RB, et al. The Banff 97 working classification of renal allograft pathology. Kidney Int. 1999;55:713-723.
  6. Randhawa PS, Demetris AJ, Pietrzak B, Nalesnik MA. Histopathology of renal post-transplant lymphoproliferation: comparison with rejection using the Banff Schema. Am J Kidney Dis. 1996;28:578-584.
  7. Solez K, Axelsen RA, Benediktsson H, et al. International standardization of criteria for the histologic diagnosis of renal allograft rejection: the Banff working classification of kidney transplant pathology. Kidney Int. 1993;44:411-422.

Vijaya B. Reddy, MD, FCAP
Surgical Pathology Committee
Rush University Medical Center
Chicago, IL