1. CMV infection in renal transplant recipients review

2. INTRODUCTION CMV is one of the most important infections in renal transplant recipients. Exposure to the virus (IgG anti-CMV antibodies in the plasma) increases with age in the general population. –more than 2/3 of donors and recipients prior to transplantation

3. Transmission : –blood transfusion or transplanted kidney –immunosuppressive drugs->increases the risk Thus, both the recipient and the donor are routinely tested for anti-CMV antibodies prior to transplantation.

4. CMV : a significant underlying cause of morbidity and mortality in the renal transplant setting. –CMV-positive patients had significantly higher incidence of CMV disease, allograft loss, and overall costs. –The impact of CMV on overall mortality (a prospective, single center study of almost 500 pts who did not receive CMV prophylaxis) a relative risk of overall mortality of 2.5 asymptomatic CMV infection was associated with a relative risk of overall mortality of 2.9

5. CMV INFECTION VERSUS DISEASE Detection of virus via culture, molecular techniques or changes in serology defines CMV infection. seroconversion with the appearance of anti-CMV IgM antibodies; a fourfold increase in preexisting anti-CMV IgG titers detection of CMV antigens in infected cells detection of CMV-DNAemia by molecular techniques; and/or isolation of the virus by culture of the throat, buffy coat, or urine. CMV disease requires clinical signs and symptoms fever, leukopenia, or organ involvement (hepatitis, pneumonitis, pancreatitis, colitis, meningoencephalitis, and rarely myocarditis) CMV chorioretinitis : relatively common in AIDS, a rare feature in transplant recipients

6. Viral load The total burden of CMV viral particles in the host may correlate with clinical evidence of disease, disease severity, or response to therapy. The number of CMV particles –by quantitative PCR –25 renal and 95 cardiac transplant recipients. : All patients with CMV DNA levels of ≥500 copies/µg of total DNA in peripheral blood had clinical evidence of disease. –In another report, the initial CMV viral load and the rate of increase of virus in the blood correlated with the risk of developing CMV disease.

7. CMV DISEASE Symptomatic CMV infections typically occur 1-4 months after transplantation –prophylaxis(-) –1-4 months after discontinuation of prophylaxis, although cases may develop later Thus, the onset of disease usually follows the period of maximal immunosuppression for the prevention and treatment of acute rejection. Risk of reactivation is increased in seropositive recipients treated with OKT3 or other forms of antilymphocyte serum.

8. the cardinal features of CMV disease (azathioprine) : marked leukopenia which usually requires the temporary discontinuation and/or reduction of immunosuppressive medications. However, leukopenia may not be as prominent –because MMF is preferred to azathioprine in most immunosuppressive regimens –prophylactic antiviral therapy is extremely effective Compared with azathioprine, the incidence of leukopenia with MMF may be lower because of its relatively selective action on the purine salvage pathway. The incidence of tissue invasive CMV disease appears to be decreasing with the current practice of administering valganciclovir or ganciclovir to most patients as prophylactic therapy. valganciclovirganciclovir

9. No fixed protocol for this clinical situation –since the degree of immunosuppression may significantly vary by individual. –Nevertheless, the antimetabolite utilized (either azathioprine or MMF) is usually permanently discontinued.azathioprine

10. Presentation of CMV disease The most common presentation is a mononucleosis-like synd. –fever, malaise, myalgias, and arthralgias, usually associated with leukopenia and mild (5 to 10 percent) atypical lymphocytosis –A mild elevation in serum aminotransferase concentrations also may be seen. –MMF : invasive CMV disease can occur in the absence of fever and leukopenia. Interstitial pneumonitis and ulcerations in the esophagus and colon are particularly troublesome and cause major morbidity. –GI bleeding among renal transplant recipients is commonly caused by erosions due to CMV. –Invasive disease is usually confirmed with endoscopic biopsy. Encephalopathy and chorioretinitis are unusual in renal transplant recipients.

11. Diagnosis Techniques for detecting CMV have improved dramatically. However, interpretation of results may be problematic. –because of the broad spectrum of clinical disease (ranging from asymptomatic viral shedding to fulminant infection) The implications of positive identification of CMV in blood or tissue depends largely upon –the clinical context and the source of the specimen

12. Several diagnostic modalities are available. Serology –a fourfold increase in CMV-IgG titer or –a markedly positive CMV-IgM titer => suggest recent infection. –less useful than antigen or PCR testing and has largely been abandoned for the diagnosis –however, still useful for pre-transplant risk stratification –currently more frequently measured with an ELISA than with complement fixing titers

13. Culture –culture of urine, buffy coat, throat, bronchoalveolar lavage fluid : the preferred method to diagnose active infection. –conventional tube culture takes weeks –rapid shell-vial culture technique (24 to 48 hrs) –more commonly, the CMV PCR –shell-vial culture technique : a fluorescence tagged monoclonal antibody is used to detect a CMV antigen expressed early in viral replication.

14. Newer techniques –pp65 antigenemia assay, PCR, quantitative CMV-PCR, and the hybrid-capture RNA-DNA hybridization assay.

15. Treatment The mononucleosis-like syndrome may resolve without the administration of antiviral drugs. A reduction in the overall level of immunotherapy is often recommended. –OKT3 (or other form of antilymphocyte serum) should be discontinuedOKT3 –azathioprine or mycophenolate mofetil should be given in reduced dosage or discontinued.azathioprinemycophenolate –We usually do not discontinue cyclosporine or tacrolimus unless there is evidence of life-threatening infection. –Corticosteroids are generally continued to prevent possible adrenal insufficiency.Corticosteroids

16. Uncontrolled trials suggest that patients with organ involvement may benefit from a 2-3week course of ganciclovir. ganciclovir Hyperimmune globulin (Cytogam) Prior to initiating this regimen, potential causes need to be excluded. –CMV infection may be associated with Pneumocystis carinii pneumonia, which should also be treated.

17. The usual dose of ganciclovir ganciclovir –5 mg/kg every 12 hrs (normal renal allograft function) –Dosing: Renal Impairment –I.V. (Induction): »Cl cr 50-69 mL/minute: Administer 2.5 mg/kg/dose every 12 hours. »Cl cr 25-49 mL/minute: Administer 2.5 mg/kg/dose every 24 hours. »Cl cr 10-24 mL/minute: Administer 1.25 mg/kg/dose every 24 hours. »Cl cr <10 mL/minute: Administer 1.25 mg/kg/dose 3 times/week following hemodialysis. –I.V. (Maintenance): »Cl cr 50-69 mL/minute: Administer 2.5 mg/kg/dose every 24 hours. »Cl cr 25-49 mL/minute: Administer 1.25 mg/kg/dose every 24 hours. »Cl cr 10-24 mL/minute: Administer 0.625 mg/kg/dose every 24 hours »Cl cr <10 mL/minute: Administer 0.625 mg/kg/dose 3 times/week following hemodialysis. –Oral: »Cl cr 50-69 mL/minute: Administer 1500 mg/day or 500 mg 3 times/day. »Cl cr 25-49 mL/minute: Administer 1000 mg/day or 500 mg twice daily. »Cl cr 10-24 mL/minute: Administer 500 mg/day. »Cl cr <10 mL/minute: Administer 500 mg 3 times/week following hemodialysis. –Hemodialysis effects: Dialyzable (50%) following hemodialysis; administer dose postdialysis. During peritoneal dialysis, dose as for Cl cr <10 mL/minute. During continuous arteriovenous or venovenous hemofiltration, administer 2.5 mg/kg/dose every 24 hours.

18. The most frequent side effect of ganciclovir :ganciclovir –Leukopenia : usually reversible –A mild elevation in the plasma Cr concentration (the role of ganciclovir in this complication is uncertain) –Crystal-induced acute renal failure(acyclovir) : a rare event with gancicloviracyclovir

19. Valganciclovir has been used to treat CMV- associated retinitis in AIDS patients.Valganciclovir excellent bioavailability of valganciclovir and pharmacokinetics=> useful for treatment of CMV disease in kidney transplant recipients Our early experience is that discontinuation of the anti-metabolite, azathioprine or mycophenolate mofetil, is essential for virus eradication when valganciclovir is used for treatment of CMV disease.azathioprine mycophenolatevalganciclovir

20. CMV-INDUCED RENAL DISEASE One of the most controversial issues –whether the virus itself can cause allograft dysfunction. –Renal function may deteriorate –factors (such as decreased renal perfusion, acute tubular necrosis, and transplant rejection) may be more important than a direct viral effect on the kidney. –There are reports describing the occurrence of a CMV-induced transplant glomerulopathy.

21. CMV nephropathy 13 biopsy samples from patients suspected of CMV disease a buffy coat CMV-PCR (within 2 to 5 days of a renal allograft biopsy for an elevated SCr) evaluated for CMV pathologically by LM,IHC, in situ hybridization and tissue PCR. qualitative and quantitative buffy coat CMV-PCR positive in 10 (77 %) tissue CMV-PCR positive in five (50 %) biopsies(2 with CMV inclusions and 3 with no inclusions) All 5 biopsies with acute rejection were associated with CMV viraemia 2/5 with allograft CMV inclusions Thus, the use of sensitive techniques provides some evidence that CMV nephropathy may be much more common than previously reported.

22. CMV infection is an independent risk factor for the development of rejection. How this might occur is not known –prevention of CMV infection may diminish the incidence of rejection and lead to improved allograft survival

23. Infection with CMV Development of coronary artery narrowing A similar relationship has been reported –between transplant renal artery stenosis and CMV infection –in a series of over 900 renal transplant recipients –75 of whom were diagnosed with renal artery stenosis via angiography –Patients with stenosis were paired with a control individual (matched for age, sex, year of transplant, and number of grafts, but without renal artery disease) –Definitive evidence of CMV infection was significantly associated with stenosis (36 versus 12 control patients, P<0.001). QJM 1998 Mar;91(3):185-9.

24. In addition, CMV has been associated with thrombotic microangiopathy (HUS/TTP) in solid organ and bone marrow transplant recipients The disorder may respond to immunoglobulin infusion

25. Viruses, particularly CMV, serve as important cofactors to many opportunistic infections.