Year : 2017 | Volume
: 17 | Issue : 3 | Page : 75--104
Infectious Diseases in Renal Transplantation; Summary of Guidelines
Jesmar Buttigieg, Mohsen El Kossi, Ahmed Halawa
University of Liverpool, United Kingdom
Consultant Transplant Surgeon, Sheffield Teaching Hospitals; Senior Lecturer (Hon), University of Liverpool
|How to cite this article:|
Buttigieg J, El Kossi M, Halawa A. Infectious Diseases in Renal Transplantation; Summary of Guidelines.J Egypt Soc Nephrol Transplant 2017;17:75-104
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Buttigieg J, El Kossi M, Halawa A. Infectious Diseases in Renal Transplantation; Summary of Guidelines. J Egypt Soc Nephrol Transplant [serial online] 2017 [cited 2018 Feb 25 ];17:75-104
Available from: http://www.jesnt.eg.net/text.asp?2017/17/3/75/219245
The advent of modern immunosuppressive therapy has revolutionized the outcomes of transplanted organs and patient’s survival. However, more potent immunosuppressive agents have also increased the recipient’s susceptibility to opportunistic infections. The aim of this guideline is to adapt current highest quality evidence in order to improve the overall outcomes of our transplant recipients and to standardise practice in our local transplant program.
General Aspects of Infectious Diseases in Kidney Transplantation
The susceptibility to post-transplant infection is a dynamic and multi-factorial process involving (1):
Immunosuppressive therapy (especially depleting induction agents, high-risk transplantation) Therapies prior to transplantation (e.g. immune-modulation, chemotherapy) Mucocutaneous-barrier breach (e.g. catheters, drains) Bone marrow suppression (e.g. drugs) Immunodeficiency (e.g. hypogammaglobulinemia, systemic lupus erythematosus) Metabolic conditions (e.g., uremia, malnutrition, diabetes) Concomitant viral infection (e.g. CMV, HCV, HBV)
Nosocomial infections and surgical complications are the most common causes of infection in the first month post-transplant. Activation of latent infection usually occurs thereafter, up to the first 6 months. Infections which occur beyond the first 6 months are usually community-acquired, but latent infections can still occur especially following intensification of immunosuppression. Table 1 provides a summary of the various micro-organisms associated with solid organ transplant infections. The patients themselves have a pivotal role in preventing post-transplant infections. Regular hand washing, avoiding close contact with people having respiratory illnesses, avoiding well-water, avoiding undercooked meat and avoiding unpasteurized dairy products is essential (1).
1. Fishman JA. Infection in solid-organ transplant recipients. N Engl J Med 2007 Dec 20;357(25):2601-14.
Pneumocystis pneumonia Cytomegalovirus Epstein-Barr virus and post-transplant lymphoproliferative disorders BK Nephropathy Herpes Simplex Varicella Oesophageal Candida infections Post-transplant diarrhoea Mycobacterium tuberculosis Hepatitis B infection Hepatitis C infection Human Immunodeficiency virus Human T-cell Lymphotrophic virus Vaccination Parasitic infections Emerging viral diseases
1. Pneumocystis jirovecii pneumonia (PCP)
Pneumocystis jirovecii is an opportunistic fungal pathogen known to cause life-threatening pneumonia in immunocompromised patients (2,3). PCP is defined as the presence of lower respiratory-tract infection due to Pneumocystis jirovecii (1). It remains a common occurrence in transplant recipients in the absence of prophylaxis.
PCP should be considered in all kidney transplant recipients (KTRs) who present with marked hypoxia, dyspnoea, and dry cough with limited physical or radiological findings. Chest X-ray usually shows reticulonodular shadowing or ground glass opacification predominantly in the peri-hilar region and lower lobes. Computed tomography is useful to define the extent of disease (7). Gold standard investigation is bronchoalveolar lavage obtained during bronchoscopy, with sensitivity and specificity ranging from 81–100% and 86–100% respectively (8,9).
KTRs should receive trimethoprim 80 mg /sulfamethoxazole 400mg (co-trimoxazole 480 mg) for 6 months post-transplantation (1,2). Co-trimoxazole prophylaxis should be re-instituted for 6 weeks during and after treatment for acute rejection (1,2). Co-trimoxazole also provides some cover for urinary tract pathogens (4). Therefore, Nitrofunatoin is suggested as prophylaxis against UTI in KTRs not receiving co-trimoxazole (1).
Desensitisation should be considered in documented allergy to co-trimoxazole ideally prior to transplantation. It can be attempted in patients with a non-severe (grade 3 or less) co-trimoxazole reaction. It should not be attempted in patients with grade 4 reactions to co-trimoxazole or other sulfa drugs. Table 1 illustrates co-trimoxazole allergy grading. If a minor reaction occurs during the desensitisation, then repeat the same step for an additional day and progress to next step only if the reaction subsides. If the reaction worsens or a severe reaction occurs, stop the desensitization process. Consider giving concurrent antihistamine (i.e. cetirizine 10 mg once daily), commenced one day prior to starting the desensitisation regimen.
Note: Desensitisation regime has been sourced from EdRen Transplantation Handbook. http://www.edren.org/pages/handbooks/transplant-handbook/infection-prophylaxis-and-treatment.php. Last accessed 7th May 2017 (10).
Dapsone PO 100 mg OD can be used as a second line prophylactic agent in patients allergic to co-trimoxazole. Consider dose reduction to 50 mg OD in severe renal dysfunction (creatinine clearance <10 ml/min) (1). Screening for glucose 6-phosphate dehydrogenase deficiency is required prior to using dapsone or primaquine.
Aerosolized pentamidine 300 mg inhaled every 3–4 weeks via Respirgard IITM nebulizer can be used as a third line agent.
Treatment of PCP (1,5):
Reduction in immunosuppression. High-dose co-trimoxazole for 3 weeks (dose adjustments). Adjunctive corticosteroids should be used as part of the treatment for KTRs with a PaO2 ≤70 mmHg on room air (40 mg orally twice daily for 5 days, followed by 40mg orally for 5 days, followed by 20 mg orally for 11 days). KTRs not meeting this criterion should continue their current dose of steroids.
Other treatment strategies in patients with proven trimethoprim–sulfamethoxazole allergy, intolerance or resistance include clindamycin plus primaquine (6) and intravenous pentamidine isethionate (1), with the former considered as less toxic.
Baker R, Jardine A, Andrews P. Renal Association Clinical Practice Guideline on post-operative care of the kidney transplant recipient. Nephron Clin Pract. 2011;118 Suppl 1:c311-47. doi: 10.1159/000328074. Epub 2011 May 6. Kidney Disease: Improving Global Outcomes (KDIGO) Transplant Work Group. KDIGO clinical practice guideline for the care of kidney transplant recipients. Am J Transplant. 2009 Nov;9 Suppl 3:S1-155. doi: 10.1111/j.1600-6143.2009.02834.x. Pneumocystis jiroveci (formerly Pneumocystis carinii). Am J Transplant 2004; 4 (Suppl 10): 135–141. Fox BC, Sollinger HW, Belzer FO et al. A prospective, randomized, double-blind study of trimethoprim-sulfamethoxazole for prophylaxis of infection in renal transplantation: Clinical efficacy, absorption of trimethoprim-sulfamethoxazole, effects on the microflora, and the cost-benefit of prophylaxis. Am J Med 1990;89: 255–274. Pneumocystis jiroveci (formerly Pneumocystis carinii). Am J Transplant 2004; 4 (Suppl 10): 135–141. Smego RA Jr, Nagar S, Maloba B, Popara M. A meta-analysis of salvage therapy for Pneumocystis carinii pneumonia. Arch Intern Med. 2001 Jun 25;161(12):1529-33. Fishman JA. Infection in solid-organ transplant recipients. N Engl J Med. 2007 Dec 20;357(25):2601-14. Khan MA, Farrag N, Butcher P. Diagnosis of Pneumocystis carinii pneumonia: immunofluorescence staining, simple PCR or nPCR. J Infect. 1999;39(1):77-80. Oren I, Hardak E, Finkelstein R, Yigla M, Sprecher H. Polymerase chain reaction-based detection of Pneumocystis jirovecii in bronchoalveolar lavage fluid for the diagnosis of pneumocystis pneumonia. Am J Med Sci. 2011;342(3):182-185. EdRen Transplantation Handbook. http://www.edren.org/pages/handbooks/transplant-handbook/infection-prophylaxis-and-treatment.php. Last accessed 7th May 2017.
2. Cytomegalovirus (CMV)
CMV is a prevalent virus of the herpes family which becomes latent following primary infection. Acute infection or reactivation may follow the institution of immunosuppression and may cause invasive disease or effects associated with secondary immune phenomena (Table 1). Acute primary infection is considered as the most severe form of the disease and frequently occurs when seronegative recipients receive allografts from seropositive donors (15).
The two main approaches to preventative therapy are universal prophylaxis and pre-emptive anti-viral therapy. Universal prophylaxis aids in preventing other viral infections of the herpes family and is generally preferred to pre-emptive strategy considering the relative ease of administration, effectiveness, similar costs and safety profile (2,3,4,5,13). Bone marrow suppression and delayed-onset primary CMV disease are two potential complications associated with the prophylactic strategy (1,15).
PCR provides an essential tool in detecting and quantifying CMV, although neurological (including retinitis) and gastrointestinal infections may present with a negative blood based assays. Invasive procedures such as lumbar-puncture and endoscopic biopsies might be necessary in both diagnosis and documentation of cure (15).
CMV infection: detection of CMV replication in blood (using PCR technique) regardless of signs and symptoms.
CMV syndrome: fever, leucopoenia, thrombocytopenia, arthralgia and malaise (15).
CMV tissue invasive disease: presence of organ-specific involvement. The diagnosis is more secure if CMV is detected in tissue biopsies, BAL in suspected pulmonary involvement and typical fundoscopic changes in chorioretinitis.
CMV disease: CMV infection plus CMV syndrome and/or CMV tissue invasive disease.
Clinical failure: failure to improve clinically after 14 days of treatment with antivirals.
Drug failure: no reduction in viral load after 14 days treatment with antivirals.
CMV serology should be performed on all donors. CMV serology should be repeated immediately pre-transplant in all recipients who were negative in the previous tests or recipients whom CMV status is unknown. A hybrid prophylactic and monitoring strategy is illustrated in Table 2. Dose of Valgancyclovir should be adjusted according to renal function as shown in the Table 3. Seronegative recipients receiving a seropositive graft (especially if they do not seroconvert) should be considered for longer periods of prophylaxis. Watch for marrow suppression (especially with Co-trimoxazole and MMF), and liver derangement. Use irradiated blood products in seronegative to seronegative transplants CMV prophylaxis is to be instituted for 6 weeks whenever lymphocyte depleting agents are used to treat rejection episodes (11).
Consider performing CMV PCR whenever there is transplant dysfunction, AR, lymphocyte depleting agents, any episode off illness that might be CMV related at any stage post-transplant.
Patients who have a moderate to high risk of CMV infection and are intolerant to Valgancyclovir (e.g. pancytopenia) should be switched to pre-emptive therapy by monitoring CMV PCR titres weekly for 16 weeks and at 5, 6, 9 and 12 months (2).
Treat all patients with CMV disease, tissue invasive disease and any patient with a CMV viral load ≥3 × 103 copies/ml.
If a patient has a detectable CMV viral load but <3 × 103 copies/ml then the test should be repeated twice weekly. Depending on the result of the 2nd test and the clinical condition of the patient, one may decide to treat or to continue the monitoring strategy.
Asymptomatic patients with a detectible CMV viral load should have their anti-metabolite reduced or stopped. CMV titre should be monitored once to twice weekly. Consider treatment dose Valgancyclovir if patient develops symptoms, or viremia does not settle with stopping the anti-metabolite alone. Patients with considerable cumulative immunosuppression or seronegative recipients might benefit from early introduction of Valgancyclovir.
Patients with CMV disease or tissue invasive disease should have their anti-metabolite stopped and treated with I.V Gancyclovir (9,13) adjusted for renal function (Table 4).
Note: Gancyclovir is considered as a cytotoxic agent and therefore re-constituted in pharmacy. It is given as an infusion over 1 hour.
Whilst it remains rare occurrence, keep in mind Gancyclovir resistance in patients with treatment or drug failure. Foscarnet, cidofovir, CMV Immunoglobulin or IVIG may be used in life-threatening circumstances (discuss with ID specialist). For further reading see reference 1.
There is some evidence that Valgancyclovir is as effective as Gancyclovir in patients with mild to moderate CMV infection and spares patients from the risks and cost of central venous access (10).
Anti-viral therapy is to be continued until complete resolution of CMV related signs and symptoms, together with undetectable CMV PCR titre performed one week apart. Typical duration is 21 days but can be longer. One can switch from Gancyclovir to treatment dose Valgancyclovir after 2 weeks of therapy if the patient is recovering well and CMV load is low.
Once CMV infection has been resolved Valgancyclovir prophylaxis is to be re-instituted for an additional 3 months. CMV titre should be monitored every 1–2 week for the next 3 months. Virtually all cases of CMV disease occur after the cessation of antiviral prophylaxis (6).
Eid AJ, Razonable RR. New developments in the management of cytomegalovirus infection after solid organ transplantation. Drugs. 2010 May 28;70(8):965-81. doi: 10.2165/10898540-000000000-00000. Khoury JA, Storch GA, Bohl DL et al. Prophylactic versus preemptive oral valganciclovir for the management of cytomegalovirus infection in adult renal transplant recipients. Am J Transplant. 2006 Sep;6(9):2134-43. Epub 2006 Jun 19. Zhang LF, Wang YT, Tian JH, Yang KH, Wang JQ. Preemptive versus prophylactic protocol to prevent cytomegalovirus infection after renal transplantation: a meta-analysis and systematic review of randomized controlled trials. Transpl Infect Dis. 2011 Dec;13(6):622-32. doi: 10.1111/j.1399-3062.2011.00652.x. Epub 2011 May Hodson EM. Jones CA. Webster AC, et al. Antiviral medications to prevent cytomegalovirus disease and early death in recipients of solid-organ transplants: a systematic review of randomised controlled trials. Lancet 2005; 365 (9477):2105-15 Kalil AC, Levitsky J, Lyden E, et al. Meta-analysis: The efficacy of strategies for prevent organ disease by cytomegalovirus in solid organ transplant recipients, Ann intern Med 2005; 143 (12): 870-80 Arthurs SK. Eid AJ. Pedersen RA, et al. Delayed-onset primary cytomegalovinis disease and the risk of allograft failure and mortality after kidney transplantation. Clin Infect Dis 2008; 46 (6); 840-6 Doyle AM. Warburton KM, Goral S, et al. 24-week oral gancicîovir prophylaxis in kidney recipients is associated with reduced symptomatic cytomegalovirus disease compared to a 12-week course. Transplantation 2006; 81 (8); 1106-11 Humar A. Lebranchu Y. Vincenti F, et al. The efficacy and safety of 200 days valganciclovir cytomegalovirus prophylaxis in high-risk kidney transplant recipients. Am J Transplant. 2010 May;10(5):1228-37. doi: 10.1111/j.1600-6143.2010.03074.x. Epub 2010 Mar 2 Humar A, Snydman D, Cylomegalovirus in solid organ transplant recipients. Am J Transplant 2009; 9 Suppl, 4:S78-86 Asberg A. Humar A. Rollag H, et al. Oral valganciclovir is noninferior to intravenous ganciclovir for the treatment of cytomegalovirus disease in solid organ transplant recipients. Am J Transplant 2007; 7 (9); 2106-13 Baker R, Jardine A, Andrews P. Renal Association Clinical Practice Guideline on post-operative care of the kidney transplant recipient. Nephron Clin Pract. 2011;118 Suppl 1:c311-47. doi: 10.1159/000328074. Epub 2011 May 6. van der Beek MT, Berger SP, Vossen AC, et al. Preemptive versus sequential prophylactic-preemptive treatment regimens for cytomegalovirus in renal transplantation: comparison of treatment failure and antiviral resistance. Transplantation 2010;89:320-6. Kidney Disease: Improving Global Outcomes (KDIGO) Transplant Work Group. KDIGO clinical practice guideline for the care of kidney transplant recipients. Am J Transplant. 2009 Nov;9 Suppl 3:S1-155. doi: 10.1111/j.1600-6143.2009.02834.x. Hodson EM, Jones CA, Strippoli GF et al. Immunoglobulins, vaccines or interferon for preventing cytomegalovirus disease in solid organ transplant recipients. Cochrane Database Syst Rev 2007: CD005129. Fishman JA. Infection in solid-organ transplant recipients. N Engl J Med. 2007 Dec 20;357(25):2601-14. EdRen Transplantation Handbook. http://www.edren.org/pages/handbooks/transplant-handbook/infection-prophylaxis-and-treatment.php. Last accessed 7th May 2017.
3. Ebstein-Barr Virus (EBV)
EBV causes infectious mononucleosis mainly in young individuals. Acute infection leads to a polyclonal expansion of B-cells, most of which are eliminated after a cytotoxic T-cell response. B-cells which evade the T-cell response give rise to latent infection. Conversely, immunosuppressed individuals are less able to clear acutely infected or latent B-cells and therefore are at a higher risk of developing uncontrolled B-cell proliferation (Table 1) which can lead to post-transplant lymphoproliferative disease (PTLD). EBV infection has been also associated with gastric and nasopharyngeal malignancy (2).
EBV infected B-cells can be donor derived (acute infection) most commonly seen in solid organ transplant or recipient derived (re-activation) most commonly seen in haemopoietic cell transplantation.
Approximately 85% of PTLD is of B-cell origin and over 80% of these are associated with EBV infection (4,7). About 15% is of T-cell lineage, of which, 30% are associated with EBV infection (4).
The incidence of PTLD in kidney, heart or liver transplants is approximately 1–3%, lung, intestine or multi-organ transplants 7–33% and bone marrow recipients <1% (1). It is a potentially life-threatening complication, with an overall mortality often exceeding 50% (3).
EBV serology should be performed on both donor and recipient, repeated immediately prior to transplant in seronegative recipients (24). EBV PCR should be assayed in the first week post-transplant and thereafter at least monthly for the first 6 months and three monthly to the end of the first year in high risk KTRs (D+/R−) (24,23,22). EBV viral load is to be monitored after treatment for AR (24,23,22).
Clinical presentation of PTLD may include; pyrexia, malaise, weight loss, night sweats, fatigue, lymphadenopathy, gastrointestinal obstruction or perforation, abdominal-mass lesions, allograft infiltrative diseases, hepatic or pancreatic dysfunction, lungs, skin and central nervous system disease. Infiltration of the allograft can mimic rejection (38).
A rising EBV viral load and elevated serum lactate dehydrogenase (LDH) may be suggestive of PTLD. Remember, EBV viral load is sensitive, but not specific, for EBV disease and PTLD, particularly in previously seronegative KTRs (23). In addition, EBV negative PTLD has been reported, albeit uncommon (23). Consider reducing immunosuppression with rising EBV titres (24,23). The ERBP suggest reducing immunosuppression when EBV PCR is persistently >104 copies/mL (22).
Risk factors for PTLD
Degree of immunosuppression (3,8,38) Recipients in their first year post-transplant (3,9) Paediatric recipients and those above 60 years of age (3). EBV seronegative patients receiving an EBV positive kidney have 10–50 times the risk compared to EBV seropositive recipients (10) Higher degree of HLA mismatch especially at the B-loci (11,13). CMV disease (38) Caucasians carry twice the risk of African descendants (14). Tacrolimus compared to Cyclosporine based regimes, dose dependant (32). Depleting agents
Analyse CSF using EBV PCR when suspecting CNS PTLD.
Flow cytometry, analysis of immunoglobulin gene rearrangements, and histological evaluation of a tissue sample with EBV RNA staining are vital in the diagnosis and management of PTLD (14,38).
A positive CD20 cytometry result indicates the presence of CD20 antigen on the patient’s B-cells and therefore eligibility for rituximab therapy.
Bone marrow aspiration and biopsy are to be considered whenever cytopenias are present. Bone marrow involvement can occur without any other system involvement.
Treatment of PTLD
Reduction in immunosuppression (see Table 2) Sequential treatment with Rituximab followed by CHOP chemotherapy. The PTLD-1 trial is the largest prospective trial in PTLD to date and has produced the best response rates and survival (90% overall response rate, 100% response rate in kidney PTLD at 61 months (35) Radiotherapy for localised and CNS disease (38)
Cytotoxic T-lymphocyte adoptive immunotherapy is another strategy which holds future potential against EBV related malignancies when conventional therapy fails. Most of the data comes from retrospective series and small observational studies in hematopoietic cell transplantation. A long-term follow suggested that such therapy is effective for both prophylaxis and therapy (36). Some major limitations of this strategy include the inability to generate cytotoxic lymphocytes in all solid organ transplant recipients, considerable time required for their generation and costs involved (2). Therefore, novel and economically feasible manufacturing techniques with faster turnover time are required before adoptive immunotherapy can be used for urgent PTLD therapy (37).
Burns DM, Crawford DH. Epstein-Barr virus-specific cytotoxic Tlymphocytes for adoptive immunotherapy of post-transplant lymphoproliferative disease. Blood Rev 2004;18(3):193–209. Smith C, Khanna R. Adoptive therapy for EBV-induced cancers: driving success with post-transplantlymphoproliferative disorder to other EBV-derived tumors. Immunotherapy. 2015;7(5):563-72. doi: 10.2217/imt.15.7. Opelz G, Dohler B. Lymphomas after solid organ transplantation: a collaborative transplant study report. Am J Transplant 2004;4(2):222–30. Hoshida Y, Li T, Dong Z, et al. Lymphoproliferative disorders in renal transplant patients in Japan. Int J Cancer 2001;91(6):869–75. Allen U, Hébert D, Moore D, Dror Y, Wasfy S; Canadian PTLD Survey Group--1998. Epstein-Barr virus-related post-transplant lymphoproliferative disease in solid organ transplant recipients, 1988-97: a Canadian multi-centre experience. Pediatric Transplant. 2001 Jun;5(3):198-203. Swerdlow SH, Campo E, Harris NL, et al. World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues, IARC Press, Lyon 2008. Opelz, G, Henderson, R, for the Collaborative Transplant Study, Lancet 1993; 342:1514.Kidney Disease: Improving Global Outcomes (KDIGO) Transplant Work Group. KDIGO clinical practice guideline for the care of kidney transplant recipients. Am J Transplant. 2009 Nov;9 Suppl 3:S1-155. Smith JM, Rudser K, Gillen D et al. Risk of lymphoma after renal transplantation varies with time: an analysis of the United States Renal Data System. Transplantation 2006; 81:175–180 Allen UD, Preiksaitis JK; AST Infectious Diseases Community of Practice. Epstein-Barr virus and posttransplant lymphoproliferative disorder in solid organ transplantation. Am J Transplant. 2013 Mar;13 Suppl 4:107-20. Caillard S, Dharnidharka V, Agodoa L, Bohen E, Abbott K. Post-transplant lymphoproliferative disorders after renal transplantation in the United States in era of modern immunosuppression. Transplantation. 2005 Nov 15;80(9):1233-43. Bakker NA, van Imhoff GW, Verschuuren EA et al. HLA antigens and post renal transplant lymphoproliferative disease: HLA-B matching is critical. Transplantation. 2005 Sep; 80(5): 595-9. Parker A, Bowles K, Bradley JA et al. Haemato-oncology Task Force of the British Committee for Standards in Haematology and British Transplantation Society. Diagnosis of post-transplant lymphoproliferative disorder in solid organ transplant recipients - BCSH and BTS Guidelines. Br J Haematol. 2010;149(5):675. Chadban SJ, Barraclough KA, Campbell SB et al. Kidney Health Australia Caring for Australians with Renal Impairment (KHA-CARI). KHA-CARI guideline: KHA-CARI adaptation of the KDIGO Clinical Practice Guideline for the Care of Kidney Transplant Recipients. Nephrology (Carlton). 2012 Mar;17(3):204-14. Heemann U, Abramowicz D, Spasovski G, Vanholder R. European Renal Best Practice Work Group on Kidney Transplantation. Endorsement of the Kidney Disease Improving Global Outcomes (KDIGO) guidelines on kidney transplantation: a European Renal Best Practice (ERBP) position statement. Nephrol Dial Transplant. 2011 Jul;26(7):2099-106. Kidney Disease: Improving Global Outcomes (KDIGO) Transplant Work Group. KDIGO clinical practice guideline for the care of kidney transplant recipients. Am J Transplant. 2009 Nov;9 Suppl 3:S1-155. Baker R1, Jardine A, Andrews P. Renal Association Clinical Practice Guideline on post-operative care of the kidney transplant recipient. 2011;118 Suppl 1:c311-47. doi: 10.1159/000328074. Epub 2011 May 6. Rausch L, Koenecke C, Koch HF et al. Matched-pair analysis: identification of factors with independent influence on the development of PTLD after kidney or liver transplantation. Transplant Res. 2016 Aug 2;5:6. Trappe R, Oertel S, Leblond V et al. Sequential treatment with rituximab followed by CHOP chemotherapy in adult B-cell post-transplantlymphoproliferative disorder (PTLD): the prospective international multicentre phase 2 PTLD-1 trial. Lancet Oncol. 2012 Feb;13(2):196-206. Heslop HE, Slobod KS, Pule MA et al. Long-term outcome of EBV-specific T-cell infusions to prevent or treat EBV-related lymphoproliferative disease in transplant recipients. Blood 115(5), 925–935 (2010). Bollard CM. Improving T-cell therapy for epstein-barr virus lymphoproliferative disorders. J Clin Oncol. 2013 Jan 1;31(1):5-7. doi: 10.1200/JCO.2012.43.5784. Epub 2012 Nov 19.
4. BK-virus nephropathy (BKVN)
BK-virus (BKV) was first reported in 1971 and isolated from urine of a renal transplant recipient with the initials BK. BKV and JC-virus (JCV) are the two polyomaviruses identified in KTRs.
Very occasionally (<5%) JCV causes a similar polyoma virus nephropathy, but in general it is more associated with the progressive multifocal leukoenchepalopathy (PML) (11). PML is a demyelinating disease of high morbidity and mortality, most commonly reported in HIV infection.
The degree of immunosuppression is probably the most important risk factor underlying BKV infection. Indeed, some consider BK replication to be a reliable marker of excess immunosuppression (1). HLA and ABO incompatible transplant, depleting antibodies and Tacrolimus have all been associated with an increased risk (1, 2).
BKV have a tropism for the urogenital epithelium and is associated with tubulointerstitial nephritis, ureteric stenosis and haemorrhagic cystitis, frequently presenting as a rise in creatinine (3). High index of suspicion is essential.
Diagnosis is usually confirmed upon detection of BK virus in blood and/or urine (11). A viral load of >104 copies/ml is usually significant. Diagnosis can be supported by finding decoy cells on urine cytology. Decoy cells are not as sensitive and specific as BKV PCR assays (9).
A definitive diagnosis of BK nephropathy requires the characteristic changes together with a positive SV40 immunochemistry (4, 5, 6, 8) (it does not distinguish between the BK and JC viruses). It is important to keep in mind that BKV lesions tend to be patchy and more frequently encountered in the medulla rather than tubules. Hence, biopsy cores should ideally include medulla (6).
KTS should be screened using BKV PCR monthly for the first 3–6 months and then every 3 months till the end of the first year (6, 7, 8). BKV PCR should be part of the screening tools employed to investigate unexplained transplant dysfunction and/or after treatment of AR (6, 7, 8).
Some recommend screening once yearly after the first year post-transplant (4).
Early identification of BKV multiplication allows for early measures in order to prevent BKVN (10). A creatinine rise in this context is considered a late finding. About 50% of all BKVN occurs in the first 3 months and 95% in the first 2 years (7).
There is no established specific therapy, but generally a BKV load of >104 copies/ml or established BKVN on biopsy calls for reduction in the immunosuppression (6, 7, 8) (Table 1).
Although some centres use antiviral agents such as cidofovir, leflunomide, and/or ciprofloxacin, to date, none have undergone rigorous clinical trials.
Gralla J, Huskey J, Wiseman AC. Trends in immune function assay (ImmuKnow; Cylex™) results in the first year post-transplant and relationship to BK virus infection. Nephrol Dial Transplant. 2012 Jun;27(6):2565-70. doi: 10.1093/ndt/gfr675. Hirsch HH, Vincenti F, Friman S et al. Polyomavirus BK replication in de novo kidney transplant patients receiving tacrolimus or cyclosporine: a prospective, randomized, multicenter study. H Am J Transplant. 2013 Jan;13(1):136-45. doi: 10.1111/j.1600-6143.2012.04320.x. Gupta M, Miller F, Nord EP, Wadhwa NK. Delayed renal allograft dysfunction and cystitis associated with human polyomavirus (BK) infection in a renal transplant recipient: a case report and review of literature. Clin Nephrol. 2003 Dec;60(6):405-14. Hirsch HH, Brennan DC, Drachenberg CB et al. Polyomavirus-associated nephropathy in renal transplantation: interdisciplinary analyses and recommendations. Transplantation. 2005 May 27;79(10):1277-86. Wiseman AC. Polyomavirus nephropathy: a current perspective and clinical considerations. Am J Kidney Dis. 2009 Jul;54(1):131-42. doi: 10.1053/j.ajkd.2009.01.271. Epub 2009 Apr 25. Baker R, Jardine A, Andrews P. Renal Association Clinical Practice Guideline on post-operative care of the kidney transplant recipient. Nephron Clin Pract. 2011;118 Suppl 1:c311-47. doi: 10.1159/000328074. Kidney Disease: Improving Global Outcomes (KDIGO) Transplant Work Group. KDIGO clinical practice guideline for the care of kidney transplant recipients. Am J Transplant. 2009 Nov;9 Suppl 3:S1-155. doi: 10.1111/j.1600-6143.2009.02834.x. Heemann U, Abramowicz D, Spasovski G, Vanholder R. European Renal Best Practice Work Group on Kidney Transplantation. Endorsement of the Kidney Disease Improving Global Outcomes (KDIGO) guidelines on kidney transplantation: a European Renal Best Practice (ERBP) position statement. Nephrol Dial Transplant. 2011 Jul;26(7):2099-106. Randhawa P, Brennan DC. BK virus infection in transplant recipients: an overview and update. Am J Transplant. 2006 Sep;6(9):2000-5. Brennan DC, Agha I, Bohl DL et al. Incidence of BK with tacrolimus versus cyclosporine and impact of preemptive immunosuppression reduction. Am J Transplant. 2005 Mar;5(3):582-94. Fishman JA. Infection in solid-organ transplant recipients. N Engl J Med. 2007 Dec 20;357(25):2601-14.
5. Herpes simplex virus (HSV)
The Herpes family consists of 8 viruses (Table 1). Serological evidence of HSV1 and HSV2 is rather common in the general population. Reactivation in immunocompetent individuals is usually self-limiting and uncomplicated. The vast majority of infections are caused by HSV1, with a minority caused by HSV2 (sexually transmitted herpes). Infections have been reported after intensification of immunosuppression in the setting of AR (2). Donor transmission is rare, as the site of latency is not transplanted (5).
Superficial HSV: Disease limited to skin and mucosa, without involvement of visceral organs. Frequently presents as ulcers involving the oral mucosa and/or genital areas.
Invasive HSV: Occurs in immunosuppressed individuals (10). It is difficult to diagnose as it can occur without cutaneous manifestations. Systemic HSV infection constitutes involvement of the lungs, liver, oesophagus, central nervous system or other visceral organs. It represents a potentially life-threatening complication. Diagnosis is confirmed using HSV PCR technique (5).
Diagnosis of oesophageal infection is usually based on gastroscopy findings and confirmed following histopathological examination of tissue biopsies or brushings taken from the edge of an ulcer. Ulcers usually have a typical appearance, with a well circumscribed and ‘volcano-like’ appearance. This is dissimilar to CMV ulcers, which have a tendency to be more linear and deeper. Fungal infections (such as candida species) can also present with oesophageal involvement.
HSV infections are uncommon while patients are receiving antiviral prophylaxis (11).
Patients not receiving Valgancyclovir should receive Acyclovir prophylaxis.
Superficial HSV infections should be treated with Acyclovir 400 mg orally five times daily for 14–21 days, usually until lesions have resolved (3,4).
Severe odynophagia or dysphagia usually requires I.V Acyclovir at 5 mg/Kg every 8 hours for 7–14 days, then switched to oral therapy.
Systemic HSV infection also require I.V Acyclovir therapy until patient has adequate clinical response (3,4).
Frequent HSV infections are usually a sign of over immunosuppression. One can also consider regular oral prophylaxis and reduction in immunosuppression (3,4).
Resistance to Acyclovir may require the use of Foscarnet (discuss with ID specialist).
Mosimann F, Cuénoud PF, Steinhäuslin F, Wauters JP. Herpes simplex esophagitis after renal transplantation. Transpl Int. 1994;7(2):79-82. Baker R, Jardine A, Andrews P. Renal Association Clinical Practice Guideline on post-operative care of the kidney transplant recipient. Nephron Clin Pract. 2011;118 Suppl 1:c311-47. doi: 10.1159/000328074. Epub 2011 May 6. Kidney Disease: Improving Global Outcomes (KDIGO) Transplant Work Group. KDIGO clinical practice guideline for the care of kidney transplant recipients. Am J Transplant. 2009 Nov;9 Suppl 3:S1-155. doi: 10.1111/j.1600-6143.2009.02834.x. Jenkins FJ, Rowe DT, Rinaldo CR Jr. Herpesvirus infections in organ transplant recipients. Clin Diagn Lab Immunol. 2003 Jan;10(1):1-7. Mendez JC, Dockrell DH, Espy MJ et al. Human beta-herpesvirus interactions in solid organ transplant recipients. J Infect Dis. 2001 Jan 15; 183(2):179-184 Osman HK, Peiris JS, Taylor CE, Karlberg JP, Madeley CR. Correlation between the detection of viral DNA by the polymerase chain reaction in peripheral blood leukocytes and serological responses to human herpesvirus 6, human herpesvirus 7, and cytomegalovirus in renal allograft recipients. J Med Virol. 1997 Nov; 53(3):288-94 Osman HK, Peiris JS, Taylor CE, Warwicker P, Jarrett RF, Madeley CR. “Cytomegalovirus disease” in renal allograft recipients: is human herpesvirus 7 a co-factor for disease progression? J Med Virol. 1996 Apr; 48(4):295-301. Singh N, Carrigan DR, Gayowski T, Marino IR. Human herpesvirus-6 infection in liver transplant recipients: documentation of pathogenicity. Transplantation. 1997 Sep 15;64(5):674-8. Koneru B, Tzakis AG, DePuydt LE et al. Transmission of fatal herpes simplex infection through renal transplantation. Transplantation 1988; 45: 653–656. Fishman JA. Infection in solid-organ transplant recipients. N Engl J Med. 2007 Dec 20;357(25):2601-14.
6. Varicella Zoster Virus (VZV)
Varicella-zoster virus causes two clinically distinct infections. Primary VZV presents as ‘chickenpox,’ manifesting as multiple cutaneous lesions that evolve through macular, papular, vesicular and pustular stages, usually involving the entire body at different stages of development together with fever and other constitutional symptoms (6). Re-activation of latent VZV infection within the sensory ganglia usually presents as ‘shingles’ characterised by a painful, unilateral vesicular eruption, which follows a dermatomal distribution. Invasive herpes zoster infection can be potentially life-threatening in immunocompromised hosts such as solid organ transplant recipients.
Uncomplicated herpes zoster (shingles): is cutaneous zoster limited to 3 dermatomes.
Herpes zoster ophthalmicus: Lesions involving the first division of the trigeminal nerve. It can affect the skin of the forehead, cornea and anterior uvea on the same side.
Ramsey-Hunt syndrome: herpes zoster involving the genticulate ganglion and presents with unilateral lower motor neuron weakness of the VII cranial nerve together with painful ear and facial eruptions on the same side (7).
Invasive herpes zoster: cutaneous zoster involving >3 dermatomes, and/or evidence of pulmonary, hepatic, CNS or other visceral organ involvement.
Potential kidney transplant recipients should have their VZV serology checked and if negative they should receive the vaccine at least 4 weeks pre-transplant. Varicella vaccine is NOT recommended after transplantation.
Primary VZV infection (chicken-pox) should be actively treated with I.V/oral acyclovir, together with a temporary reduction in the overall immunosuppression (2,3). Initially, acyclovir 10 mg/Kg IV every 8 hours which is later switched to oral therapy once there is significant improvement (6). Valacyclovir can be used instead of acyclovir.
Uncomplicated herpes zoster can be treated with oral acyclovir at a dose of 800 mg five times per day for at least 7 days (2,3,6). Valacyclovir can be used instead of acyclovir.
Disseminated and invasive herpes zoster should be actively treated with I.V acyclovir 10mg/Kg every 8 hours for at least 7 days, together with a temporary reduction in the overall immunosuppression (2,3,6). Longer treatment may be necessary in patients with extensive disease or central nervous system involvement (6).
In all circumstances treatment should be continued until all lesions have scabbed (2,3).
KTRs who are immunologically naive to varicella and have significant exposure to individuals with active infection should receive VZV immunoglobulin within 96 hours or if this is not achievable, a course of oral acyclovir within 7–10 days post-exposure (2,3,6). Significant exposure is defined as exposure to a household contact or any other prolonged close proximity contact usually indoors. The dose of VZV immunoglobulin, VariZIGTM is 125 units/10 kg of body weight in single IM dose (max. dose is 625 units, min. 125 units). Acyclovir is given at a dose of 800 mg four times per day for 7 days (6).
The use of varicella zoster immunoglobulin in this setting has been shown to prevent or alter varicella infection in immunosuppressed individuals after significant exposure (4–6).
Baker R, Jardine A, Andrews P. Renal Association Clinical Practice Guideline on post-operative care of the kidney transplant recipient. Nephron Clin Pract. 2011;118 Suppl 1:c311-47. doi: 10.1159/000328074. Epub 2011 May 6. Kidney Disease: Improving Global Outcomes (KDIGO) Transplant Work Group. KDIGO clinical practice guideline for the care of kidney transplant recipients. Am J Transplant. 2009 Nov;9 Suppl 3:S1-155. doi: 10.1111/j.1600-6143.2009.02834.x. Heemann U, Abramowicz D, Spasovski G, Vanholder R. European Renal Best Practice Work Group on Kidney Transplantation. Endorsement of the Kidney Disease Improving Global Outcomes (KDIGO) guidelines on kidney transplantation: a European Renal Best Practice (ERBP) position statement. Nephrol Dial Transplant. 2011 Jul;26(7):2099-106. Varicella-zoster infections. In: Pickering L, Baker C, Long S, McMillan J (eds). Red book: 2006 report of the committee on infectious disease of the American Academy of Pediatrics, 27th edn. American Academy of Pediatrics: Elk Grove Village, IL, 2006, pp. 711–725. Guidelines for the prevention and management of infectious complications of solid organ transplantation: HHV-6, HHV-7, HHV-8, HSV-1 and −2, VZV. Am J Transplant 2004; 4: 66–71. Boeckh M. Prevention of VZV infection in immunosuppressed patients using antiviral agents. Herpes 2006; 13: 60–65. Pergam SA, Limaye AP; AST Infectious Diseases Community of Practice. Varicella zoster virus (VZV) in solid organ transplant recipients. Am J Transplant. 2009 Dec;9 Suppl 4:S108-15. doi: 10.1111/j.1600-6143.2009.02901.x. Sweeney CJ, Gilden DH. Ramsay Hunt syndrome. J Neurol Neurosurg Psychiatry. 2001 Aug;71(2):149-54.
7. Oesophageal candida
Nystatin oral suspension (suspension dose in ?units/ml) 1 ml every 6 hours for 1–3 months after transplantation can be used as prophylaxis against oesophageal candida (1). Oral Nystatin 1 ml every 6 hours for 1 month should be used after treatment with depleting antibodies.
Patients should shake the oral suspension well prior to use, and the suspension should be administered by placing half of the dose in each side of the mouth with a dropper and retained for as long as possible.
Six hourly dose is cumbersome and my limit compliance. Other strategies include oral fluconazole keeping in mind systemic absorption and possible interactions with the CNI metabolism.
Baker R, Jardine A, Andrews P. Renal Association Clinical Practice Guideline on post-operative care of the kidney transplant recipient. Nephron Clin Pract. 2011;118 Suppl 1:c311-47. doi: 10.1159/000328074. Epub 2011 May 6.
8. Post-transplant diarrhoea
Diarrhoea is a common and frequently debilitating complication after kidney transplantation. It has been associated with worse graft and patient survival (11).
Post-transplant diarrhoea is often attributed to immunosuppressive drugs and/or infectious causes (Table 1). Timely identification of the enteric pathogen is of chief importance in instituting correct therapy, and avoiding unnecessary discontinuation of MMF with subsequent increased risk of rejection.
Flow-chart 1 provides a comprehensive strategy for investigating and treating post-transplant diarrhoea.
First line stool investigation tests should include; standard stool cultures for pathogenic bacteria, examinations for ova, cysts and parasites, Clostridium difficile toxin assay and viral screen for Rotavirus, Adenovirus, and Norovirus. Consider screening for cryptosporidium and Yesinia if above tests are negative.
Coste JF, Vuiblet V, Moustapha B, et al. Microbiological diagnosis of severe diarrhea in kidney transplant recipients by use of multiplex PCR assays. J Clin Microbiol 2013; 51: 1841. Roos-Weil D, Ambert-Balay K, Lanternier F, et al. Impact of norovirus/sapovirus-related diarrhea in renal transplant recipients hospitalized for diarrhea. Transplantation 2011; 92: 61. Aulagnon F, Scemla A, DeWolf S, Legendre C, Zuber J. Diarrhea after kidney transplantation: a new look at a frequent symptom. Transplantation. 2014 Oct 27;98(8):806-16. Dubberke ER, Burdette SD. Clostridium difficile infections in solid organ transplantation. Am J Transplant 2013; 4: 42. Arslan H, Inci EK, Azap OK, et al. Etiologic agents of diarrhea in solid organ recipients. Transpl Infect Dis 2007; 9: 270. Champion L, Durrbach A, Lang P, et al. Fumagillin for treatment of intestinal microsporidiosis in renal transplant recipients. Am J Transplant 2010; 10: 1925 Durand CM, Marr KA, Arnold CA, et al. Detection of cytomegalovirus DNA in plasma as an adjunct diagnostic for gastrointestinal tract disease in kidney and liver transplant recipients. Clin Infect Dis 2013; 57: 1550 Florescu MC, Miles CD, Florescu DF. What do we know about adenovirus in renal transplantation? Nephrol Dial Transplant 2013; 28: 2003. Maes B, Hadaya K, deMoor B, et al. Severe diarrhea in renal transplant patients: results of the DIDACT study. Am J Transplant 2006; 6: 1466. Bunnapradist S, Neri L, Wong W, et al. Incidence and risk factors for diarrhea following kidney transplantation and association with graft loss and mortality. Am J Kidney Dis 2008; 51: 478. Roos-Weil D, Ambert-Balay K, Lanternier et al. Impact of norovirus/sapovirus-related diarrhea in renal transplant recipients hospitalized for diarrhea. Transplantation. 2011 Jul 15;92(1):61-9. doi: 10.1097/TP.0b013e31821c9392.
Kotton CN, Lattes R; AST Infectious Diseases Community of Practice. Parasitic infections in solid organ transplant recipients. Am J Transplant. 2009 Dec;9 Suppl 4:S234-51.
9. Mycobacterium tuberculosis (TB)
Active TB in KTRs is usually due to reactivation of latent disease under the influence of immunosuppression (3). Therefore, patients with latent TB on dialysis should be identified and treated prior to transplantation (1).
Latent TB infection (LTBI) is identified using Tuberculin Skin Test (TST) and Interferon-Gamma Release Assays (IGRAs).
TB prophylaxis should be considered in the following clinical scenarios (discuss with ID specialist):
KTRs with LTBI (see flow diagram). History of TB, NOT adequately treated (4). CXR findings consistent with previous TB (apical fibronodular lesions, calcified solitary nodule, calcified lymph nodes, or pleural thickening, NOT adequately treated (4). A CT chest should be performed in these patients to look for disseminated disease and to serve as a baseline study. Close contact with TB (i.e. family member/partner or sharing accommodation) Recently transplanted in a highly endemic country (see WHO country profiles. Ref. 1) Immigrants from a highly endemic country benefit from testing for latent TB Receiving an organ from a donor known to have untreated latent TB.
TST or QuantiFERON® tests in cadaveric transplant may prove to be difficult due to time constraints. QuantiFERON® may have a role in this context, however very limited data is available (9). When transplant is non-urgent, the donor can be treated for LTBI prior to transplantation, abrogating the need for recipient prophylaxis.
TST and QuantiFERON® have significant limitations and are considered unreliable for LTBI screening in the ESKD population (7). In this setting, QuantiFERON® was shown to be superior to TST for detecting LTBI (7) and IGRAs results were more closely associated with recent TB exposure than were positive TST results (8). In one study it was suggested that sensitivity is better maintained when performing the QuantiFERON® assay immediately before (not after) the HD process (6).
False positive TST can also occur in patients with previous BCG. In contrast, IGRA are not rendered positive by previous BCG vaccine (2).
Prophylaxis consists of Isoniazid 300 mg once daily orally plus pyridoxine 25 to 50 mg daily for 6–9 months. Rifampin containing regimes are usually avoided due to significant interactions with both CNI and mTORi (4). Liver function tests should be monitored every two weeks for six weeks, thereafter monthly (10).
Treatment of TB in KTRs has been shown to respond to standard antimycobacterial therapy (4). Discuss with Infectious Disease specialist.
Flow diagram: Screening solid organ transplant candidates for latent tuberculosis. Sourced: UpToDate. https://www.uptodate.com/contents/image?imageKey=ID%2F102601&topicKey=ID%2F1407&source=see_link. Last accessed 7th May 2017.
*Either test is acceptable, depending on availability and cost.
¶ For those with two indeterminate IGRAs, the decision regarding the need for treatment of latent TB will need to be made on a case-by-case basis according to the individual’s risk-benefit ratio, with consideration of signs of prior infection (e.g. granulomas on chest imaging), prior contact with people with known disease, other history of probable exposure, and risk of drug toxicities.
Δ Factors that make an individual at high risk for TB exposure includes but is not limited to:
A previous positive TST without history of BCG vaccine after infancy. Close contact with a person with active tuberculosis. Radiographic changes consistent with prior granulomatous disease in a person from a country with a high prevalence of TB.
World Health Organisation. http://www.who.int/tb/challenges/ltbi/en/ Centers for Disease Prevention. https://www.cdc.gov/tb/publications/factsheets/testing/igra.htm Baker R, Jardine A, Andrews P. Renal Association Clinical Practice Guideline on post-operative care of the kidney transplant recipient. Nephron Clin Pract. 2011;118 Suppl 1:c311-47. doi: 10.1159/000328074. Epub 2011 May 6. Kidney Disease: Improving Global Outcomes (KDIGO) Transplant Work Group. KDIGO clinical practice guideline for the care of kidney transplant recipients. Am J Transplant. 2009 Nov;9 Suppl 3:S1-155. doi: 10.1111/j.1600-6143.2009.02834.x. Hursitoglu M, Cikrikcioglu MA, Tukek T et al. Acute effect of low-flux hemodialysis process on the results of the interferon-gamma-basedQuantiFERON-TB Gold In-Tube test in end-stage renal disease patients. Transpl Infect Dis. 2009 Feb;11(1):28-32. doi: 10.1111/j.1399-3062.2008.00348.x. Epub 2008 Sep 18. Triverio PA, Bridevaux PO, Roux-Lombard P et al. Interferon-gamma release assays versus tuberculin skin testing for detection of latent tuberculosis in chronic haemodialysis patients. Nephrol Dial Transplant. 2009 Jun;24(6):1952-6. doi: 10.1093/ndt/gfn748. Epub 2009 Jan 22. Winthrop KL, Nyendak M, Calvet H et al. Interferon-gamma release assays for diagnosing mycobacterium tuberculosis infection in renal dialysis patients. Clin J Am Soc Nephrol. 2008 Sep;3(5):1357-63. doi: 10.2215/CJN.01010208. Schmidt T, Schub D, Wolf M et al. Comparative analysis of assays for detection of cell-mediated immunity toward cytomegalovirus and M. tuberculosis in samples from deceased organ donors. Am J Transplant. 2014 Sep;14(9):2159-67. Subramanian AK, Morris MI, AST Infectious Diseases Community of Practice. Mycobacterium tuberculosis infections in solid organ transplantation. Am J Transplant 2013; 13 Suppl 4:68.
10. Hepatitis B Virus (HBV)
Chronic HBV infection is one of the leading causes of liver disease and hepatocellular carcinoma worldwide (57,58). Recipient positivity for HBsAg is an independent risk factor for death after kidney transplantation, including increased risk of allograft loss (59). Indeed, transplantation in HBV infected patients is a balance of risks between worsening or re-activation of pre-existing infection and the risks of remaining on dialysis. The re-activation risk in HbcAb positive is considered low. In general, kidney transplantation is precluded in compensated cirrhosis and one should consider a combined liver-kidney transplant in decompensated cirrhosis (60).
HBV serology should be checked in all potential donors, including HB core antibody and DNA. HBV serology checked every 6 months and again immediately before transplantation in all recipients. HB surface antigen positive patients and HB surface antigen negative with HB core antibody positive, HB surface antibody negative profile should also be tested for HB e-antigen, HB e-antibody, HB core IgM antibody, and HBV DNA and Hepatitis Delta antibody. Table 1 provides a summary for HBV profile interpretation. HBV vaccination is to be routinely administered to all our dialysis patients (see local protocol). Standard induction and maintenance immunosuppression applies for these KTRs (2,27). Flowchart below (1,6,7) provides a summary for the treatment of HBV in kidney transplantation.
The impact on the outcomes of HBV-naive recipients of a kidney from HBsAg negative/HbcAb positive donor appears to be low to negligible (61). A recent meta-analysis, including 1385 KTRs, showed that the total rate of sero-conversion after kidney transplantation in this setting was 3.24%. Furthermore, none of these KTRs had signs of hepatitis, higher mortality, or decreased graft survival (62). Conversely, the majority of transplant centres engraft kidneys from HBsAg positive donors only in matched HBsAg positive recipients as it carries a significant risk of de-novo infection (61). Superinfection with donor HBV is not usually clinically significant. HbsAg positive kidneys should therefore be considered suitable for grafting into naive recipients ONLY in urgent situations where the benefit clearly outweighs the risk of acquired HBV infection. Recipient consent is imperative in both situations.
Interferon (IFN) therapy should be avoided in KTR (2,27). Lamivudine has been shown to reduce reactivation and improves post-transplant survival. Entecavir is more potent than lamivudine against HBV and offers a good safety profile in renal patients. Tenofovir is also more potent than Lamivudine, although data on its use post-transplantation is sparse and may be associated with tubular dysfunction. Entecavir is generally preferred as it is associated with least risk of HBV resistance (1.2% after 6 years if used as first-line therapy) and nephrotoxicity after transplantation (1,6).
Discontinuation of antiviral prophylaxis can be carefully attempted only in patients with negative HBeAg, stable liver function and no resistance to antivirals once immunosuppression is at the lowest level. Success rates range from 41.7 to 66.7% (4,5). Immunosuppression should be kept at the lowest level possible. In case of negative HBsAg and positive HBcAb recipient, the risk of reactivation is considered to be low especially in patients who have HBsAb >10 IU/mL. Currently there is insufficiently robust evidence to clearly recommend the administration of prophylaxis, but some feel that Lamivudine prophylaxis is a reasonable option in this setting. HBV Immunoglobulin should be considered in HBV positive donors (see flowchart).
In such cases 4,000 IU can be administered immediately prior to transplantation and levels kept >500 IU/L during first month post-transplant.
Table 1: Interpretation of HBV virological markers. Adapted from Centers for Disease Control and Prevention. https://www.cdc.gov/hepatitis/hbv/pdfs/serologicchartv8.pdf. Accessed on the 1st May 2017.
Flowchart 2: HBV infection and kidney transplantation (adapted from references 1, 6, 7).
§See main text regarding risk of HBV transmission.
¶HBsAb levels to be quantified pre-transplant (if time allows) and give a booster dose if levels are <10 IU/L. Otherwise give a booster dose regardless of HBsAb levels unless one was given in the previous 8 weeks. In the post-transplant period the HBsAb levels should be kept above 10 IU/L by administering booster doses as required.
HBV antivirals in renal impairment
Tsai MC, Chen YT, Chien YS, Chen TC, Hu TH. Hepatitis B virus infection and renal transplantation. World J Gastroenterol. 2010 Aug 21;16(31):3878-87. Chan TM, Fang GX, Tang CS, et al. Preemptive lamivudine therapy based on HBV DNA level in HBsAg-positive kidney allograft recipients. Hepatology 2002; 36:1246. Cho JH, Lim JH, Park GY, et al. Successful withdrawal of antiviral treatment in kidney transplant recipients with chronic hepatitis B viral infection. Transpl Infect Dis 2014; 16:295. Pilmore HL, Gane EJ. Hepatitis B-positve donors in renal transplantation: increasing the deceased donor pool. Transplantation. 2012 Aug 15;94(3):205-10. doi: 10.1097/TP.0b013e31824e3db4. Huprikar S, Danziger-Isakov L, Ahn J, Naugler S, Blumberg E, Avery RK, Koval C et al. Solid organ transplantation from hepatitis B virus positive donors: consensus guidelines for recipient management. Am J Transplant. 2015 May;15(5):1162-72. doi: 10.1111/ajt.13187. Epub 2015 Feb 23. B. J. McMahon, “Epidemiology and natural history of hepatitis B,” Seminars in Liver Disease, vol. 25, supplement 1, pp. 3–8,2005. D. Lavanchy, “Hepatitis B virus epidemiology, disease burden, treatment, arid current and emerging prevention and control measures,” Journal of Viral Hepatitis, vol. 11, no. 2, pp. 97–107,2004. Fabrizi F, Martin P, Dixit V et al. HbsAg Seropositive status and survival after renal transplantation: meta-analysis of observational studies. Am J Transpl 2005; 5:2913–21. Tsai MC, Chen YT, Chien YS, Chen TC, Hu TH. Hepatitis B virus infection and renal transplantation. World J Gastroenterol. 2010 Aug 21;16(31):3878-87. Veroux M, Ardita V, Corona D et al. Kidney Transplantation From Donors with Hepatitis B. Med Sci Monit. 2016 Apr 28;22:1427-34. Mahboobi N, Tabatabaei SV, Blum HE, Alavian SM. Renal grafts from anti-hepatitis B core-positive donors: a quantitative review of the literature. Transpl Infect Dis. 2012 Oct; 14(5):445-51.
11. Hepatitis C virus (HCV)
HCV infection in patients with CKD is associated with more rapid liver disease progression and reduced graft and patient survival following kidney transplantation (14). Nonetheless, there are definite survival advantages with a kidney transplant compared to patients who remain on dialysis. Therefore, HCV infection per se is not considered a contraindication to kidney transplantation (1).
HCV related kidney transplant dysfunction is usually immune-complex mediated and presents with recurrent or de-novo glomerulonephritis, usually of the membranporliferative type (MPGN) and frequently associated with mixed cryoglobulinaemia. HCV infection is also associated with NODAT and PTLD.
HCV serology is useful as initial screening test for recipient and donor. Seroconversion is detected in 1–6 weeks after exposure. HCV RNA testing decreases the window period to just few days. Recipient HCV serology should be checked every 6 months and re-checked immediately prior to transplantation. Antibody production may be absent in dialysis patients.
Positive HCV serology should be followed up by HCV PCR in both recipients and donor (1). A subset of HCV infected patients clear the virus without therapy. These patients are HCV antibody positive but have undetectable HCV RNA levels. HCV genotyping is essential to target therapy, determine duration and assess response to treatment.
KDIGO guidelines (2008) recommend that a liver biopsy should be considered in HCV infected kidney transplant candidates (1). However, recent advances in non‐invasive algorithms such as AST to platelet ratio index and elastography with FibroScan® have been used with increasing confidence to assess disease severity even in CKD patients (3,4,5). A brief update of KDIGO guidelines suggest that the extent of liver fibrosis in HCV infected patients with stage 4–5 CKD should be evaluated non-invasively. The presence of cirrhosis excludes a kidney alone transplant in most centres, as these patients do better with a combined kidney-liver transplant (9).
IFN-based therapy should be AVOIDED in KTRs as it is associated with higher rejection rates (1). An IFN-free and ribavirin-free regimen should be also used in dialysis patients as they are not very well tolerated (8).
Direct Acting Antivirals (DAAs) have revolutionised the treatment of HCV infection, achieving an impressive sustained virlogical response and >95% cure rate. The EASL Recommendations on Treatment of Hepatitis C (2015) recommends that antiviral therapy should be considered for all dialysis patients who will be candidates for kidney transplantation (8). However, not all DAA are safe in the CKD population, making it more difficult to treat one genotype compared to another (Table 1).
Simeprevir, daclatasvir, and the combination of ritonavir boosted paritaprevir, ombitasvir and dasabuvir are cleared by hepatic metabolism and therefore can be used safely in patients with severe renal disease (8). This FDA has recently approved grazoprevir and elbasvir for HCV genotypes 1 and 4 (10). This combination does not require renal dose adjustment and has led to 99% sustained virlogical response in genotype 1 infected patients with CKD stage 4–5 (2).
Sofosbuvir is a first-in-class nucleotidic inhibitor that is the backbone of most antiviral combinations (Table 1). The use of Sofosbuvir in patients with eGFR <30 ml/min/1.73m2 is controversial, and therefore should be used with extreme caution. The EASL guidelines (2015) recommend that Sofosbuvir should not be administered to patients with an <30 ml/min/1.73m2 or with ESKD until more data is available (8). The American Association for the Study of Liver Diseases and Infectious Diseases Society of America HCV guidelines state that Sofosbuvir containing regimens can be considered for patients with creatinine clearance <30 mL/min under expert care, as efficacy and safety data are not yet available (13). These patients had higher rates of anaemia, worsening glomerular filtration rate and serious adverse events (11). Therefore, treatment of genotype 2, 3, 5 and 6 in the CKD population remains challenging.
Eradication of HCV prior to kidney transplant may avoid liver-related mortality and HCV related graft dysfunction in the post-transplant period. When possible, antiviral therapy should be given before enlisting for renal transplantation (8). However, one can only safely treat genome type 1 and 4. Some argue that this option would not necessarily benefit all patients as it removes the option of receiving a renal graft from an HCV infected donor (6). Patients infected by other HCV genomes may proceed to kidney transplant and subsequently have their HCV cured, having better kidney function and therefore more DAA options (8).
Transplantation of kidneys from HCV infected patients should be reserved ONLY for recipients with positive HCV PCR unless in emergency situations (1).
Kidney Disease: Improving Global Outcomes. KDIGO clinical practice guidelines for the prevention, diagnosis, evaluation, and treatment of hepatitis C in chronic kidney disease. Kidney Int Suppl 2008; 109: S1–S99 Stanislas Pol, Michel Jadoul, Anaïs Vallet-Pichard; An update on the management of hepatitis C virus-infected patients with stage 4–5 chronic kidney disease while awaiting the revised KDIGO Guidelines. Nephrol Dial Transplant 2017; 32 (1): 32-35. doi: 10.1093/ndt/gfw023 Castera L. Noninvasive methods to assess liver disease in patients with hepatitis B or C. Gastroenterology 2012; 142: 1293‐1302. Jiang Y, Huang E, Mehrnia A, et al. Can aminotransferase‐to‐platelet ratio index and other non‐invasive markers effectively reduce liver biopsies for renal transplant evaluation of hepatitis C virus‐positive patients? Nephrol Dial Transplant 2014; 29: 1247‐1252. Liu CH, Liang CC, Huang KW, et al. Transient elastography to assess hepatic fibrosis in hemodialysis chronic hepatitis C patients. Clin J Am Soc Nephrol 2011; Proposed Scope of Work for the Update to KDIGO Clinical Practice Guideline for the Prevention, Diagnosis, Evaluation, and Treatment of Hepatitis C in Chronic Kidney Disease http://www.kdigo.org/clinical_practice_guidelines/Hep%20C%20Update/KDIGO%20Hep%20C%20GL%20Update%20Public%20Review%20Oct%2012.pdf Belga S, Doucette KE. Hepatitis C in non-hepatic solid organ transplant candidates and recipients: A new horizon. World J Gastroenterol. 2016 Jan 28;22(4):1650-63. doi: 10.3748/wjg.v22.i4.1650. European Association for Study of Liver. EASL Recommendations on Treatment of Hepatitis C 2015. J Hepatol. 2015 Jul;63(1):199-236. doi: 10.1016/j.jhep.2015.03.025. Epub 2015 Apr 21. Van Wagner LB, Baker T, Ahya SN, Norvell JP, Wang E, Levitsky J. Outcomes of patients with hepatitis C undergoing simultaneous liver-kidney transplantation. J Hepatol 2009;51:874–880. Zepatier™, (Elbasvir and Grazoprevir) Tablets for Oral Use, Merck & Co, Whitehouse Station, NJ, USA, 2016. [Ref list] Saxena V, Koraishy FM, Sise et al. Safety and efficacy of sofosbuvir-containing regimens in hepatitis C-infected patients with impaired renal function. Liver Int. 2016 Jun;36(6):807-16. doi: 10.1111/liv.13102. Epub 2016 Mar 24. Maruyama A, Partovi N, Yoshida EM, Erb SR, Azalgara VM, Hussaini T. A review of direct-acting antivirals for the treatment of hepatitis C in patients with advancedchronic kidney disease. Nephrol Dial Transplant. 2015 Oct 19. pii: gfv361. [Epub ahead of print] American Association for the Study of Liver Diseases and the Infectious Diseases Society of America. HCV guidance: recommendations for testing, managing, and treating hepatitis C. Unique patient populations: patients with renal impairment, 2015. http://www.hcvguidelines.org/full-report/unique-patient-populations-patients-renal-impairment Bunchorntavakul C, Maneerattanaporn M, Chavalitdhamrong D. Management of patients with hepatitis C infection and renal disease. World J Hepatol. 2015 Feb 27;7(2):213-25. doi: 10.4254/wjh.v7.i2.213.
12. Human Immunodeficiency Virus (HIV)
HIV infection on its own is not a contraindication for transplantation (1–4). Indeed, today HIV positive individuals are also considered as potential cadaveric donors to HIV positive recipients (living kidney donation when HIV positive is contraindicated). In one study, the survival among HIV positive recipients of HIV positive donors was was 84% at 1 year, 84% at 3 years, and 74% at 5 years. The corresponding rates of graft survival were 93%, 84%, and 84% (5).
The UK guidelines for kidney transplantation in patients with HIV, published in 2015 (1) give us the most up-to-date and comprehensive guide to kidney transplantation in HIV positive ESKD patients.
All potential donors should be screened for HIV infection, ideally using serology and RNA levels. All potential KTRs should be screened for HIV infection (1–4) An HIV positive patient should be active on the transplant list only if:
Fully adherent to HAART CD4+ T-cell counts are >100 cells/μL (ideally >200 cells/μL) and have been stable for the past 3 months HIV RNA has been undetectable during the past 6 months No opportunistic infections occurred in past 6 months No history of PML, intestinal cryptosporidium or lymphoproliferative disorder.
Full serological testing and pre-transplant vaccines should be performed as per other kidney transplant candidates (1). VZV vaccine can be given in HIV-infected individuals provided the CD4+ T-cell counts are >200 cells/μL. Additionally, patients should undergo HLA-B5701 status and HIV resistance profile.
Discussion with the ID specialists is strongly advised.
Basiliximab is generally preferred to depleting agents for induction. Maintenance immunosuppression should be the same as in non-HIV recipients (i.e. triple therapy including CNI, anti-proliferative agent and steroids) A 4 week trial of CNI is strongly recommended pre- transplant in order to find the optimal dose to be used.
Potentially nephrotoxic anti-retrovirals (e.g. tenofovir formulation) should ideally be avoided from the outset. HAART therapy, once established, should continue after transplantation.
In patients with Ritonavir-boosted PI (e.g. Kaletra®) there is a significant increase in Tacrolimus exposure. Drastic dose reductions (e.g. 0.5 mg once every 5–14 days) and close monitoring is usually required. Considering such complicated dosing regimens, and the risk of non-compliance, one can opt for Cyclosporin in this setting. The anticipated dose is between 20–50mg/day.
NNRTIs (e.g. Efavirenz, Nevirapine) cause a slightly decreased CNI dose exposure, requiring a slight dose increase. No effect anticipated with NRTIs.
Protocol biopsies should be considered at 1 month, 3 months and 12 months (high immunological risk). In one study, the 1 and 3‐year cumulative incidences of graft rejection were 31% and 41% respectively (8).
Acute rejection (AR) should be treated in the same way as HIV negative recipients. The choice of immunosuppressive agent should be taken on a case by case basis. It is generally considered safe to give pulsed steroids. There is increasing evidence that ATG can be safely used in the setting of steroid resistant AR (6).
Post-transplant prophylaxis and monitoring is generally the same as in HIV negative recipients. Lifelong co-trimoxazole prophylaxis, at 960 mg/day if tolerated (7). HIV viral load and CD4 counts should be measured within one month and subsequently every 2–3 months for the first year. Thereafter every 3–6 months thereafter (1). If patients require depleting agents, the HIV load should be monitored more closely.
Lifelong Co-trimoxazole prophylaxis should provide protection against PCP and Troxoplasmosis (especially in patients with Toxoplasma IgG positive). Dapsone 50 mg once daily plus pyrimethamine 50 mg once weekly is an alternative in recipients who are intolerant to co-trimoxazole.
If CD4 cells fall to ≤50 cells/μL, one should provide prophylaxis against Mycobacterium avium complex. This can be stopped when the CD4 count is >100 cells/µL for 6 months (1).
HIV positive recipients are at increased risk of virus‐mediated cancers such as Kaposi’s sarcoma, non‐Hodgkin’s lymphoma, HPV‐associated cervical and anal cancers, liver malignancy and therefore require lifelong surveillance.
In HIV positive donors, the HIV viral load should be <50 copies/mL and CD4 count >200/µL for at least 6 months prior to brain injury and there is no history of treatment failure or drug resistance.
Kidney & Pancreas Transplantation in Patients with HIV. Second Edition. 2015.
http://bts.org.uk/wp-content/uploads/2016/09/05_BTS_Kidney_HIV.pdf Baker R, Jardine A, Andrews P. Renal Association Clinical Practice Guideline on post-operative care of the kidney transplant recipient. Nephron Clin Pract. 2011;118 Suppl 1:c311-47. doi: 10.1159/000328074. Epub 2011 May 6. Kidney Disease: Improving Global Outcomes (KDIGO) Transplant Work Group. KDIGO clinical practice guideline for the care of kidney transplant recipients. Am J Transplant. 2009 Nov;9 Suppl 3:S1-155. doi: 10.1111/j.1600-6143.2009.02834.x. Heemann U, Abramowicz D, Spasovski G, Vanholder R. European Renal Best Practice Work Group on Kidney Transplantation. Endorsement of the Kidney Disease Improving Global Outcomes (KDIGO) guidelines on kidney transplantation: a European Renal Best Practice (ERBP) position statement. Nephrol Dial Transplant. 2011 Jul;26(7):2099-106. Muller E, Barday Z, Mendelson M, Kahn D. HIV positive to HIV-positive kidney transplantation results at 3 to 5 years. N Engl J Med. 2015 Feb 12;372(7):613-20. doi: 10.1056/NEJMoa1408896. Locke JE, James NT, Mannon RB, et al. Immunosuppression regimen and the risk of acute rejection in HIV-infected kidney transplant recipients. Transplantation 2014; 97: 446-50. Schwartz BS, Mawhorter SD and the AST Infectious Diseases Community of Practice. Parasitic infections in solid organ transplantation. Am J Transplant 2013; 13 Suppl 4: 280-303. Stock PG, Barin B, Murphy B et al. Outcomes of kidney transplantation in HIV-infected recipients. N Engl J Med. 2010 Nov 18;363(21):2004-14. doi: 10.1056/NEJMoa1001197.
13. Human T-cell lymphotropic virus type 1 (HTLV-1)
HTLV-1 is a retrovirus which causes T-cell leukaemia/lymphoma and HTLV-1 associated myelopathy (HAM) leading to severe spastic paraparesis (1,2). There is usually a latency period of 2 to 3 decades before the onset of symptoms (5).
Highly endemic areas include Japan, Caribbean, South America, tropical and South Africa, Iran, Romania, and Melanesia (5). Despite the apparent low incidence in Europe, a number of post-transplant HTLV-1 associated primary T-cell lymphoma and HAM cases were reported in France, Spain, Germany and UK (6–9).
International transplantation guidelines provide no recommendation on HTLV-1 screening at present and many centres do not routinely screen for HTLV-1 virus prior to transplantation.
In Japan, screening is more common, with one transplant centre suggesting using kidneys from HTLV-I carriers for HTLV-I-positive recipients (3). Some suggest a more universal screening approach and urge international bodies to issue recommendations (5).
Screening should be considered in recipients and donors who travelled or resided in highly endemic areas.
Kidney Disease: Improving Global Outcomes (KDIGO) Transplant Work Group. KDIGO clinical practice guideline for the care of kidney transplant recipients. Am J Transplant. 2009 Nov;9 Suppl 3:S1-155. doi: 10.1111/j.1600-6143.2009.02834.x. Naghibi O, Nazemian F, Naghibi M, Ali Javidi DB. Prognosis of HTLV-1 positive renal transplant recipients in Iran. Saudi J Kidney Dis Transpl. 2011 Jul;22(4):670-4. Nakamura N1, Tamaru S, Ohshima K, Tanaka M, Arakaki Y, Miyauchi T. Prognosis of HTLV-I-positive renal transplant recipients. Transplant Proc. 2005 May;37(4):1779-82. Ramanan P, Deziel PJ, Norby SM, Yao JD, Garza I, Razonable RR. Donor-derived HTLV-1 associated myelopathy after transplantation: a call for targeted screening. Am J Transplant. 2015 Apr;15(4):1125. doi: 10.1111/ajt.13146. Epub 2015 Mar 13. Gallo RC, Willems L, Hasegawa H; Global Virus Network’s Task Force on HTLV-1. Screening transplant donors for HTLV-1 and −2. Blood. 2016 Dec 29;128(26):3029-3031. doi: 10.1182/blood-2016-09-739433. Epub 2016 Nov 9. Ramanan P, Deziel PJ, Norby SM, Yao JD, Garza I, Razonable RR. Donor-transmitted HTLV-1- associated myelopathy in a kidney transplant recipient–case report and literature review. Am J Transplant. 2014;14(10):2417-2421. Younger DS. HTLV-1-associated myelopathy/tropical spastic paraparesis and peripheral neuropathy following live-donor renal transplantation. Muscle Nerve. 2015;51(3):455-456. Glowacka I, Korn K, Potthoff SA, et al. Delayed seroconversion and rapid onset of lymphoproliferative disease after transmission of human T-cell lymphotropic virus type 1 from a multiorgan donor. Clin Infect Dis. 2013;57(10):1417-1424. Armstrong MJ, Corbett C, Rowe IA, Taylor GP, Neuberger JM. HTLV-1 in solid-organ transplantation: current challenges and future management strategies. Transplantation. 2012; 94(11):1075-1084.
It is important to establish the patient’s immunisation history, prior infection exposures, travel history and current patient serology in order to tailor an appropriate vaccination regimen.
All KTRs should receive inactivated vaccines as per normal population (Table 1) except for HBV (see HBV section) and HIV (see HIV section). All KTRs should receive the seasonal inactivated influenza vaccine unless experienced a severe allergy to a prior dose of seasonal influenza vaccine or to a component of the vaccine (1,3) KTRs should receive the pneumococcal vaccine (Pneumovax23) every 5 years (1,2) Live attenuated vaccines (Table 1) should be avoided post-transplantation. It is recommended to allow at least 4 weeks from the time of vaccination with a live attenuated vaccine and transplantation (1,2) Close household contacts should also be vaccined where appropriate (e.g. Varicella for children of VZV seronegative KTRs (1).
Baker R, Jardine A, Andrews P. Renal Association Clinical Practice Guideline on post-operative care of the kidney transplant recipient. Nephron Clin Pract. 2011;118 Suppl 1:c311-47. doi: 10.1159/000328074. Epub 2011 May 6. Kidney Disease: Improving Global Outcomes (KDIGO) Transplant Work Group. KDIGO clinical practice guideline for the care of kidney transplant recipients. Am J Transplant. 2009 Nov;9 Suppl 3:S1-155. doi: 10.1111/j.1600-6143.2009.02834.x. Centers for Disease Control and Prevention. https://www.cdc.gov/flu/professionals/vaccination/vaccine_safety.htm Kotton CN, Hibberd PL. Travel medicine and the solid organ transplant recipient. Am J Transplant 2009;9 Suppl 4:S273-81.
15. Parasitic infections
Screening should be considered in recipients and donors who travelled or resided in highly endemic areas.
A. Toxoplasma Gondaii
Toxoplasma Gondaii infection is rather common, involving about a third of the world population and 22.5% of USA population (1). Mode of transmission is mainly through contaminated food and water sources, but also vertical transmission and organ transplantation (1). In solid organ transplantation, the highest incidence occurs after heart transplantation, followed by liver and kidney (3). Transmission from seropositive donors to seronegative recipients usually occurs in the first 3 months, whilst reactivation of latent infection or de-novo infection usually occurs after the initial 3 to 6 months (2).
Infection is typically asymptomatic in immunocompetent patients, but can present with non-specific symptoms such as fever, cervical lymphadenopathy and myalgia (2). In contrast, toxoplasma infection can lead to significant complications in pregnant and immunocompromised hosts, carrying high mortality rates with disseminated disease.
Clinical manifestations may include; encephalitis, myocarditis, pneumonitis, hepatosplenomegaly, chorioretinitis, pancytopenia, or disseminated diseases (4,6). Encephalitis can present with changes in cognitive function, seizures and/or focal motor, sensory and cerebellar signs (1).
Recipient and donor Toxoplasma serology may be useful to evaluate risk. This practice is recommended only in the British Guidelines for kidney and pancreas transplantation in patients with HIV infection (5), but not in international guidelines involving non-HIV infected population.
Universal prophylaxis against PJP provides in the first 3–6 months, provides sufficient cover for Toxoplasma Gondaii. In HIV positive recipients, lifelong prophylaxis is recommended (5) (see HIV section).
Diagnosis can be reached via clinical suspicion, serological evidence (although could be negative in immunosuppression), PCR technique and identification of tachyzoides on tissue samples or body smears (1,6). Definitive diagnosis requires one of the latter two techniques (6). Multiple ring enhancing lesions on MR examination of the brain is highly suggestive of toxoplasma infection especially in IgG seropositive immunocompromised patients.
Guidance on optimal treatment in solid organ transplantation is generally obtained from studies in HIV positive patients. This involves Pyrimethamine/Sulphadiazine combination plus folinic acid until there is resolution of signs and symptoms, usually for 4–6 weeks (1,7). Pyrimethamine/clindamycin combination can be used in patients intolerant to sulpha drugs.
Montoya JG, Liesenfeld O. Toxoplasmosis. Lancet. 2004 Jun 12;363(9425):1965-76. Khurana S, Batra N. Toxoplasmosis in organ transplant recipients: Evaluation, implication, and prevention. Trop Parasitol. 2016 Jul-Dec;6(2):123-128. Schaffner A. Pretransplant evaluation for infections in donors and recipients of solid organs. Clin Infect Dis. 2001;33(Suppl 1):S9–14 Muñoz P, Valerio M, Eworo A, Bouza E. Parasitic infections in solid-organ transplant recipients. Curr Opin Organ Transplant. 2011 Dec;16(6):565-75. Kidney & Pancreas Transplantation in Patients with HIV. Second Edition. 2015. http://bts.org.uk/wp-content/uploads/2016/09/05_BTS_Kidney_HIV.pdf Schwartz BS, Mawhorter SD and the AST Infectious Diseases Community of Practice. Parasitic infections in solid organ transplantation. Am J Transplant 2013; 13 Suppl 4: 280-303.
B. Trypansonoma cruzi
Chagas’disease, or American trypanosomiasis, is considered endemic in 21 Latin American countries (5). Worldwide estimates suggest that 8–10 million people are infected (2), whilst in Europe the estimates point to approximately 68,000 and 122,000 cases, with Spain being the country most affected (3).
It is caused by the protozoan parasite Trypanosoma cruzi and most infections are transmitted by the endemic triatomine insects. In urban areas the parasite can be also acquired via blood transfusion, organ transplantation and congenital transmission (1). Sporadic cases in European and Japanese travelers to endemic areas have been identified, possibly acquiring the disease via the oral route (5).
The acute phase is characterised by parasitaemia, frequently presenting with fever, headache, lymphadenopathy, dyspnoea, abdominal pain and chest pain. Eventually, signs and symptoms may fade away spontaneously, developing into the chronic phase which is initially asymptomatic and can last for many years (6). This silent phase is very easily missed as many European health professionals have little experience with the detection and management of Chagas disease (5). Eventually it can progress to cardiac, digestive, skin (Chagas panniculitis) and neurologic involvement.
High rates of morbidity and mortality are witnessed in immunosuppressed patients due to the severe clinical manifestations. Consider screening in recipients and donors who travelled or resided in highly endemic areas.
Nifurtimox 8–10 mg/kg/day divided in four doses for 120 days or benznidazole 5–7 mg/kg/day divided in two doses for 30–90 days 30–60 days achieves parasitic cure in most acute cases (7).
Carvalho MF, de Franco MF, Soares VA. Amastigotes forms of Trypanosoma cruzi detected in a renal allograft.Rev Inst Med Trop Sao Paulo. 1997 Jul-Aug;39(4):223-6. L. Basile, J.M. Jansa, Y. Carlier, D.D. Salamanca, A. Angheben, A. Bartoloni, et al. Chagas disease in European countries: the challenge of a surveillance system. Euro Surveill, 16 (2011) pii 19968 J. Gascon, C. Bern, M.J. Pinazo. Chagas disease in Spain, the United States and other non-endemic countries. Acta Trop, 115 (2010), pp. 22–27 Basile L, Jansà JM, Carlier Y et al. Working Group on Chagas Disease. Chagas disease in European countries: the challenge of a surveillance system. Euro Surveill. 2011;16(37):pii=19968. Rassi A Jr, Rassi A, Marin-Neto JA. Chagas disease. Lancet. 2010;375(9723):1388-402. Kotton CN, Lattes R; AST Infectious Diseases Community of Practice. Parasitic infections in solid organ transplant recipients. Am J Transplant. 2009 Dec;9 Suppl 4:S234-51.
C. Strongyloides stercoralis
Strongyloides stercoralis is nemathelminth infection which is able to persist in the human intestine for decades after the original infection and is usually asymptomatic in half of the patients (3). Strongyloides stercoralis is most prevalent in tropical and subtropical area including Latin America, South East USA, parts of Africa and India.
When immunosuppression is instituted, the larvae replication cycle becomes unchecked, leading to invasion of the duodenal wall, migration into the venous system and ultimately the lungs. This can cause a fulminant infection similar to an ARDS-like picture known as Hyperinfection syndrome, which frequently leads to respiratory failure and death (3). It has been reported in a number of renal transplant recipients (3). Migration of these larvae, cause simultaneous translocation of other pathogenic bacteria, causing concomitant bacterial septicaemia (3).
A comprehensive residency and travel history should be conducted before transplantation even if it is in the remote past. The Infectious Diseases Society of America, American Society of Transplantation, Centers for Disease Control and Prevention, and the American Society of Blood and Marrow Transplantation recommend Strongyloides stercoralis ELISA IgG serology testing for patients from endemic areas, gastrointestinal symptoms or eosinophilia before transplantation (1–3).
First line therapy is Ivermectin 200 μg/kg/day for 2 days. Albendazole 400 mg twice daily for two days can be used as a second line agent. Longer therapies are required in both treatment strategies in hyperinfection (4).
Centers for Disease Control and Prevention, Infectious Disease Society of America, American Society of Blood and Marrow Transplantation.Guidelines for preventing opportunistic infections among hematopoietic stem cell transplant recipients. MMWR Recomm Rep. 2000 Oct; 49(RR-10):1-125, CE1-7. Review Screening of donor and recipient prior to solid organ transplantation. Am J Transplant. 2004 Nov; 4 Suppl 10():10-20 Roxby AC, Gottlieb GS, Limaye AP. Strongyloidiasis in transplant patients. Clin Infect Dis. 2009 Nov 1;49(9):1411-23. doi: 10.1086/630201. Kotton CN, Lattes R; AST Infectious Diseases Community of Practice. Parasitic infections in solid organ transplant recipients. Am J Transplant. 2009 Dec;9 Suppl 4:S234-51.
Leishmaniasis is not endemic Egypt (3). Infection may be asymptomatic or may manifest as cutaneous, mucocutaneous or the visceral form (2).
A systematic review by Antinori and colleagues (2008) reports a total of 79 cases of Leishmaniasis in solid organ transplant recipients, two-thirds of which coming from the Mediterranean basin (1). Among these, 77% were described in kidney transplant recipients (1).
Leishmaniasis post-transplant can be either due to re-activation of a previous infection or de-novo infection either after being bitten by an infected sand fly mosquito or after receiving an infected organ or blood products (1).
Visceral Leishmaniasis: Incubation period between 3–8 months. Usual clinical features include fever, weight loss, hepatosplenomegaly (usually spleen much larger than liver), lymhadenopathy, pancytopenia and hypergammaglobulinaemia (4,5). In the post-transplant period, pancytopenia is often attributed to drug induced marrow suppression, frequently leading to anti-metabolite cessation (1). One has to keep a high index of suspicion, considering the endemicity of Leishmaniasis in the Mediterranean.
Cutaneous Leishmaniasis: Incubation period 2 weeks to several months. Papule at the site of a sandfly bite increases in size, crusts, and ulcerates (5).
Mucocutaneous Leishmaniasis: Incubation period 1–3 months. Present with long-lasting ulcers involving skin, oral mucosa, tongue, lips, gums and/or palate. Frequently the patient has swallowing difficulties (5).
Detection of amastigotes in bone marrow aspirates using microscopy is the most commonly used diagnostic procedure. Leishmania serology and PCR are also useful in the diagnosis of Leishmaniasis.
Treatment of visceral and mucocutaneous Leishmaniasis involves Pentavalent antimony (as stibogluconate or meglumine antimonite) or Liposomal Amphotericin B or Miltefosine (5). Pentavalent antimony (as stibogluconate or meglumine antimonite), Fluconazole, Ketoconazole, Miltefosine, Pentamidine and topical Paromomycin have all been used to treat cutaneous Leishmaniasis (5). One has to keep in mind that data on their use in transplant recipients is very sparse.
Suggested further reading:
Piscopo TV, Mallia Azzopardi C. Leishmaniasis. Postgrad Med J. 2007 Feb;83(976):649-57.
Antinori S, Cascio A, Parravicini C, Bianchi R, Corbellino M. Leishmaniasis among organ transplant recipients. Lancet Infect Dis. 2008 Mar;8(3):191-9. doi: 10.1016/S1473-3099(08)70043-4. Pace D. Leishmaniasis. J Infect. 2014 Nov;69 Suppl 1:S10-8. doi: 10.1016/j.jinf.2014.07.016. Epub 2014 Sep 17. Epidemiology of Leishmaniasis accessed from:
http://www.who.int/leishmaniasis/burden/en/ Zijlstra EE, el-Hassan AM. Leishmaniasis in Sudan. Visceral leishmaniasis. Trans R Soc Trop Med Hyg. 2001 Apr; 95 Suppl 1():S27-58. Piscopo TV, Mallia Azzopardi C. Leishmaniasis. Postgrad Med J. 2007 Feb;83(976):649-57.
Giardia Lamblia is one of the most common parasitic infections in the post-transplant period (1,6). It has been reported in renal, pancreas, intestine and bone marrow transplantation (1,2). Oral‐faecal is the main mode of transmission, but also via transplantation form infected donors such as in pancreatic transplant (4).
It frequently presents with chronic unremitting diarrhoea in the post-transplant period (3). Post-transplant diarrhoea is frequently attributed to mycophenolate mofetil and therefore a high index of suspicion is required especially in endemic areas.
Diagnosis is achieved with direct microscopy of stool samples and microscopy of endoscopic biopsy samples. Villous atrophy is frequently identified on microscopic examination.
First line therapy includes Tinidazole and Nitazoxanide. Metronidazole is also highly effective against Giardia Lamblia (5).
Nankivell BJ, Kuypers DR. Diagnosis and prevention of chronic kidney allograft loss.Lancet 2011;378:1428–37 Ajumobi AB, Daniels JA, Sostre CF, Trevino HH. Giardiasis in a hematopoietic stem cell transplant patient. Transpl Infect Dis. 2014 Dec;16(6):984-7. Weclawiak H, Ould-Mohamed A, Bournet B et al. Duodenal villous atrophy: a cause of chronic diarrhea after solid-organ transplantation. Am J Transplant. 2011 Mar;11(3):575-82. doi: 10.1111/j.1600-6143.2010.03423.x. Epub 2011 Feb 7. Kristensen AA, Horneland R, Birn H, Svensson M. Giardia lamblia infection after pancreas-kidney transplantation. BMJ Case Rep. 2016 Jan 18;2016. pii: bcr2015211515. doi: 10.1136/bcr-2015-211515. Schwartz BS, Mawhorter SD and the AST Infectious Diseases Community of Practice. Parasitic infections in solid organ transplantation. Am J Transplant 2013; 13 Suppl 4: 280-303. Kotton CN, Lattes R; AST Infectious Diseases Community of Practice. Parasitic infections in solid organ transplant recipients. Am J Transplant. 2009 Dec;9 Suppl 4:S234-51.
Together with Giardia Lamblia, Cryptosporidium is one of the most common parasitic infections presenting with chronic diarrhoea in the post-transplant period (1,7). Whilst it is usually a self-limiting infection lasting only a few days in immunocompetent individuals, infection in solid organ transplant recipients is more protracted and can also be life-threatening (2).
Presentation is typically with chronic, profuse, watery diarrhoea and malabsorption syndromes. Other non-specific symptoms include fever, nausea, vomiting and crampy abdominal pain (2).
Transmission is mostly via the faecal-oral route, but has also been reported to be transmitted sexually and via respiratory secretions (2).
Cryptosporidium infection in solid organ transplant recipients has been reported in kidney (3), liver (4), heart (5) and intestines (6), although most commonly seen with kidney transplantation. It has been associated with a variety of immunosuppressive agents including both cyclosporine and tacrolimus (2).
Stool microscopy for ova, cysts and parasites remains the primary and most economical diagnostic methodology, whilst PCR provide the highest diagnostic sensitivity (2). Microscopy of endoscopic biopsies is also a useful when stool examination is negative.
Treatment requires fluid resuscitation, reduction in immunosuppression and anti-parasitic agents such as nitazoxamide, paromomycin, azithromycin or combination of these (2,7,8).
Nankivell BJ, Kuypers DR. Diagnosis and prevention of chronic kidney allograft loss. Lancet 2011;378:1428–37 Florescu DF, Sandkovsky U. Cryptosporidium infection in solid organ transplantation. World J Transplant. 2016 Sep 24;6(3):460-71. doi: 10.5500/wjt.v6.i3.460. Bhadauria D, Goel A, Kaul A et al. Cryptosporidium infection after renal transplantation in an endemic area. Transpl Infect Dis 2015;17: 48-55 [PMID: 25620388 DOI: 10.1111/tid.12336] Vajro P, di Martino L, Scotti S et al. Intestinal Cryptosporidium carriage in two livertransplanted children. J Pediatr Gastroenterol Nutr 1991; 12: 139 Krause I, Amir J, Cleper R et al. Cryptosporidiosis in children following solid organ transplantation. Pediatr Infect Dis J 2012; 31: 1135-1138 Delis SG, Tector J, Kato T et al. Diagnosis and treatment of cryptosporidium infection in intestinal transplant recipients. Transplant Proc 2002; 34: 951-952 Schwartz BS, Mawhorter SD and the AST Infectious Diseases Community of Practice. Parasitic infections in solid organ transplantation. Am J Transplant 2013; 13 Suppl 4: 280-303. Kotton CN, Lattes R; AST Infectious Diseases Community of Practice. Parasitic infections in solid organ transplant recipients. Am J Transplant. 2009 Dec;9 Suppl 4:S234-51.
It is a helmintheic disease caused by the metacystode stage of Echinococcus granulosus or Echinococcus multilocularis. Human and other mammals (sheep and cattle) are intermediate host, whilst canines are definitive host. Main mode of transmission is by ingesting viable eggs of the tapeworm from definitive host such as fox and dogs.
Echinococcus multilocularis infection is considered to more serious compared to Echinococcus granulosus. The former causes Alveolar Echinococcosis whilst the latter causes Cystic Echinococcosis. Infection can remain silent for many years and sometimes remains undiagnosed or identified incidentally after abdominal imaging. The clinical course is reminiscent of neoplastic disease, frequently presenting with slow-growing hepatic lesions and metastatic spread which can be potentially fatal (1). Indeed, the WHO classification of disease extension resembles tumour classification and termed P (parasite in the liver) N (Neighboring organs) M (Metastasis). Early diagnosis is of chief importance as disease can eventually become unresectable. Echinococcal disease is frequently complicated by infections, biliary obstruction and liver cirrhosis (1).
There are only few reported cases of Echinococcosis is the setting of solid organ transplantation. Alveolar Echinococcosis treated with liver transplantation has high rate of recurrence and extrahepatic spread. In one collaborative report, the five-year survival without recurrence was 58% (2). Most cases in kidney transplantation are Cystic Echinococcosis and one case of Alveolar Echinococcosis (3). It is thought that intensified immunosuppression can lead to enhanced parasitosis compared to immunocompetent patients.
Microscopic examination of liver biopsy material is considered as gold standard for diagnosis (1). However this can be associated with a high risk of infection spread. Serum Echinococcal antibody sensitivity varies between 60–95% and may be negative in immunosuppressed patients (3,4). Imaging studies are also useful in the diagnostic process, although it might be difficult to differentiate the lesions from a malignant process.
Treatment requires a prolonged albendazole therapy (sometimes combined with praziquantel in case of intra-operative spillage) and surgical resection ideally before transplantation (4).
Kotton CN, Lattes R; AST Infectious Diseases Community of Practice Am J Transplant. Parasitic infections in solid organ transplant recipients. 2009 Dec;9 Suppl 4:S234-51. Koch S, Bresson-Hadni S, Miguet JP et al; European Collaborating Clinicians. Experience of liver transplantation for incurable alveolar echinococcosis: a 45-case European collaborative report. Transplantation. 2003 Mar 27;75(6):856-63. Geyer M, Wilpert J, Wiech T et al. Rapidly progressive hepatic alveolar echinococcosis in an ABO-incompatible renal transplant recipient. Transpl Infect Dis. 2011 Jun;13(3):278-84. doi: 10.1111/j.1399-3062.2010.00583.x. Epub 2010 Oct 26. Schwartz BS, Mawhorter SD and the AST Infectious Diseases Community of Practice. Parasitic infections in solid organ transplantation. Am J Transplant 2013; 13 Suppl 4: 280-303.
16. Emerging viral diseases
Screening should be considered in recipients and donors who travelled or resided in highly endemic areas.
A. West Nile virus (WNV)
WNV is continuously spreading across the European countries and other continents. European centre for disease prevention has identified WNV in the EU Member States including a number of cases in the Mediterranean countries such as Greece (262 cases of severe neuro-invasive disease in 2010), Corsica, Algeria, Italy and Sicily (1,2). One of the possible WNV vectors is the Aedes albopictus (known as the Asian tiger mosquito) which is now also endemic in the Maltese islands.
WNV infections are most commonly asymptomatic and only about 20–40% develop clinical symptoms including; fever, headache, lymphadenopathy, myalgia, fatigue, skin rash, diarrhea, and vomiting (West Nile fever).
Severe neuro-invasive West Nile disease occurs only in <1% of the infected patients and can present with 3 different syndromes: meningitis, encephalitis, and acute flaccid paralysis
WNV has now spread globally to Europe beyond the Mediterranean Basin and United States. Indeed, it is now considered to be an endemic pathogen worldwide especially in Africa. More than 110 mosquito species and subspecies and more than 32 genera of ticks have been identified. Birds especially passerines are the most commonly infected animals and serve as the prime reservoir host in Egypt. Besides, not less than 150 species of migratory birds visit Egypt annually in addition to 350 resident ones (3).
There are cases of WNV transmission via blood transfusions and organ transplantation. The incubation period is between 2-14 days after one is bitten by an infected mosquito, but it is advised not to donate blood in the subsequent 120 days (4). Some centres perform donor WNV serology prior to transplantation; however this practice is unlikely to impact on any donation decisions considering the considerable length of time for the results to be issued. The treatment of WNV neuro-invasive disease is primarily supportive with some reports suggesting that Ribavirin and Interferon may be effective (5,6).
WNV RNA PCR of both blood and CSF (EDTA bottle) and WNV serology are both available via Bioscientia.
European centre for disease prevention.
http://ecdc.europa.eu/en/healthtopics/west_nile_fever/West-Nile-fever maps/pages/index.aspx#sthash.oTVw5ZYp.dpuf Rizzoli A, Jiménez-Clavero MA, Barzon L, Cordioli P, Figuerola J, Koraka P et al. The challenge of West Nile virus in Europe: knowledge gaps and research priorities. Euro Surveill. 2015;20(20):pii=21135. Article DOI:http://dx.doi.org/10.2807/1560-7917.ES2015.20.20.21135 El-Bahnasawy MM, Khater MK, Morsy TA. The mosquito borne West Nile virus infection: is it threating to Egypt or a neglected endemic disease? J Egypt Soc Parasitol. 2013 Apr;43(1):87-102 Centers for Disease Control and Prevention.
https://www.cdc.gov/westnile/faq/blood.html Sayao AL, Suchowersky O, Al-Khathaami A et al. Calgary experience with West Nile virus neurological syndrome during the late summer of 2003. Can J Neurol Sci. 2004;31(2):194. Jordan I, Briese T, Fischer N, Lau JY, Lipkin WI. Ribavirin inhibits West Nile virus replication and cytopathic effect in neural cells. J Infect Dis. 2000 Oct;182(4):1214-7. Epub 2000 Aug 22.
Rabies is acute fatal encephalitis caused by bites of rabid mammals (1).
There are case reports of corneal, kidney and liver transplant transmission (2,3). Incubation period ranges from several weeks to months (2).
Rabies is present on all continents except Antarctica. The majority of human infections occur in Asia and Africa (4). Egypt is one of the high risk countries for rabies (5). Therefore one has to consider this in potential donors who have travelled to high risk areas and who died from presumed viral encephalitis.
KTRs that travel to endemic areas and get bitten or scratched by a mammal should follow standard procedures as per normal population.
Center for Disease Control and Prevention. https://www.cdc.gov/mmwr/preview/mmwrhtml/mm5326a6.htm Zhou H, Zhu W, Zeng J et al. Probable Rabies Virus transmission through Organ Transplantation, China 2015. Emerg Infect Dis. 2016 Aug;22(8):1348-52. doi: 10.3201/eid2208.151993. Epub 2016 Aug 15. International Association of Medical Assistance to Travellers (IAMAT). Accessed from: https://www.iamat.org/country/egypt/risk/rabies Rabies Risks terrestrial animals by Country; Updated 3 December 2015. Accessed from: https://www.gov.uk/government/publications/rabies-risks-by-country/rabies-risks-in-terrestrial-animals-by-country