CMV & BKV in transplantation Prof.V.Sakhuja Head, Deptt. Of Nephrology PGIMER, Chandigarh.

CMV Member of Herpesviridae (HHV-5) Infection acquired in first 2 decades in 90% : IgG ab positive Dormant infection lifelong in neutrophils, PBMC, macrophages Disease only when host-virus relationship is disturbed by immunosuppression

Types of infection Seronegative recipients D+ Primary infection: at highest risk, virus of donor origin D - Infection in 5%, at lowest risk, from transfusions Seropositive recipients D - Reactivation infection: virus of recipient origin D+ Superinfection: virus of donor or recipient origin Most patients in India belong to the D+R+ category

Determinants of risk Serostatus of donor & recipient Blood transfusions Immunosuppression Reactivation : ATG, Aza, MMF Replication: CNI, steroids

The risk of CMV disease is lowest after transplantation of which of the following : Liver Heart Intestine Kidney

Type of transplant Incidence Kidney 8% Heart, Liver, Intestine 20-30% Heart-Lung 39% Kidney-Pancreas 50% Marrow 50-80% Infection vs disease Infection: viral replication but no symptoms Disease: viral replication with manifestations

Direct effects Develop in first 3 months if no prophylaxis used CMV syndrome Fever, leukopenia, thrombocytopenia Organ disease GI colitis, gastritis,esophageal ulcers Hepatitis transaminitis Pneumonia hypoxia, resp. failure Retinitis > 6 months post Tx, isolated

Indirect effects “Immunoparalysis”: increased risk of other infections: bacterial,PJ, fungi, hepatitis C Increased risk of PTLD* Acute rejection Chronic allograft injury PTDM** Decreased graft and patient survival * Basgoz et al’95 ** Hjelmesaeth et al’04

Lab diagnosis Serology & viral cultures have no role CMV pp65 antigenemia in neutrophils: semiquantitative Not possible when ANC <1000/ul CMV viral load in plasma/whole blood: >2500-5000 copies/ml of plasma is significant; highest loads in organ disease, intermediate load in CMV syndrome, lowest in infection Histology: GI mucosa

Prevention Universal Prophylaxis :Prevents indirect effects, better graft and patient survivals , more drug toxicity Pre-emptive therapy: When positive for DNA or antigenemia (testing done once a week),does not prevent indirect effects, less drug toxicity Large trials on prophylaxis Very few trials comparing the two

CMV : Prophylaxis1 Options Oral ganciclovir 1g tds Valganciclovir 900mg od Start within 10 days post Tx Duration D+ R- 6 months2 D+R+, D- R+ 3months D- R- Not required After ATG Rx of rejection 1-3 months Pre-emptive therapy: Regimen same as for CMV disease; not suitable for D+R- group 1Humar et al ’ 09 2IMPACT study’ 09

Deferred therapy1 Reduce immunosuppression (stop MMF/Aza) GCV 5mg/kg i.v. b.d. x till CMV-DNA < 1000 copies/ml; modify dose in graft dysfunction VGC 900 mg bd x 3 wks, then 900 mg od x 4 wks CMV Ig 100 mg/kg x 4 doses for pneumonia Role of secondary prophylaxis for 1-3 months uncertain 1Kotton et al ’ 10

BKV (Polyoma)infection Virtually unknown in Tx before 1995 Primary infection in childhood in >80%*; latent infection in tubular & transitional epithelium Nephropathy in 1-10%, in first year ** Asymptomatic slow rise in s. creatinine Not seen with non-kidney tx, native kidneys unaffected *Hogan et al’ 80 **Hirsch et al’ 02

Risk factors Deceased donor Ischemia – reperfusion injury No. of HLA mismatches Acute rejection & its treatment (ATG) Tac-MMF-steroid combination Intensity of immunosuppression

Which of the following is the most reliable test for making a presumptive diagnosis of polyomavirus nephropathy ? Plasma viral load Urine viral load Electron microscopy of urine sediment Urine cytology for decoy cells

Diagnosis : step wise approach Screening for “decoy” cells in urine every 3 months in first 2 years, then once a year. High negative predictive value of > 95% EM of urine for 45 nm viral particles & “Haufen” Urine viral load > 7 log 10 geq/ml Plasma viral load > 4 log 10 geq/ml : more specific than urine Renal biopsy : 2 cores

Diagnosis Possible PVN 1. Urine decoy cells 2. Presence of urinary Haufen on EM 3. Urine viral load > 7 log geq/ml Presumptive PVN Plasma viral load > 4 log geq/ml for > 3 wks

Definitive PVN Pattern A Intranuclear inclusions in tubular epi Minimal inflammation, int.fibrosis < 10% Medulla mainly affected B Intranuclear inclusions Moderate interstitial inflammation tubulitis and tubular necrosis, int.fibrosis < 25% C Intranuclear inclusions Tubular atrophy, int. fibrosis > 25% IHC : SV 40 large T antigen in nuclei

Reduction of immunosuppression Switch from Tac to CsA vs Tac reduction (4-6ng) and MMF reduction to 250 mg bd : Survivals equal 1 CNI elimination (SRL/pred) vs reduction of all agents :88 % survival after elimination vs 56 %2 Tacro 3 ng/ml, CsA 100 ng/ml as first step3 Wait for upto 12 wks – monitor viremia every 2 wks 1 Wadei et al’06 2 Weiss et al’08 3 Egli et al ’09

Ancillary therapies No randomised trials Cidofovir Inhibits intracellular virus genome replication 0.25 -1/mg/kg IV biweekly x 8 wks 0 of 8 on cidofovir lost function vs 9/131 Anterior uveitis Ciprofloxacin 500 mg/d (in vitro data) Kuypers et al ‘05

Ancillary therapies Leflunomide 100 mg o.d. x 3d, 20-60 mg/d (trough 50 – 100 ng/ml), stop MMF 15% graft loss reported in one study1 Ineffective in other studies2 Risk of hemolytic anemia, hepatitis, myelosuppression 1 Josephson et al ‘06 2 Faguer et al ‘07

Ancillary therapies IV Ig 150 mg/kg IV biweekly x 8 wks Prevented graft loss, did not clear viremia 1,2 No benefits in 2 studies 3,4 1 Sener et al ’06 2 Sharma et al ’09 3 Wadei et al ’06 4 Weiss et al ‘08

Concurrent acute rejection C4d in ptc or arteritis/glomerulitis/fib. necrosis :diagnosis easy Interstitial inflammation, tubulitis only : diagnosis difficult No evidence based guidelines Reduce immunosuppression and give IVIg 100mg/kg biweekly x 8 weeks

Retransplantation Successful retransplantation is the rule1 after waiting period on dialysis Blood PCR to show absence of viremia before Tx Viruria ? can be ignored Recurrence rate of 15%2 Prior allograft nephrectomy only for pre emptive transplant Minimize immunosuppression after retransplant 1 Wiseman’09 2 Hirsch et al ‘06