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

2. 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

3. 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

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

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

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

7. 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

8. 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

9. 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:
> copies/ml of plasma is significant; highest loads in organ disease, intermediate load in CMV syndrome, lowest in infection
Histology: GI mucosa

11. 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

12. CMV : Prophylaxis1 Options Oral ganciclovir 1g tds
Valganciclovir mg od
Start within 10 days post Tx
Duration
D+ R months2
D+R+, D- R months
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 ’ IMPACT study’ 09

13. 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

14. 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

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

16. 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

17. 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

18. 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

21. 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

23. 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’ Weiss et al’ Egli et al ’09

24. Ancillary therapies No randomised trials Cidofovir
Inhibits intracellular virus genome replication /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

25. Ancillary therapies Leflunomide
100 mg o.d. x 3d, 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 ‘ Faguer et al ‘07

26. 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

27. 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

28. 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