1. CMV and BK infections in renal transplant recipients

2. CMV infections

3. Introduction
Human CMV or human herpesvirus 5: ubiquitous dsDNA virus with large heterogeneity of CMV strains.
The seroprevalence of CMV ranges from 30%-97% and increases with age.
After primary infection, the virus establishes a lifelong latency within the host
Seropositivity(IgM/IgG CMV ab) do not offer protection against CMV.

4. Why bother the transplant folks…
Reactivation of latent CMV likely happens through activation of viral immediate-early (ie) gene transcription
These genes are not transcriptionally active in latently infected cells
Induction of ie gene expression through activation of the major ie promoter/enhancer (MIEP) appears to be required for CMV reactivation.
TNF-alpha(induced by the allogeneic response after transplantation)activates nuclear factor-kB, which then stimulates expression of the MIEP

5. Why bother the transplant folks…
Use of antilymphocyte antibody
Appearance of sepsis and transplant rejection, which are TNF-associated complications
TNF independent:
Ischemia-reperfusion injury: through ROS
Stress (through catecholamines)
Inflammation (through prostaglandins),
Drugs (eg, pentoxifylline and catecholamines) activate the MIEP using the cAMP pathway

6. Diagnosis Antigenemia assay:
-Rapid semiquantitative immunofluorescent assay
-Detects phosphoprotein 65 (pp65) produced in CMV-infected PMNs in blood
-Results expressed as number of pp65-positive cells/leukocytes evaluated.
-Good sensitivity and high specificity.
-Easy and does not require expensive equipment.
But
-Is a manual process that requires technical skill, labor intensive
-Subjective
-Not standardized
-Need to be processed within 6-8 hours of collection
-Cannot be perfomed when the neutrophil count is low(<200)

7. Diagnosis PCR assay: Detects CMV DNA copies/ml
Higher sensitivity and similar specificity as pp65 antigenemia assay
High NPV but lower PPV
Usually at least a 3-fold (0.5 log copies/mL) change in values is needed to represent significant changes in viral replication

8. Diagnosis Tissue-invasive CMV disease: -culture
-histopathologic testing with immunostaining
-immunohistochemical analysis
-in situ DNA hybridization.
Recommended to use CMV DNA PCR on BAL, CSF, or biopsy specimens as a fast, sensitive,and quantitative test.

9. CMV infection in Kidney transplant recipients
In the absence of preventive measures, 40%-100% of all KTRs develop CMV infection and up to 67% develop CMV disease.
Using current preventive strategies, the incidence is decreased to 17%-92% and 0%-37% of KTRs, respectively.
Incidence higher after SPK
Occur most often in first 100 days after transplantation, at the time of the highest immunosuppressive load.

10. Types of CMV diseases CMV syndrome : fever, atypical lymphocytosis,
neutropenia or thrombocytopenia,malaise
Tissue invasive disease: pneumonia, gastrointestinal, hepatitis, pancreatitis, encephalitis, chorioretinitis, myocarditis, nephritis, cystitis, mucocutaneous
Not always associated with a positive blood PCR result
Indirect effects: immunomodulatory effects, mortality, rejection, infections including other herpes viruses

13. Risk of CMV Strongly dependent on donor and recipient serostatus.
R-/D+: high risk
R+/D+ or - : Intermediate risk
R-/D-: low risk (incidence of CMV disease<5%)

14. Risk of CMV
Blood transfusion, much less with leukocyte-depleted blood products
Type of immunosuppression: mTOR vs CNI, anti-lymphocyte antibody vs basiliximab
-Older donor
-SPK
-Acute rejection
-Impaired transplant function

15. Prevention: Prophylaxis vs Pre-emptive therapy
Prophylaxis: Routine prophylaxis with anti-viral post transplant, and post treatment with ATG/steroids Meds -Valgancyclovir -Oral/IV Gancyclovir -Valacyclovir Duration: -3 months: intermediate risk +/- low risk -6 months: high risk -1-3 months: post treatment with ATG/steroids

16. Prevention: Prophylaxis vs Pre-emptive therapy
-Monitor CMV weekly
-Start meds when positive at pre-specified threshold
-Effective at preventing CMV disease
-Potentially lower cost and no incidence of drug side effects
-Possibility of stimulating CMV-specific immune
Benefit of Prophylaxis: prevents indirect effects of virus
-?lower rejections and better long term transplant survical
-?decrease all-cause mortality and lower incidence of opportunistic infections

17. Recommendations
American Society of Transplantation and The Transplantation Society
-promote the use of prophylaxis with PO Valgancyclovir, PO/IV ganciclovir or valacyclovir for 3-6 months in D+/R- transplantations
-But consider pre-emptive therapy with valganciclovir or IV ganciclovir a suitable option population.
Three-month prophylaxis and preemptive considered equally useful in D+/R+ and D-/R+

18. Things to remember
Antiviral dosage must always be adjusted to kidney function
D-/R- may not need prophylaxis against CMV, prophylaxis with acyclovir against HSV and VZV still needed

19. CMV treatment: general principles
Valganciclovir noninferior to IV ganciclovir with non–life-threatening disease
Patients with serious CMV disease should still be treated with IV Ganciclovir
Adjust immunosuppression( ?CNI or anti-metabolite)
Weekly CMV VL
Treatment until CMV undetectable, minimum 2 weeks
Secondary prophylaxis for 1-3 months
Gancyclovir resistance is possible(UL97, UL 54 mutations)

20. BK virus

21. What is BK?
Named after a Sudanese patient who suffered from underwent a LRRT. Postoperative course was complicated with 2 mild rejections.
5 months after transplant, admitted with graft dysfunction and ureteric obstruction.
Tissue culture from the donor’s ureter revealed a virus with unique cytopathic effect that distinguished it from the rest of the polyoma viruse

22. Introduction
Ubiquitous: worldwide seroprevalence in adults of 75%, 30%-90% in US and Europe
After primary infection, remains latent in the renal epithelium due to its tropism to the urinary tract

23. Pathogenic in the immunocompromised population, mainly among patients with transplants.
Interestingly, among K and KP patients, BKV primarily causes BKV-associated nephropathy (BKVAN) and ureteral stenosis. In SCT patients, primarily causes hemorrhagic cystitis
BKVAN in native kidneys after nonkidney organ transplantation is rarely reported, even in settings of the same degree of immunosuppression.
Factors associated with the process of kidney transplantation might play a role(ischemia-reperfusion injury, and tissue trauma) that activate the latent virus in the donated kidney; donor–recipient transmission can be postulated

24. Course of BK reactivation
Evolves from reactivation of the latent BKV, manifests as BK viruria; to BK viremia; to BKVAN; to graft dysfunction
Causes direct cytopathic injury by viral invasion.
Decreased immunosuppressive medication after BKV reactivation might induce rejection
?Link between BKV and bladder/prostate cancer

25. Risk factors for BKVAN Choice of immunosuppression
-Cyclosporine vs Tacrolimus
-mTor vs CNI
Degree of viremia
<10,000 copies/mL generally are not associated with graft adverse effects,
Spontaneous clearance rate in the low viremia reported to be as high as 95%
Viral load > 10,000 copies/mL for greater than 3 weeks is a surrogate marker for presumptive BKVAN

26. Diagnosis
Prevalence of BK viremia ranges from 7% to 27%, most cases during the first year
Incidence of BKVAN ranges between 1% to 27%
Depends on surveillance protocol(possible early detection and intervention before graft injury)

27. Diagnosis Decoy cells: urine cytology
-high sensitivity, low specificy)
BK Viruria: Urine PCR
-2/3 patients do not develop viremia
BK viremia: Blood PCR

28. Recommendations KDIGO guidelines, AST recommendations:
-Options include
monthly screening with quantitative plasma BKV PCR test for the first 3 to 6 months, followed by every 3 months until 24 months after transplant;
(2) biweekly urine tests (BKV PCR or cytology), followed
by a quantitative plasma PCR test, if positive, for the
first 3 months, then monthly until month 6, and then
every 3 months until 24 months after transplant

29. Kidney biopsy: things ot remember
Early BKV infection can be limited to focal areas and easily missed.
Can morphologically look like rejection
Simian virus 40 stain widely used

30. Treatment Reduce immunosuppresion Leflunomide Cidofocir/Brincidofovir
IVIG

31. ?Retransplant
Yes!. Just esnure no active viremia