—  SHORT COURSE #61  —

Kidney and Liver Transplant - Update and Issues

Case 7 - Renal and Hepatic Transplant Infections

Arthur H. Cohen, Juan Lechago and Cynthia C. Nast



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Allografts are susceptible to the same infections as are native organs, and such abnormalities as acute infectious interstitial nephritis, xanthogranulomatous pyelonephritis, and hepatitis B and C will not be covered in this part of the course. Excluding these, the most common viral infections impacting kidney and liver allografts will be addressed herein. Viral infections occur in approximately 35% of renal allografts, resulting in significant short and long term graft dysfunction. The viral agents discussed below are those most likely to confront the transplant pathologist with unique features , producing disease of major consequence to the organ recipient.

Cytomegalovirus (CMV) is one of the most frequent infectious agents in both liver and kidney transplant recipients, accounting for more than one-third of renal allograft viral infections, and both organs can harbor latent viral infections, which are asymptomatic in up to 75% of patients [1, 2, 3] . In recipients of both organs , serologic evidence of disease is observed to a greater degree compared with parenchymal injury, the latter associated with primary infection. When there is active renal infection, the kidney may show tubulo-interstitial nephritis with interstitial edema and a mononuclear inflammatory infiltrate. Tubular inflammation is present to varying degrees with associated tubular epithelial cell injury simulating acute cell mediated rejection. The presence of viral inclusions in tubular epithelium, endothelial cells, or interstitial or circulating monocytes is crucial in distinguishing these disease processes, while the identification of vascular inflammation is diagnostic for acute rejection [4]. Immunohistochemical staining can contribute to virus identification, but PCR may induce over-expression of latent inactive virus. CMV infection can initiate or follow acute rejection episodes and the two entities may co-exist [5]; in fact CMV may induce more renal injury through initiation of rejection than by direct viral-associated damage and may be linked to chronic vascular rejection or chronic allograft nephropathy [6, 7, 8] . Glomerular capillary luminal monocytic inflammation was previously thought to represent CMV infection [9], but in the absence of CMV inclusions is now thought to be acute allograft glomerulopathy, a form of acute rejection [10 ]. Hepatic allografts involved with active CMV infection have parenchymal inflammatory changes, which may take the form of microabscesses or microgranulomas [11, 12] often containing cells with CMV inclusions. Liver biopsies also show heterogeneous inflammatory foci throughout the hepatic lobule [12 ] and chronic injury may result [6]. Immunohistochemical staining again aids in virus detection.

Patients with CMV infection usually present within one to four months of transplantation and may have any of the signs and symptoms of this viral disease including fever, mononucleosis-like syndrome, gastroenteritis, pneumonia, and neutropenia [1, 3] . There may be allograft failure or hepatitis. CMV infection may initiate reactivation of Epstein-Barr virus (EBV) infection in patients with latent EBV, inducing additional graft injury as described below. Treatment for CMV is with appropriate anti-viral agents such as ganciclovir.

CMV Renal Pathology CMV Hepatic Pathology
Tubulo-interstitial nephritis
plasma cells, mononuclear cells
tubulitis
interstitial edema
CMV inclusions
tubular cells, monocytes,
endothelial cells
Glomerulopathy
infected monocytes in capillaries		 Microabscess formation
Microgranulomas
Patchy lobular inflammation
Focal hepatocyte destruction
Hepatocyte CMV inclusions

EBV occurs in transplant patients as primary infection or as a latent infection that is reactivated. Reactivation can occur within the first week post-engraftment, and in some patients induces a T cell response which may induce acute rejection [13 ]. However,t he primary importance of this virus is its role in the transformation of lymphocytes and induction of a post-transplant lymphoproliferative disorder (PTLD). PTLD is found in 1-2% of renal and 2-5% of liver allograft recipients, usually occuring between 2 and 5 years postengraftment }. In 5-15% of cases [14, 15] where malignancy develops there is a T cell lymphoma. In the kidney, the abnormal lymphocytes are often large, with cleaved, non-cleaved, immunoblastic and plasmacytoid cells with mitotic activity. These cells occur in dense infiltrates or nodular aggregates [18 ]. There may be irregular patchy parenchymal necrosis, and the interstitium may lack edema or there may be concurrent acute cell mediated rejection, which can make diagnosis more challenging particularly in the earlier lesions [19 ]. The liver contains similar lymphoid cells in portal tracts without eosinophils or prominent cholangitis [20].

EBV secondarily infects B-lymphocytes, which then undergo malignant transformation. The coincident diminished T-cell surveillance due to immunosuppression allows the outgrowth of the transformed cells, which then develop into the lymphoproliferative disorder [21, 22] . In some cases the transformed cells themselves may be immunosuppressive through release of viral IL-10 [23]. Risk factors include primary EBV infection and the intensity of the immunosuppressive regimen. The more undifferentiated the lymphocytes become the more aggressive the lesion, with mortality rates of up to 80% for monoclonal monomorphic PTLD. There are EBV negative PTLDs and these lesions are increasing in frequency with a later onset at 50-60 months after transplantaton [24]. Treatment includes reduction of immunosuppression and anti-viral agents. Newer theraPies such as anti-CD20 are being evaluated as adjuvant treatment. For less well-differentiated and more aggressive lesions, primary lymphoma treatment may be indicated.

EBV+ PTLD Diagnosis PTLD Classification
Two of 3 features required
EBV infection
PTLD architecture
Oligoclonal or monoclonal population 		Reactive hyperplasia
infectious mono-like
plasma cell hyperplasia
Polymorphic PTLD
polyclonal or monoclonal
Monomorphic
lymphomatous
Plasma cell rich
often EBV-

Polyoma virus is a member of the papovavirus family; the BK virus is primarily the cause of polyoma-induced nephropathy following transplantation although JC virus causes disease to a lesser extent [25]. There are 3 distinct forms of genito-urinary injury caused by polyoma virus, only one of which involves the renal parenchyma. In this type, which may affect up to 5% of renal transplant recipients, polyoma infects the tubular epithelium particularly of the collecting ducts, with resulting cytopathic changes [26]. Infected tubular cells are enlarged with basophilic intranuclear inclusions occasionally surrounded by halos; ultrastructurally the viral inclusions are composed of 40-45 nm paracrystalline arrays. The tubulo-interstitium may contain a minimal inflammatory infiltrate or display a patchy or diffuse brisk tubulo-interstitial nephritis with plasma cells and tubulitis [27-29]. Immunostains for BK or SV40 (simian polyoma) are helpful in confirming the diagnosis. BK virus also resides in ureteric epithelium and has been reported in association with ureteral stenosis in transplant recipients [30]. Patients with the more common tubular infection and tubulo-interstitial nephritis present with renal dysfunction and may be on more intense triple immunosuppressive regimens with tacrolimus and mycophenolate [31 ]. Patients can be monitored by measuring viral plasma load [32 ]. Treatment consists of reduction of immunosuppression although careful monitoring for superimposed acute rejection is required and the virus may persist leading to early graft loss [26, 33, 34] .

Human herpesvirus-6 (HHV-6) infects almost all individuals by the age of 4, and shows evidence of replication due to reactivation in approximately 30% of liver allograft recipients. HHV-6 often replicates together with CMV in doubly infected patients, with infection more severe than with either virus alone, and CMV may actually reactivate HHV-6 [6, 35, 36, 37] . HHV-6 has been reported to worsen recurrent hepatitis C infection [38 ]. HHV-6 predominantly infects CD4+ lymphocytes and lesser numbers of CD8+ lymphocytes, natural killer cells and macrophages, but not hepatocytes. Following clinically relevant reactivation a systemic syndrome resembling CMV infection is produced. The exact role HHV-6 plays in liver and renal transplantation remains to be determined, but there are suggestions that it may cause immune reactions initiating rejection episodes in hepatic transplants [6, 39, 40] .

References

  1. Brennan DC: Cytomegalovirus in renal transplantation. J Am Soc Nephrol 12:848-855, 2001.

  2. Rubin RH: Infectious disease problems. In Transplantation of the Liver eds WC Maddrey, ER Schiff, MF Sorrell; Lippincott Williams & Wilkins, Philadelphila p275-295, 2001.

  3. Mutimer D: CMV infection of transplant recipients. J Hepatol 25:259-269, 1996.

  4. Wang KM, Chan YH, Chan SK, Mak CK, Chau KF, Li CS: Cytomegalovirus-induced tubulointerstitial nephritis in a renal allograft treated by foscarnet therapy. AM J Nephrol 20:222-224, 2000.

  5. Sageda S, Nordal KP, Hartmann A, et al: The impact of cytomegalovirus infection and disease on rejection episodes in renal allograft recipients. Am J Transplant 2:850-856, 2002.

  6. Cainelli F, Vento S: Infections and solid organ transplant rejection: a cause-and-effect relationship? Lancet Infect Dis Dept;2:539-549, 2002.

  7. Helantera I, Koskinen P, Tornroth T, et al: The impact of cytomegalovirus infections and acute rejection episodes on the development of vascular changes in 6-month protocol biopsy specimens of cadaveric kidney allograft recipients. Transplantation 75:1858-1864, 2003.

  8. Nett PC, Heisey DM, Fernandez LA, Sollinger HW, Pirsch JD: Association of cytomegalovirus disease and acute rejection with graft loss in kidney transplantation. Transplantation 78:1036-1041, 2004.

  9. Richardson WP, Colvin RB, Cheesemeen SH, et al: Glomerulopathy associated with cytomegalovirus viremia in renal allografts. N Engl J Med 305:57-63, 1981.

  10. Herrera GA, Alexander RW, Cooley CF, et al: Cytomegalovirus glomerulopathy: a controversial lesion. Kidney Int 29:725-733, 1986.

  11. Lamps LW, Pinson CW, Raiford DS, Shyr Y, Scott MA, Washington MK: The significance of microabscesses in liver transplant biopsies: a clinicopathological study. Hepatol 28:1532-1537, 1998.

  12. MacDonald GA, Greenson JK, DelBuono EA, et al: Mini-microabscess syndrome in liver transplant recipients. Hepatol 26:192-198, 1997.

  13. Jabs WJ, Maurmann S, Wagner HJ, Muller-Steinhardt M, Steinhoff J, Fricke L: Time course and frequency of Epstein-Barr virus reactivation after kidney transplantation: linkage to renal allograft rejection. J Infect Dis 190:1600-1604, 2004.

  14. Nalesnik MA: Clinicopathologic characteristics of post-transplant lymphoproliferative disorders. Recent Results Cancer Res 159:9-18, 2002.

  15. Muti G, Cantoni S, Oreste P, et al: Post-transplant lymphoproliferative disorders: improved outcome after clinico-pathologically tailored treatment. Haematologica 87:67-77, 2002.

  16. Colina F, Juca NT, Moreno E, Ballestin C, Farina J, Nevado M, Lumbreras C, Gomez- Sanz R: Histological diagnosis of cytomegalovirus hepatitis in liver allografts. J Clin Pathol 48:351-7, 1995.

  17. Harris NL, Ferry JA, Swerdlow SH: Post-transplant lymphoproliferative disorders: summary of society for hematopathology workshop. Semin Diagn Pathol 14:8-14, 1997.

  18. Randhawa PS, Magnone M, Jordan M, Shapiro R, Demetris AJ, Nalesnik M: Renal allograft involvement by Epstein-Barr virus associated post-transplant lymphoproliferative disease. Am J Surg Path 20:563-571, 1996.

  19. Koike J, Yamaguchi Y, Hoshidawa M, et al: Post-transplant lymphoproliferative disorders in kidney transplantation: histological and molecular genetic assessment. Clin Transplant 16 Suppl 8:12-17, 2002.

  20. Nuckols JD, Baron PW, Stenzel TT, et al: The pathology of liver-localized post-transplant lymphoproliferative disease: a report of three cases and a review of the literature. Am J Surg Pathol 24:733-741, 2000.

  21. Paya CV, Fung JJ, Nalesnik MA, et al: Epstein-Barr virus-induced post-transplant lymphoproliferative disorders. ASTS/ASTP EBV-PTLD Task Force and the Mayo Clinic Organized International Consensus Development Meeting. Transplantation 68:1517-1525, 1999.

  22. Shroff R, Rees L: The post-transplant lymphopr o liferative disorder – a literature review. Pediatr Nephrol 19:369-377, 2004.

  23. Nast CC, Moudgil A, Zuo YJ, Toyoda M, Jordan SC: Long-term allograft acceptance in a patient with post-transplant lymphoproliferative disorder: correlation with intragraft viral interleukin-10. Transplantation 64:1578-1582, 1997.

  24. Birkeland SA, Hamilton-Dutoit S: Is posttransplant lymphoproliferative disorder caused by any specific immunosuppressive drug or by the transplantation per se? Transplantation 76:984-988, 2003.

  25. Randhawa P, Baksh F, Aoki N, Tschirhart D, Finkelstein S: JC virus infection in allograft kidneys:analysis by polymerase chain reaction and immunohistochemistry. Transplantation 15:1300-1303, 2001.

  26. Hirsch HH: Polyomavirus BK nephropathy: a re-emerging complication in renal transplantation. Am J Transplant 2:25-30, 2002.

  27. Randhawa PS, Finkelstein S, Scantlebury V, et al: Human polyoma virus-associated interstitial nephritis in the allograft kidney. Transplantation 15:103-109, 1999.

  28. Drachenberg CB, Beskow CO, Cangro CB, et al: Human polyoma virus in renal allograft biopsies: morphological findings and correlation with urine cytology. Hum Pathol 30:970- 977, 1999.

  29. Drachenberg RC, Drachenberg CB, Papadimitriou JC, et al: Morphological spectrum of polyoma virus disease in renal allografts: diagnostic accuracy of urine cytology. Am J Transplant 1:373-381, 2001.

  30. Pappo O, Demetris AJ, Raikow RB, Randhawa PS: Human polyoma virus infection of renal allografts: histopathologic diagnosis, clinical significance and literature review. Mod Pathol 9:105-109, 1996.

  31. Mengel M, Marsedel M, Radermacher J, et al: Incidence of polyomavirus-nephropathy in renal allografts: influence of modern immunosuppressive drugs. Nephrol Dial Transplant 18:1190-1196, 2003.

  32. Hirsch HH, Knowles W, Dickenmann M, et al: Prosepective study of polyomavirus type BK replication and nephropathy in renal-transplant recipients. N Engl J Med 347:488-496, 2002.

  33. Barri YM, Ahmad I, Ketel BL, Barone GW, Walker PD, Bonsib SM, Abul-Ezz SR: Polyoma virus infection in renal transplantation: the role of immunosuppressive therapy. Clin Transplant 15:240-246, 2001.

  34. Ramos E, Drachenberg CB, Papadimitriou JC, et al: Clinical course of polyoma virus nephropathy in 67 renal transplant patients. J Am Soc Nephrol 13:2145-2151, 2002.

  35. DesJardin JA, Cho E, Supran S, Gibbons L, Werner BG, Snydman DR: Association of human herpesvirus 6 reactivation with severe cytomegalovirus-associated disease in orthotopic liver transplant recipients. Clin Infect Dis 15:1358-1362, 2001.

  36. Lautenschlager I, Lappalainen M, Linnavuori K, Hockerstedt K: CMV infection is usually associated with concurrent HHV-6 and HHV-7 antigenemia in liver transplant patients. J Clin Virol 25 Suppl 2:S57-61, 2002.

  37. Razonable RR, Paya CV: The impact of human herpesvirus-6 and –7 on the outcome of liver transplantation. Liver Transpl 8:651-658, 2002.

  38. Singh N, Husain S, Carrigan DR, et al: Impact of human herpesvirus-6 on the frequency and severity of recurrent hepatitis C virus hepatitis in liver transplant recipients. Clin Transplant 16:92-96, 2002.

  39. Griffiths PD, Ait-Khaled M, Bearcroft CP, et al: Human herpesviruses 6 and 7 as potential pathogens after liver transplant: prospective comparison with the effect of cytomegalovirus. J Med Virol 59:496-501, 1999.

  40. Lautenschlager I, Hockerstedt K, Linnavuori K, Taskinen E: Human herpesvirus-6 infection after liver transplantation. Clin Infect Dis 26:702-7, 1998.