|Year : 2006 | Volume
| Issue : 2 | Page : 189-199
|Infection and Cancer Following Renal Transplantation
Consultant Nephrologist, Royal Free Hospital, London, United Kingdom
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| Abstract|| |
Ever increasingly potent but non-specific immunosuppression has necessarily brought with it the continuing risk of opportunistic infections and virus-induced malignancies. The improvement in graft and patient survival rates from transplantation has depended to a certain extent on parallel improvements in the diagnosis and treatment of infectious complications. This review will highlight some of the current problems and progress. The risks of infection are largely related to the total burden of immunosuppression rather than any particular drug, although sirolimus and the anti CD25 antibodies may be an exception. Almost all the post-transplant infections are treatable; a precise microbiological diagnosis is essential so that specific therapy can be used. Newer molecular diagnostic techniques are increasingly widely available, e.g.quantitative polymerase chain reaction. The transplant community will inevitably be faced with highly resistant bacteria such as. Methicillin resistant Staphylococcus Aureus (MRSA) and will have to develop appropriate strategies. New infectious organisms continue to be identified [e.g. Burkitt's Virus (BKV), West Nile virus and Avian influenza) and will continue to tax the ingenuity of transplant physicians and microbiologists.
|How to cite this article:|
Sweny P. Infection and Cancer Following Renal Transplantation. Saudi J Kidney Dis Transpl 2006;17:189-99
| Introduction|| |
The range of microorganisms encountered post-transplantation  is very similar to that seen in a patient with the acquired immunodeficiency syndrome (AIDS) [Table - 1] and is clearly a direct consequence of potent immuno-suppression (IS). The timetable for infection  is a helpful concept. In the first month, microorganisms encountered are usually those seen after any invasive operation undertaken in a hospital, e.g. wound, chest and catheter related infections. Wound infections can be serious as they may reach to the anastamotic site and be followed by the development of a mycotic aneurysm with a subsequent catastrophic fatal rupture. Between month one and month six, when IS is at its height, opportunistic infections occur [Table - 1]. After six months, provided graft function is good, (and IS is reduced to a lower maintenance dose) the risk of infection reduces towards normal but remains increased with patients at risk for the rest of the life of the transplant.
CMV remains an important post-transplant pathogen. ,, Diagnosis is available in real time [PP65 antigen testing or polymerase chain reaction, (PCR)] and quantitative viral loads help in guiding management. The rate of increase provides an indication of the risk of disease.  Opinion is more or less equally divided between employing universal prophylaxis or pre-emptive therapy [Table - 2].  The threat of CMV has largely been contained but increasing knowledge about the indirect effects of CMV continues to interest the transplant community [Table - 3]. A vaccine is in development.
The Viral-Induced Cancers
The risk of developing malignancy is about 2-3 fold increased following renal transplantation if all tumors are taken into account. Certain viral-induced tumors are increased many hundred fold. , Mechanisms include loss of immune surveillance because of immunosupression, increased TGFβ particularly with cyclosporin A, and both direct and indirect effects of certain viruses , which produce various virokines and anti-apoptotic proteins [Table - 4]. The human herpes virus HHV 4 (or the Epstein-Barr virus) and HHV8 (or the Kaposi sarcoma virus) can induce malignancy. Both hepatitis B and C viruses (HBV and HCV) are associated with hepatocellular cancer (HCC). , The human papilloma virus (HPV) is responsible for squamous cell carcinoma (SSC) of the skin and anogenital areas.
Other malignancies associated with transplantation are listed in [Table - 5].
Post-Transplant Lymphoproliferative Disorder (PTLD)
PTLD arises in 1-2% of the renal transplant population. The incidence is higher when EBV antibody positive donors donate to EBV antibody negative recipients (e.g. children receiving a live donor transplant from their parent) and is increased if the patient receives augmented immunosuppression or develops CMV. PTLD is a complex group of conditions in which B cells (or less frequently T cells) proliferate and can spread widely to produce a range of conditions ranging from a glandular fever-like syndrome to an obvious lymphoma [Table - 6]. , In most cases, PTLD is a Bcell proliferative state induced by the EBV virus (85%).  The diagnosis is based on immunohistology that relies on the demonstration of EBV coded proteins expressed in B-cells (eg. Epstein-Barr nuclear antigen - EBNA).
Accurate classification is important and has implications for prognosis and management. Early lesions in which there is no evidence of monoclonality and no oncogene expression behave more like an infection than a cancer and may regress completely with immunosuppression dose reduction (ISDR). If diagnosis is delayed and frank malignant transformation has occurred, then additional strategies are required [Table - 6]. Recently, two new forms of effective treatment have been employed. The anti CD20 humanized monoclonal antibody, rituximab  and cytotoxic T lymphocytes (CTL) have been very effective.  Despite these forms of therapy, some patients do require conventional cytotoxic therapy when the tumor is life threatening. There is an increased risk of overwhelming infection when cytotoxic therapy follows on from post-transplant immunosuppression. Some case reports indicate that changing immunosuppression to sirolimus may be beneficial  Anti IL-6 antibody may also be of benefit.,
The incidence of Kaposi's sarcoma (KS) parallels the prevalence of HHV8 antibody in the general population. It occurs in <0.5% of transplant patients in Northern Europe and the US but is seen in nearly 5% of transplant patients from endemic areas, e.g. Saudi Arabia and the Mediterranean population. KS is induced by the HHV8 virus  and usually presents at 18-24 months post-transplant. , In some cases, the disease is limited to the skin but visceral spread may occur (40%). The condition can be fatal when widespread. As with PTLD, the diagnosis is made by immunohistology.
Again, as with PTLD, ISDR may be associated with tumor regression in many but not all cases. Recently, there have been several publications suggesting that changing immunosuppression from a calcineurin inhibitor (CNI) and mycophenolate mofetil (MMF) to sirolimus is associated with tumor regression without the attendant risk of rejection that occurs with immediate or rapid ISDR. , This is the first time that a potent immunosuppressive agent in its own right has been shown to have anti-tumor properties.  As with PTLD, lesions which do not regress with these measures may respond to conventional cytotoxic therapy.
Squamous Cell Cancer (SCC)
The relationship between HPV and skin SCC is less clear than that between EBV and PTLD and HHV8 and KS.,, However, the relationship between the HPV and anogenital cancer  is much more secure [Table - 7]. Nevertheless, HPV does express genes that clearly could have an important role in promoting SCC and some particular types of the virus are closely related to anogenital cancers [Table - 7]. ISDR is also indicated in the presence of SCC but of itself is less effective than in PTLD or KS. In patients of skin type I and II, SCCs of the skin are extremely common and after 20 years of immunosuppression nearly 80% of patients may be affected [Table - 8]. Sun exposure is clearly very important. It is important to note that there is a field change in the skin induced by the HPV. Various immunomodulating forms of therapy ,, can be used to reduce the risk of actinic keratosis changing into overt SSCs (imiquimod, retinoids and topical diclofenac) [Table - 9].
The Role of Antivirals in Post Transplant Tumors
The EBV virus responds to acyclovir but only as far as proliferative/lytic cycles are concerned. In PTLD, EBV is present in a non-proliferating form as episomal DNA, which is not susceptible to antiviral therapy. Nevertheless, some studies have shown that the incidence of PTLD is reduced in patients receiving prophylactic acyclovir.  It is possible that viral dissemination from some lytic cycles present in the tumor are responsible for further spread.
A similar argument applies to KS as ganciclovir is effective in vitro against the HHV8 virus. When retransplantation is considered in patients who have had PTLD or KS, prophylactic antivirals and immunosuppression using sirolimus should be considered.
HPV is susceptible to cidofovir and topical therapy may have a role to play in anogenital cancer in addition to local excision and ISDR. , Again, attempts to preserve the graft without provoking rejection by the use of sirolimus are being attempted. Sirolimus therapy is not the only answer to post-transplant cancers as tumors have arisen in patients immunosuppressed with sirolimus although there is data to suggest that the risk of cancer in sirolimus patients is reduced.,
Hepatocellular Cancer (HCC)
Both HBV and HCV infection are associated with an increased incidence of HCC, particularly in the presence of cirrhosis and probably in the transplant carrier in general. ,, It is likely that the incidence and rate of progression will be increased in the transplant recipient. It is not known whether prolonged treatment with lamivudine post-renal transplant will reduce the risks of HCC. Viral resistance is likely to be a problem with prolonged therapy. Treatment of HCV post-transplantation is unsatisfactory as IFNα may provoke acute rejection.
BK Virus and BK Nephropathy
The BK virus has a predilection for the distal tubular cells of the kidney. Reactivation after transplant is common (60%) and can cause a specific interstitial nephritis (1-8%) which if it develops can result in a 50% rate of graft loss.  Most cases develop within the first year but continued monitoring is recommended for several years.  Monitoring can be by urine cytology (decoy cells) or urine E/M. Positive results require confirmation by PCR. Renal biopsy is diagnostic as sections can be stained for BKV antigens.
Although controlled trials are not available, cidofovir may be of value in low doses as the drug is concentrated in the kidney. ISDR may be sufficient without antiviral agents.
| Bacterial Infections Post-Renal Transplantation|| |
Although diagnosis and treatment are relatively straightforward, some infections remain a problem for the transplant patient., Listeria can cause a septicemic illness and meningitis. Nocardia is somewhat similar in its clinical presentation to Staphylococcus aureus causing cavitating pneumonia, skin and muscle abscesses and occasionally a space-occupying lesion (SOL) in the brain. The main concern with bacterial infections post-transplant is with mycobacteria both tubercular and atypical infections. Reactivation of Mycobacterium tuberculosis common and may present with any of many different symptoms, eg, pneumonia, skin, joint and a CNS SOL.  In at risk patients, isoniazid prophylaxis is usually effective but care should be taken in patients with pre-existing liver disease. The drug interactions between antituberculous drugs (particularly rifampicin) and immusuppressants (particularly the CNI and sirolimus) are important. It may be necessary to administer two or three times the usual dose to get effective blood levels, and the CNI may need to be administered three times daily. Accurate diagnosis is crucial and resistance testing (now available by molecular biological techniques) is important as resistance is an increasing problem. If atypical mycobacterial infection is found, then resistance testing is essential as treatment regimens may be complex and need to be prolonged.
Urinary Tract Infections
Urosepsis is the commonest cause of septicemia post-transplant. Infection within the first few months is potentially the most damaging and can cause an acute graft pyelonephritis.  After six months, most infections are of the lower tract and will respond to short courses of appropriate antibiotics. Some patients have recurrent frequent infections and may develop progressive scarring in the graft. Such patients require full investigation and may benefit from long-term rotating or suppressive antibiotics. Infection may occur with urea splitting organisms (eg. corynebacterium urealyticum) which leads to calcium deposition in the calyces, collecting system, ureter and bladder, viz. encrusted pyelitis.
Deep fungal infections remain a serious and potentially fatal complication of organ transplantation. 48 The risk factors are summarized in [Table - 10]. Diagnosis often requires biopsy as well as culture. Some molecular diagnostic tests are available [Table - 11]. Over the last few years newer antifungal drugs have been introduced which are less toxic than amphotericin (eg. Voriconazole, posiconazole and caspofungin, mycofungin).,
Pneumocystis pneumonia (PCP) (caused by pneumcystis jirovecii) is a serious complication of renal transplantation, which is rarely seen these days as almost all patients, are routinely prophylaxed with co-trimoxazole. The clinical presentation of a patient with cough, fever and breathlessness raises a long list of diagnostic possibilities. Most cases will turn out to be community acquired viral infections, which are likely to be self-limiting. In order to identify patients at risk of a much more serious infection, oxygen saturations before and after exercise should be done and can identify patients who need admission and probable bronchoalveolar lavage.
In certain geographical areas, strongyloides stercoralis is a serious and potentially fatal post-transplant infection. A pre-transplant eosinophilia may be present but is lost in the presence of steroid therapy. Serological testing is available. This parasite can complete its life cycle in the immunosuppressed host. Penetration of larval forms through the gut wall can result in recurrent episodes of gram negative sepsis. More than one course of thiabendazole may be required for eradication.
The molecular biological revolution is having a great impact on the diagnostic tools available to the clinicians [Table - 11]. Viral infection, particularly CMV, can be diagnosed in a matter of few hours and treatment started before patients became sick. Response to treatment can be followed and duration of therapy appropriately adjusted in the light of quantitative PCRs.
Patients at risk of PTLD and KS may be identified by rising titers of viral DNA in the blood. The decision for a renal biopsy to diagnose BKV nephropathy can be made from a high viral load in the blood. Some resistance testing for MTB can be obtained without the need for prolonged culture. The range of diagnostic tests available and the need to apply them appropriately means that the transplant team must develop a close working relationship with the microbiologist.
| Conclusions|| |
The most important post-transplant infection is CMV but effective prophylactic or preemptive strategies have gone a long way to minimizing its deleterious effects. In fair skinned races, HPV related skin lesions have become increasingly common post-transplant. Diagnosis at the pre-malignant stage allows for early ISDR and the use of immune modifying topical therapies to reduce the risk of overt cancer.
Perhaps the most feared complication is EBVinduced PTLD but the advent of rituximab and CTL therapy means that not only can the disease be controlled but also the graft is preserved. In certain parts of the world, a very different spectrum of infection and cancer is seen (e.g. in Saudi Arabia). The hepatitis viruses, KSV and mycobacterial infection pose a significant threat to these immunosuppressed organ recipients. Prophylaxis by pre-transplant vaccination (eg. HBV and soon EBV, CMV and HPV) will dramatically reduce the burden of post-transplant infection and hopefully also of malignancy. Better monitoring allows for timely ISDR and there is now the possibility of switch regimens away from the CNI drugs. Recently published guidelines for the prevention and management of infectious complications of solid organ transplantation are required reading for all who care for solid organ transplant recipients. 
| References|| |
|1.||Rubin RH, Wolfson JS, Cosimi AB, et al. Infection in the renal transplant recipient. Am J Med 1981;70:405-11. [PUBMED] |
|2.||Rubin RH & Young LS. Clinical approach to infection in the compromised host. 3 rd ed 1994 Plenum Medical New York. |
|3.||Brennan DC. Cytomegalovirus in Renal Transplantation. J Am Soc Nephrol 2001; 12:848-55. [PUBMED] [FULLTEXT]|
|4.||Rowshani AT, Bemelman FJ, Van Leeuwen EM, Van Lier RA, Berge IJ. Clinical and immunological aspects of cytomegalovirus in solid organ transplant recipients. Transplantation 2003;79:381-6. |
|5.||Griffiths PD, Walter S. Cytomegalovirus. Curr Opin Infect Dis 2005;18(3):241-5. |
|6.||Mattes FM, Hainsworth EG, Hassan-Walker AF, et al. Kinetics of cytomegalovirus load decrease in solid organ transplant recipients after pre-emptive therapy with valganciclovir. J Infect Dis 2005;191(1):89-92. |
|7.||Debate: Emery VC. Prophylaxis for CMV should not now replace Pre-emptive therapy in Solid Organ Transplantation versus Hart GD & Paya CV. Prophylaxis for CMV should now replace pre-emptive therapy in Solid Organ Transplantation. Rev Med Virol 2001;11: 73-81 and 83-6. |
|8.||Sagedal S, Hartmann A, Rollag H. The Impact of early cytomegalovirus infection and disease in renal transplant recipients. Clin Microbiol Infect 2005;11:518-30. [PUBMED] [FULLTEXT]|
|9.||Morath C, Mueller M, Goldschmidt H, et al. Malignancy in Renal Transplantation. J Am Soc Nephrol 2004;15:1582-8. [PUBMED] [FULLTEXT]|
|10.||Moosa MR. Racial and ethnic variations in incidence and pattern of malignancy after kidney transplantation. Medicine (Baltimore) 2005;84(1):12-22. |
|11.||Talbot SJ, Crawford DH. Viruses and Tumours - an update. Eur J Cancer 2004; 40:1998-2005. [PUBMED] [FULLTEXT]|
|12.||Liebowitz D. Epstein-barr virus and a cellular signalling pathway in lymphomas from immunosuppression patients. New Engl J Med 1998;338:1413-21. [PUBMED] [FULLTEXT]|
|13.||Fabrizi F, Lunghi G, Poordad FF, Martin P. Management of hepatitis B after renal transplantation: an update. J Nephrol 2002; 15:113-33. [PUBMED] [FULLTEXT]|
|14.||Aroldi A, Lampertico P, Montagnino G, et al. Natural history of hepatitis B and C in renal allograft recipients. Transplantation 2005;79(9):1132-6. |
|15.||Harris NL, Ferry JA, Swerdlow SH. Posttransplant lymphoproliferative disorders: summary of society for hemopathology workshop. Semin Diagn Pathol 1997;14:8-14. [PUBMED] |
|16.||Nalesnik MA. Clinicopathologic characteristics of post transplant lymphoproliferative disorders. Recent Results Cancer Res 2002; 159:9-18. [PUBMED] |
|17.||Milpied N, Vasseur B, Parquet N, et al. Humanized anti CD20 monoclonal antibody (Rituximab) in post transplant B-lymphoproliferative disorder: a retrospective analysis on 32 patients. Ann Oncol 2000;11(Supp):113-6. |
|18.||Haque T, Wilkie GM, Taylor C, et al. Treatment of Epstein-Barr virus-positive post transplantation lymphoproliferative disease with partly HLA-matched allogenic cytotoxic T cells. Lancet 2002;360:436-42. [PUBMED] [FULLTEXT]|
|19.||Zaltzman JS, Prasad R, Chun H, Jothy S. Resolution of renal allograft-associated post transplant lymphoproliferative disorder with the introduction of sirolimus. Nephrol Dial Transplant 2005;20:1748-51. |
|20.||Little RF, Yarchoan R. Treatment of gammaherpes virus-related neoplastic disorders in the immunocompromised host. Semin Hematol 2003;40(2):163-71. |
|21.||Durandy A. Anti-B cell and anti cytokine therapy for the treatment of post transplant lymphoproliferative disorder: past, present and future. Transpl Infect Dis 2001;3(2):104-7. |
|22.||Schwartz RA. Kaposi's Sarcoma: an update. J Surg Oncol 2003;87:146-51 |
|23.||Frances C. Kaposi's sarcoma after renal transplantation. Nephrol Dial Transplant 1998;13:2768-73. |
|24.||Stallone G, Schena A, Infante B, et al. Sirolimus for Kaposi's Sarcoma in renal transplant recipients. N Eng J Med 2005; 352(13):1317-23. |
|25.||Campistol JM, Gutierrez-Dalmau A, Torregrosa JV. Conversion to sirolimus: a successful treatment for post transplantation Kaposi's sarcoma. Transplantation 2004;77(5):760-2. |
|26.||Harwood CA, McGregor JM, Proby CM, Breuer J. Human papillomavirus and the development of non-melanoma skin cancer. J Clin Pathol 1999;52:249-53. [PUBMED] [FULLTEXT]|
|27.||Ramsay HM, Fryer AA, Reece S, Smith AG, Harden PN. Clinical risk factors associated with non-melanoma skin cancer in renal transplant recipients. Am J Kidney Dis 2000;36:167-76. [PUBMED] |
|28.||Dreno B. Skin cancers after transplantation. Nephrol Dial Transplant 2003;18(6):1052-8. |
|29.||Penn I. Cancers of the anogenital region in renal transplant recipients analysis of 65 cases. Cancer 1986;58(39):611-6. |
|30.||Stockfleth E, Meyer T, Benninghoff B, Christophers E. Successful treatment of actinic keratosis with imiquimod cream 5%: a report of six cases. Br J Dermatol 2001;144:1050-3. [PUBMED] [FULLTEXT]|
|31.||McKenna DB, Murphy GM. Skin cancer chemoprophylaxis in renal transplant recipients: 5 years experience using low dose acitretin. Br J Dermatol 1999;140:656-60. [PUBMED] [FULLTEXT]|
|32.||McGillis ST, Fein H. Topical treatment strategies for non-melanoma skin cancer and precursor lesions. Semin Cutan Med Surg 2004;23(3):174-83. |
|33.||Malouf MA, Chhajed PN, Hopkins P, Plit M, Turner J, Glanville AR. Anti-viral prophylaxis reduces the incidence of lymphoproliferative disease in lung transplants. J Heart Lung Transplant 2002;21(5):547-54. |
|34.||Otley CC, Coldiron BM, Stasko T, Goldman GD. Decreased skin cancer after cessation of therapy with transplant-associated immunosuppressants. Arch Dermatol 2001;137:459-63. [PUBMED] [FULLTEXT]|
|35.||Snoeck R, Noel JC, Muller C, De Clercq E, Bossens M. Cidofovir, a new approach for the treatment of cervix intraepithelial neoplasia grade III (CIN III). J Med Virol 2000;60:205-9 [PUBMED] [FULLTEXT]|
|36.||Mathew T, Kreis H, Friend P. Two-year incidence of malignancy in sirolimus - treated renal transplant recipient: results from five multicentre studies. Clin Transplant 2004; 18(4):446-9. |
|37.||Gane E, Pilmore H. Management of chronic viral hepatitis before and after renal transplantation. Transplantation 2002; 74(4):427-37. |
|38.||Ridruejo E, Mando OG, Davalos M, Diaz C, Vilches A. Hepatocellular carcinoma in renal transplant patients. Transplant Proc 2005;37(5):2086-8 |
|39.||Fabrizi F, Martin P, Ponticelli C. Hepatitis C virus infection and renal transplantation. Am J Kidney Dis 2001;38(5):919-34. |
|40.||Fishman JA. Bk virus nephropathy - polyoma virus adding insult to injury. N Eng J Med 2002;347(7):527-30. |
|41.||Hirsch HH, Brennan DC, Drachenberg CB, et al. Polyomavirus-associated nephropathy in renal transplantation: interdisciplinary analyses and recommendations. Transplantation 2005; 79(10):1277-86. |
|42.||Kuypers DR, Vandooren AK, Lerut E, et al. Adjuvant low-dose cidofovir therapy for BK polyomavirus interstitial nephritis in renal transplant recipients. Am J Transplant 2005;5:1997-2004. [PUBMED] [FULLTEXT]|
|43.||Schmaldienst S, Horl WH. Bacterial infections after renal transplantation. Contrib Nephrol 1998;124:18-33. |
|44.||Sweny P. Bacterial infections in renal allograft recipients. pp. 304-309. In the infectious complications of renal disease. Eds: Sweny P, Rubin R, Tolkoff-Rubin. Oxford University Press 2003. |
|45.||Rubin RH. Management of tuberculosis in the transplant recipient. Am J Transplant 2005;5(11):2796-8. |
|46.||Schmaldienst S, Dittrich E, Horl WH. Urinary tract infections after renal transplantation. Curr Opin Urol 2002;12:125-30. |
|47.||Meria P, Jungers P. Encrusted pyelitis: an underdiagnosed condition. Nephrol Dial Transplant 2000;15:943-5. [PUBMED] [FULLTEXT]|
|48.||Bag R. Fungal pneumonias in transplant recipients. Curr Opin Pulm Med 2003;9:193-8. [PUBMED] [FULLTEXT]|
|49.||Kulberg BJ, Sobel JD, Ruhnke M, et al. Voriconazole versus a regimen of amphotericin B followed by fluconazole for candidaemia in non-neutropenic patients: a randomized non-inferiority Trial. Lancet 2005;366:1435-42. |
|50.||Candoni A, Mestroni R, Damiani D, et al. Caspofungin as first line therapy of pulmonary invasive fungal infections in 32 immunocompromised patients with hematologic malignancies. Eur J Haematol 2005;75(3):227-33. |
|51.||Lufft V, Kliem V, Behrend M, Pichlmayr R, Koch KM, Brunkhorst R. Incidence of pneumocystis carinii pneumonia after renal transplantation. Impact of immunosuppression. Transplantation 1996; 62(3):421-3. |
|52.||Green M, Avery RK, Preiksaitis J. Guidelines for the prevention and management of infectious complications of solid organ transplantation. Am J Transplant 2004; Suppl 10:1-166. |
Consultant Nephrologist, Royal Free Hospital, London
Source of Support: None, Conflict of Interest: None
[Table - 1], [Table - 2], [Table - 3], [Table - 4], [Table - 5], [Table - 6], [Table - 7], [Table - 8], [Table - 9], [Table - 10], [Table - 11]
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