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Differential diagnosis between infection and rejection in renal allografts
Differential Diagnosis Between Infection and Rejection in Renal Allografts R.B. Colvin and S. Mauiyyedi
I
NFECTION and rejection each cause renal allograft dysfunction but have diametrically opposite therapy. Infection injuries the kidney (1) by direct parenchymal infection (e.g., polyoma virus), (2) indirectly by a systemic response to the infection (e.g., immune complexes or thrombotic microangiopathy [e.g. hepatitis C virus],1 (3) promoting a rejection reaction (e.g., CMV), (4) induction of neoplastic cells which infiltrate the kidney (e.g., EpsteinBarr virus), and (5) toxic or allergic responses to antimicrobial drugs.2 Here the most common infections that mimic graft rejection will be reviewed: polyoma virus, HCV, and EBV. Rejection can be unequivocally diagnosed if either endarteritis (acute cellular rejection) or C4d deposition in peritubular capillaries (acute humoral rejection) is present.2,3 Tubulitis and an interstitial infiltrate are common in infections and are nonspecific. BK polyomavirus causes interstitial nephritis and ureteral stenosis in immuno-incompetent patients, a complication more prevalent since 1995, coincident with the introduction of tacrolimus and mycophenolate (MMF). The key step in the diagnosis is the recognition of enlarged tubular cell nuclei, with lavender stippled inclusions, particularly collecting ducts in the cortex and outer medulla. Apoptosis of tubular cells and plasma cells are conspicuous.4 Immunohistochemistry for polyoma large T antigen and electron microscopy are useful confirmatory tests. The use of PCR to detect viral DNA in the circulation has been reported to distinguish those with interstitial nephritis from noninvasive urothelial shedding of the virus.5 The risk factors for BK interstitial nephritis among those with “polyoma-uria” include transplantation after 1995, recurrent rejection episodes and switching from cyclosporine (CsA)/azathioprine to tacrolimus/MMF.6 Others have noted a high frequency of MMF-treated patients.7 Increased immunosuppression (treating for presumed rejection) has led to loss of 67% of grafts; decreased immunosuppression has preserved function in most, but 38% are left with Cr ⬎ 3 mg/dL. HCV is associated with three forms of allograft injury: (1) acute and chronic allograft glomerulopathy,8,9 (2) immune complex–mediated glomerulonephritis (membranoproliferative type I or membranous glomerulonephritis),10 and (3) thrombotic microangiopathy related to antiphospholipid antibodies. The differential diagnosis rests primarily on the demonstration of immune complexes by IF or EM.9 0041-1345/01/$–see front matter PII S0041-1345(00)02676-2
The other pathogenetic mechanism most often associated with chronic renal allograft glomerulopathy in our experience is chronic humoral rejection (60%), as evidenced by C4d deposition in the peritubular capillaries and circulating anti-donor antibodies.9 The thrombotic microangiopathy may be mistaken for immunophilin inhibitor toxicity and has a poor prognosis.11 These lesions also resemble acute humoral rejection which is best diagnosed by staining frozen sections for C4d and checking the serum for antidonor MHC antibodies.3 EBV causes posttransplant lymphoproliferative disease (PTLD), which may be restricted to the kidney and be manifested by a dense mononuclear infiltrate of lymphoblasts and tubulitis, sometimes confused with acute rejection. PTLD is distinctive in having a densely packed monomorphic lymphoblasts without other cell types and with no edema. The diagnosis is made by immunohistochemistry for B cells (CD20, /) and in situ hybridization for EBER.12 PTLD restricted to the graft is more likely to be of donor origin and to respond to therapy.2
REFERENCES 1. Mauiyyedi S, Baid S, Pascual M, et al: Mod Pathol 13:176A, 2000 2. Colvin RB: In Jennette JC, et al (eds): Heptinstall’s Pathology of the Kidney. Philadelphia: Lippincott-Raven; 1998, p 1409 3. Collins AB, Schneeberger EE, Pascual MA, et al: J Am Soc Nephrol 10:2208, 1999 4. van Gorder MA, Della Pelle P, Henson JW, et al: Am J Pathol 154:1273, 1999 5. Nickeleit V, Klimkait T, Binet IF, et al: N Engl J Med 342:1309, 2000 6. Binet I, Nickeleit V, Hirsch HH, et al: Transplantation 67:918, 1999 7. Howell DN, Smith SR, Butterly DW, et al: Transplantation 68:1279, 1999 8. Cosio FG, Roche Z, Agarwal A, et al: Am J Kidney Dis 28:752, 1996 From the Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts, USA. Address reprint requests to Dr R.B. Colvin, Dept of Pathology, Massachusetts General Hospital, Warren 225, Boston, MA 02140. © 2001 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010
1778
Transplantation Proceedings, 33, 1778–1779 (2001)
DIFFERENTIAL DIAGNOSIS 9. Mauiyyedi S, Della Pelle P, Saidman S, et al: J Am Soc Nephrol (in press) 10. Gallay BJ, Alpers CE, Davis CL, et al: Am J Kidney Dis 26:662, 1995
1779 11. Baid S, Pascual M, Williams WW Jr, et al: J Am Soc Nephrol 10:146, 1999 12. Randhawa PS, Magnone M, Jordan M, et al: Am J Surg Pathol 20:563, 1996
I
NFECTION and rejection each cause renal allograft dysfunction but have diametrically opposite therapy. Infection injuries the kidney (1) by direct parenchymal infection (e.g., polyoma virus), (2) indirectly by a systemic response to the infection (e.g., immune complexes or thrombotic microangiopathy [e.g. hepatitis C virus],1 (3) promoting a rejection reaction (e.g., CMV), (4) induction of neoplastic cells which infiltrate the kidney (e.g., EpsteinBarr virus), and (5) toxic or allergic responses to antimicrobial drugs.2 Here the most common infections that mimic graft rejection will be reviewed: polyoma virus, HCV, and EBV. Rejection can be unequivocally diagnosed if either endarteritis (acute cellular rejection) or C4d deposition in peritubular capillaries (acute humoral rejection) is present.2,3 Tubulitis and an interstitial infiltrate are common in infections and are nonspecific. BK polyomavirus causes interstitial nephritis and ureteral stenosis in immuno-incompetent patients, a complication more prevalent since 1995, coincident with the introduction of tacrolimus and mycophenolate (MMF). The key step in the diagnosis is the recognition of enlarged tubular cell nuclei, with lavender stippled inclusions, particularly collecting ducts in the cortex and outer medulla. Apoptosis of tubular cells and plasma cells are conspicuous.4 Immunohistochemistry for polyoma large T antigen and electron microscopy are useful confirmatory tests. The use of PCR to detect viral DNA in the circulation has been reported to distinguish those with interstitial nephritis from noninvasive urothelial shedding of the virus.5 The risk factors for BK interstitial nephritis among those with “polyoma-uria” include transplantation after 1995, recurrent rejection episodes and switching from cyclosporine (CsA)/azathioprine to tacrolimus/MMF.6 Others have noted a high frequency of MMF-treated patients.7 Increased immunosuppression (treating for presumed rejection) has led to loss of 67% of grafts; decreased immunosuppression has preserved function in most, but 38% are left with Cr ⬎ 3 mg/dL. HCV is associated with three forms of allograft injury: (1) acute and chronic allograft glomerulopathy,8,9 (2) immune complex–mediated glomerulonephritis (membranoproliferative type I or membranous glomerulonephritis),10 and (3) thrombotic microangiopathy related to antiphospholipid antibodies. The differential diagnosis rests primarily on the demonstration of immune complexes by IF or EM.9 0041-1345/01/$–see front matter PII S0041-1345(00)02676-2
The other pathogenetic mechanism most often associated with chronic renal allograft glomerulopathy in our experience is chronic humoral rejection (60%), as evidenced by C4d deposition in the peritubular capillaries and circulating anti-donor antibodies.9 The thrombotic microangiopathy may be mistaken for immunophilin inhibitor toxicity and has a poor prognosis.11 These lesions also resemble acute humoral rejection which is best diagnosed by staining frozen sections for C4d and checking the serum for antidonor MHC antibodies.3 EBV causes posttransplant lymphoproliferative disease (PTLD), which may be restricted to the kidney and be manifested by a dense mononuclear infiltrate of lymphoblasts and tubulitis, sometimes confused with acute rejection. PTLD is distinctive in having a densely packed monomorphic lymphoblasts without other cell types and with no edema. The diagnosis is made by immunohistochemistry for B cells (CD20, /) and in situ hybridization for EBER.12 PTLD restricted to the graft is more likely to be of donor origin and to respond to therapy.2
REFERENCES 1. Mauiyyedi S, Baid S, Pascual M, et al: Mod Pathol 13:176A, 2000 2. Colvin RB: In Jennette JC, et al (eds): Heptinstall’s Pathology of the Kidney. Philadelphia: Lippincott-Raven; 1998, p 1409 3. Collins AB, Schneeberger EE, Pascual MA, et al: J Am Soc Nephrol 10:2208, 1999 4. van Gorder MA, Della Pelle P, Henson JW, et al: Am J Pathol 154:1273, 1999 5. Nickeleit V, Klimkait T, Binet IF, et al: N Engl J Med 342:1309, 2000 6. Binet I, Nickeleit V, Hirsch HH, et al: Transplantation 67:918, 1999 7. Howell DN, Smith SR, Butterly DW, et al: Transplantation 68:1279, 1999 8. Cosio FG, Roche Z, Agarwal A, et al: Am J Kidney Dis 28:752, 1996 From the Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts, USA. Address reprint requests to Dr R.B. Colvin, Dept of Pathology, Massachusetts General Hospital, Warren 225, Boston, MA 02140. © 2001 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010
1778
Transplantation Proceedings, 33, 1778–1779 (2001)
DIFFERENTIAL DIAGNOSIS 9. Mauiyyedi S, Della Pelle P, Saidman S, et al: J Am Soc Nephrol (in press) 10. Gallay BJ, Alpers CE, Davis CL, et al: Am J Kidney Dis 26:662, 1995
1779 11. Baid S, Pascual M, Williams WW Jr, et al: J Am Soc Nephrol 10:146, 1999 12. Randhawa PS, Magnone M, Jordan M, et al: Am J Surg Pathol 20:563, 1996