Nephrology Hypertension

Kidney Transplantation: Prevention and Management of Transplant Associated Complications - Cytomegalovirus

Does this patient have cytomegalovirus?

Cytomegalovirus (CMV) after Kidney Transplantation

CMV is a human herpes virus (DNA virus).

Approximately 2/3 of adults have been exposed to CMV and are consequently seropositive.

CMV can be contracted from the general community, transmitted via solid organ transplantation, or may be a reactivation of latent disease.

Definitions

  • CMV infection: asymptomatic CMV viremia (defined by positive blood PCR)

  • CMV Disease: Viral symptoms and fever

  • Tissue Invasive Disease: pneumonitis, hepatitis, esophagitis, enteritis, colitis, myelosuppression. Occasionally retinitis or graft involvement

  • In the absence of prophylaxis, the CMV disease is seen most commonly 6-12 weeks after transplantation or after augmentation of immunosuppression for rescue therapy of rejection.

What tests to perform?

CMV serology (IgG) is routinely performed in order to stratify risk prior to transplant. It is not useful for diagnostic purposes after transplantation.

CMV PCR is the current gold standard diagnostic test for evaluating viremia.

Common tests

The evaluation starts with common tests:

  • Complete blood count (CBC): look for leucopenia/ pancytopenia or anemia

  • (Liver function tests (LFTs): look for hepatitis

  • ABG: evaluate for hypoxia

  • Creatinine: Evaluation renal allograft function

  • Chest X-ray (CXR): Evaluate presence of pneumonitis

  • Blood/Urine cultures: evaluate for presence of concurrent infections

Specific testing

  • CMV PCR

When clinically indicated, invasive testing should be aggressively pursued to include

  • Endoscopy:

    • Upper if suspecting esophagitis, gastritis or enteritis. Look for concurrent candida, erosions and source of bleeding

    • Colonoscopy if suspecting colitis, evaluate source of bleeding or presence of concurrent infection or malignancy

  • Bronchoscopy and BAL: for evaluation of pneumonitis and presence of concurrent infection such as pneumocystis.

How should patients with or at risk for cytomegalovirus be managed?

Impact of CMV donor/recipient status

Risk stratification by serological status of the kidney donor and recipient defines the need and duration of prophylaxis therapy.

  • Donor+/Recipient- highest rates of CMV infection (60%)

  • D-/R+ and D+/R+ patients have intermediate risk of infection

  • CMV negative recipients (R-) from CMV negative donors (D-) have the lowest rates of CMV infection (<2%)

CMV prevention

The primary focus of CMV management post transplantation is prevention of CMV disease (although not necessarily CMV infection). Two major strategies have been employed

Preemptive treatment

This requires periodic PCR monitoring for CMV and initiation of antiviral therapy once uremia is detected.

  • Associated with similar costs as prophylaxis (PCR is expensive)

  • Requires a robust system to ensure that testing is performed appropriately

  • Associated with higher incidence of viremia

  • May negatively impact graft survival

Prophylaxis

Routine provision of antiviral therapy for patients at risk. This is the preferred option though it puts the patient at risk from the myelosuppressive adverse effects of the antiviral therapy and may increase the risk of viral resistance.

  • Valganciclovir is the treatment of choice.

  • Usual dose is 450mg/d

  • Duration depends on risk stratification by donor and recipient CMV serology

    • D+/- 24 weeks

    • D-/R+: and D+/R+ 12 weeks

    • D-/R-: Anti-CMV prophylaxis currently not recommended (patients are usually given acyclovir for 12 weeks to prevent other herpes virus infections

Management of patients with tissue Invasive CMV

In addition to supportive care, there are several principals of management:

  1. Reduce immunosuppression when possible. This usually involves discontinuing the antimetabolite (MMF/MPA/AZA).

  2. Prompt and aggressive approach to diagnostic testing (see above)

  3. Initiate antiviral therapy

    • IV ganciclovir (usually 5mg/kg bid for normal GFR, dose reduced for lower GFR or

    • Oral valganciclovir 900mg/d

  4. Minimal duration of therapy: 12 weeks

  5. Perform PCR testing while on therapy to exclude presence of resistant disease

  6. Perform PCR testing after discontinuation of therapy to evaluate for relapsed disease

  7. For CMV Ig negative patients, consider adjunctive therapy with CMV hyperimmune globulin every 2 weeks

  8. Resistant disease can be treated with second and third line agents such as foscarnet or cidofovir. Caution with dosing is required as these agents are nephrotoxic

  9. There is limited data on the use of leflunomide for resistant CMV

What happens to patients with cytomegalovirus?

  • For most patients at risk, CMV can be successfully prevented by administering prophylactic antiviral therapy.

  • In the highest risk category (D+/R-), the risk of viremia after discontinuing therapy is as high as 50% even after 24 weeks duration. Such disease tends to be relatively minor and tissue invasive disease is uncommon.

  • For patients with established tissue invasive disease, the risk of complications, morbidity and mortality is high in spite of therapy

CMV Outcomes

  • CMV remains is an important cause of morbidity, mortality and cost post transplant.

  • CMV infection is associated with an increased risk for rejection, interstitial fibrosis and tubular atrophy in allografts leading to premature graft failure

  • Multisystem involvement may ensue: eg. Pulmonary (pneumonitis), Gastrointestinal (Colitis (esophagitis, bleeding/perforation, hepatitis), Heme (Myelosuppression). Neuro (meningo-encephalitis, retinitis).

  • Increased risk of concurrent opportunistic infections

  • May increase the risk of new-onset post-transplant Diabetes Mellitus.

How to utilize team care?

  • Consult pharmacy for GFR appropriate dosing of antiviral therapy.

  • Consider PICC line placement for prolonged IV therapy

  • Consult Infectious Disease for management of intercurrent infections and advise on invasive disease

  • Consult pulmonary critical care if patient is hypoxic and has pulmonary infiltrates on CXR for bronchoscopy and BAL. Such patients can decompensate rapidly and may require intubation and mechanical ventilation

  • Consult GI for endoscopic examination to examine for evidence of enteric disease, bleeding complications and evaluation of intercurrent infections or neoplastic processes.

What is the evidence?

Rubin, RH. "Infectious disease complications of renal transplantation". Kidney Int. vol. 44. 1993. pp. 221-236.

Shelhamer, JH, Gill, VJ, Quinn, TC, Crawford, SW, Kovacs, JA, Masur, H, Ognibene, FP. "The laboratory evaluation of opportunistic pulmonary infections". Ann Intern Med. vol. 124. 1996. pp. 585-599.

Winston, DJ, Wirin, D, Shaked, A, Busuttil, RW. "Randomised comparison of ganciclovir and high-dose acyclovir for long-term cytomegalovirus prophylaxis in liver-transplant recipients". Lancet. vol. 346. 1995. pp. 69-74.

Schnitzler, MA, Lowell, JA, Hmiel, SP, Hardinger, KL, Liapis, H, Ceriotti, CS, Brennan, DC. "Cytomegalovirus disease after prophylaxis with oral ganciclovir in renal transplantation: the importance of HLA-DR matching". J Am Soc Nephrol. vol. 14. 2003. pp. 780-785.

Doyle, AM, Warburton, KM, Goral, S, Blumberg, E, Grossman, RA, Bloom, RD. "24-week oral ganciclovir prophylaxis in kidney recipients is associated with reduced symptomatic cytomegalovirus disease compared to a 12-week course". Transplantation. vol. 81. 2006. pp. 1106-1111.

Humar, A, Lebranchu, Y, Vincenti, F, Blumberg, EA, Punch, JD, Limaye, AP, Abramowicz, D, Jardine, AG, Voulgari, AT, Ives, J, Hauser, IA, Peeters, P. "The efficacy and safety of 200 days valganciclovir cytomegalovirus prophylaxis in high-risk kidney transplant recipients". Am J Transplant. vol. 10. 2010. pp. 1228-1237.

Akalin, E, Bromberg, JS, Sehgal, V, Ames, S, Murphy, B. "Decreased incidence of cytomegalovirus infection in thymoglobulin-treated transplant patients with 6 months of valganciclovir prophylaxis". Am J Transplant. vol. 4. 2004. pp. 148-149.

Strippoli, GF, Hodson, EM, Jones, C, Craig, JC. "Preemptive treatment for cytomegalovirus viremia to prevent cytomegalovirus disease in solid organ transplant recipients". Transplantation. vol. 81. 2006. pp. 139-145.

Reischig, T, Jindra, P, Hes, O, Svecova, M, Klaboch, J, Treska, V. "Valacyclovir prophylaxis versus preemptive valganciclovir therapy to prevent cytomegalovirus disease after renal transplantation". Am J Transplant. vol. 8. 2008. pp. 69-77.

Khoury, JA, Storch, GA, Bohl, DL, Schuessler, RM, Torrence, SM, Lockwood, M, Gaudreault-Keener, M, Koch, MJ, Miller, BW, Hardinger, KL, Schnitzler, MA, Brennan, DC. "Prophylactic versus preemptive oral valganciclovir for the management of cytomegalovirus infection in adult renal transplant recipients". Am J Transplant. vol. 6. 2006. pp. 2134-2143.

Reischig, T, Jindra, P, Hes, O, Bouda, M, Kormunda, S, Treska, V. "Effect of cytomegalovirus viremia on subclinical rejection or interstitial fibrosis and tubular atrophy in protocol biopsy at 3 months in renal allograft recipients managed by preemptive therapy or antiviral prophylaxis". Transplantation. vol. 87. 2009. pp. 436-444.

Leung Ki, EL, Venetz, JP, Meylan, P, Lamoth, F, Ruiz, J, Pascual, M. "Cytomegalovirus infection and new-onset post-transplant diabetes mellitus". Clin Transplant. vol. 22. 2008. pp. 245-249.

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