Infection after kidney transplantation

1. Infection following renal transplantation
Maj. Chaken Maniyan M.D.
Nephrology Fellow, Phramongkutklao Hospital
6.1.2017
Topic review

2. Scope
§ Epidemiology of post KT infection
§ 4 categories exposures
§ Timeline of various infection
§ Selected important post KT infection
§BK virus
§Cytomegalovirus

3. Incidence of infectious diseases in
solid-organ transplant recipient
David R. Snydman Clin Infect Dis. 2001;33:S5-S8

4. Epidemiologic Exposures :
4 categories
§ Donor-derived infections Most often infections
§ Recipient-derived infections
§ Nosocomial infections
§ Community infections
Fishman JA: Infection in solid-organ transplant recipients. N Engl J Med 357: 2601–2614, 2007

5. Donor-Derived Infections
§Bacteremia or fungemia infections (S.aureus, Candida
species, Gram-neg bacteria) in donors at the time of
donation can cause local (abscess) or systemic (bacteremic)
infections, and may selectively adhere to anastomotic sites
(vascular, urinary) to produce leaks or mycotic aneurysms.
§Virus: (CMV,BK) : greatest risk : seropositive to seronegative
recipients
§Latent infections, such as tuberculosis, toxoplasmosis, or
strongyloidiasis
Seminars in Nephrology, Vol 27, No 4, July 2007, pp 445-461

6. § Colonization or latent infections that reactivate in the
setting of immune suppression
§ Common pathogens :TB ,parasites (e.g., Strongyloides
stercoralis & T. cruzi), viruses (CMV, EBV, herpes simplex,
varicella–zoster virus ,HBV, HCV, and HIV), and endemic
fungi( Histoplasma capsulatum, Coccidioides immitis, &
Paracoccidioides brasiliensis)
Recipient -Derived Infections
Fishman JA: Infection in solid-organ transplant recipients. N Engl J Med 357: 2601–2614, 2007

7. §Patients waiting for transplantation :colonized with
nosocomial, antimicrobial-resistant organisms :MRSA,
VRE ,fluconazole-resistant candida species, C. difficile, &
antimicrobial-resistant GNB or aspergillus species.35-
43
§Cause pneumonia or may infect hematomas, ascitic
fluid, wound & catheters
Fishman JA: Infection in solid-organ transplant recipients. N Engl J Med 357: 2601–2614, 2007
Nosocomial Infections and Antimicrobial Resistance

8. § Contaminated food or water, family or coworkers
§ Common: respiratory viruses and atypical pathogens
§ CMV & EBV may produce severe 1o infection in
nonimmune host
§ Geographically systemic mycoses (Blastomyces,
Coccidioides, and Histoplasma)
§ Mycobacterium
§ Strongyloides stercoralis infection
Fishman JA: Infection in solid-organ transplant recipients. N Engl J Med 357: 2601–2614, 2007
Community Infections

9. Timeline of Infection after Solid organ Transplantation
Fishman JA: Infection in solid-organ transplant recipients. N Engl J Med 357: 2601–2614, 2007

10. The first month
1.Infection before transplantation
2.Bacterial or candidal infection
§ undetected systemic infection in the donor-
§ contamination during the organ procurement
3.Infection of surgical wound , lungs ,
vascular access , drainage catheters
Fishman JA: Infection in solid-organ transplant recipients. N Engl J Med 357: 2601–2614, 2007

11. One to six months after transplantation
§ 70% febrile episodes => CMV
§ Infectious disease syndrome :
§ CMV , EBV , HBV , HCV
§Opportunistic infection :
§PCP , L. monocytogenes,Aspergillus
Fishman JA: Infection in solid-organ transplant recipients. N Engl J Med 357: 2601–2614, 2007

12. More than 6 months after
transplantation
§Divided into 3 groups in terms of infection risk
1. good result of transplantation : resemble as general
2. chronic viral infection ( absence of effective therapy )
3. poor result of transplantation
Opportunistic infection :PCP , Nocardia , L. monocytogenes,
Aspergillus
Fishman JA: Infection in solid-organ transplant recipients. N Engl J Med 357: 2601–2614, 2007

13. Incidence of invasive fungal infections
among transplant recipients
Singh N. Infect Dis Clin North Am 2003; 17: 11

14. §Human herpes viruses
§HSV1,2 ,VZV, EBV,CMV, HHV6,HHV7,HHV8
§Respiratory viruses
§Influenza, parainfluenza, RSV adenovirus
§Polyomavirus (BK, JC virus)
§Norovirus
§Hepatitis B , C
Viral infection

15. Bohl, D. L. et al. Clin J Am Soc Nephrol 2007;2:S36-S46
- dsDNA virus,belong to the Papovaviridae virus family
- Progression from viruria to viremia to nephropathy
generally is accepted as a Stepwise transition
Polyomavirus

16. Polyomavirus: virology
Circular, dsDNA genome
~5200 base pairs
Early genes (regulatory): large T-
antigen and small t-antigen
Late genes (structural):VP1,VP2,
VP3, and agnoprotein
Non-coding control region
(NCCR): contains the origin and
transcription factor binding sites

17. §Primary infection : childhood (oral and/or respiratory exposure)
à resolved àVIRAL ENTER latent phase : urogenital tract
(kidneys (transitional epithelium, renal tubular epithelium, and
parietal epithelium of Bowman's capsule)), bladder, prostate) &
hematolymphoid tissue
§Reactivation : Latent infection :old age, DM ,pregnancy,
immunosuppressed state
§Clinical : transient renal dysfunction
hemorrhagic cystitis (BMT recipients)
ureteral obstruction/ ureteric stenosis
Lacking ; systemic symptoms
P.Randhawa,Transplantation Review 2007(21);77-85
Clinical feature

18. BKV infection after kidney
transplantation
§Reactivation/primary infection in KTx recipients
§Asymptomatic infection
§Ureteral stenosis
§Systemic vasculopathy
§Interstitial nephropathy (BKV nephropathy)
§onset of the disease occurs at a mean period of 10-13
months posttransplantation but at least 25% of cases are diagnosed
later
§ 10-80% graft loss: but, with increased awareness and improved diagnostic
techniques, the rate of graft loss has lowered
Dall A,. Clin J Am Soc Nephrol 2008; 3 Suppl 2:S68.

20. Patient
determinants
§Age>50; male gender; diabetes
§Negative serostatus before transplantation
§Absence of HLA-C7
Organ
determinants
§Degree of ABO/ HLA matching
§Prior rejection episodes
§Renal tissue injury
§BK antibody status in donors
Viral
determinants
§Viral subtypes: variantVP1 & NCCR ;PATHOGENICITY
§Synergistic viral infection : CMV infection
Immuno
suppression
Major risk factor for BKVN: “over-immunosuppression”
rather than a specific agent
P.Randhawa,Transplantation Review 2007(21);77-85

21. BKVN diagnosis
§A definitive diagnosis of BKVN requires
§Characteristic cytopathic changes. PLUS
§Positive immunohistochemistry tests using antibodies
against SV40 large T antigen (specificity 100%)
§Diagnosis may be missed on 1/3 biopsies àneed two
biopsy cores, prefer medulla
Dall A,. Clin J Am Soc Nephrol 2008; 3 Suppl 2:S68.

22. BKVN diagnosis
§Viropathic lesions are often focal and patchy in nature
and BK is tropic for the medullary and not cortical
§A presumptive diagnosis may be made by PCR
demonstration of BK replication in plasma
Dall A,. Clin J Am Soc Nephrol 2008; 3 Suppl 2:S68.

23. Clinical
management
Test Modality BKVN
Possible presumptive definitive
Screening test §Decoy cells in urine
cytology(>10cell/cytospin)
§BKV DNA in urine
§BKV RNA in urine
+ + +
Adjunct test §Q-BKV DNA in blood
§Q-BKV RNA in urine
- + +
Biopsy §Histology
§Adjunct tools:
immunohistochemistry
In situ hybridization
- -
+
Patterns
A-C
Intervention
indicated
no ? yes
BKV nephropathy after KTx
Hirsch, Brennan, Drachenberg, Ginevri et al. Transplantation 2005.

24. Diagnostic Test Threshold
value
PPV (%) NPV (%)
Plasma BKV DNA PCR
(copies/ml)
Presence to >
10,000
50 to 85 100
Decoy cells
(cells/cytospin)
Presence to > 10 27 to 90 99-100
Urine BKV DNA PCR
(copies/ml)
> 1 x 107
67 100
Noninvasive tests for BKV nephropathy
Clin J Am Soc Nephrol. 2007 Jul;2 Suppl 1:S36-46.

25. Decoy cells
enlarged nucleus with a
single large basophilic
intranuclear inclusion
Cytospin smears were prepared
from fresh urine samples,
fixed in alcohol and
stained with Papanicolaou stain.

28. Intranuclear basophilic viral inclusions
without a surrounding halo

29. Histologic
Pattern
Biopsy Findings Outcome
(ESRD)
Differential
A Intranuclear viral inclusions with
absent or minimal inflammation
13 % Normal
Coexisting diagnosis
B Intranuclear viral inclusions
moderate to severe interstitial
inflammation
55 % Interstitial nephritis
ATN
Acute rejection
C Intranuclear viral inclusions
moderate to severe tubular
atrophy and fibrosis
100 % CAN
Histologic pattern of BKV nephropathy
Drachenberg et al. Hum Path 2005; 36:1245
BKVN is generally distinguished from rejection by the presence of BKV inclusions
and immunohistologic or in situ hybridization evidence of virally infected cells

30. Screening and management of kidney transplant patients for BKV replication
and polyomavirus-associated nephropathy (PyVAN).
Hirsch HH, Brennan DC, Drachenberg CB, et al. American Journal of Transplantation 2013; 13: 179–188

31. BK virus screening
§ Screening all KTRs for BKV with plasma NAT (2C) at Least
§ monthly for the first 3–6 months after KT(2D); then
every 3 months until the end of the first post-transplant
year (2D);
§whenever there is an unexplained rise in SCr (2D)
§after treatment for acute rejection (2D)

32. Treatment of BKVN by
modification of immunosuppression
American Journal of Transplantation 2009; 9 (Suppl 3): S44–S58

33. § We suggest reducing immunosuppressive
medications when BKV plasma NAT is persistently
greater than 10 000 copies/mL (107 copies/L). (2D)
Treatment of BKVN by
modification of immunosuppression

34. Reduction of immunosuppressive drugs : 1st primary
treatment
Leflunomide
Cidofovir
IVIG
Quinolones
Ancillary Therapies
§After immunosupressive dose reduction : slow
decrease PVAN activity ; typical wk >> mo
§If serial blood sampling : no evidence of improvement
or renal function : decline >>> Should be add ancillary
treatment
AJKD,Vol 54, No 1 (July), 2009: pp 131-142

35. CMV Infection after KT
§β-human herpes virus (HHV-5)
§Most common OI after transplantation
§Renal transplant recipients : lowest risk compared
with other solid organ transplant
§CMV disease in 30-78% of recipients if prophylaxis
is not administered
§High mortality if untreated (up to 90%)

36. Effect of CMV
Inflammation
(cytokines, growth factors)
Latent CMV Active CMV infection
(local, viremia and invasion)

37. Terminology
§Active CMV infection
§Asymptomatic / symptomatic
§Characterized by viral replication with specific immune
response to CMV
§Dx by detection of virus via culture, molecular techniques
or changes in serology
§ 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 PCR
§ isolation of the virus by culture of the throat, buffy coat, or urine

38. Terminology
§Primary CMV infection
§Infection in the previously uninfected seronegative
host
§Secondary CMV infection
§Infection in previously infected seropositive host
§Caused by reactivation of latent endogenous virus or
reinfection/suprainfection of new virus strain

39. Terminology
§CMV disease
§Symptomatic acute CMV infection
§CMV syndrome – fever, fatigue, leukopenia,
thrombocytopenia, increased CMV titer from
specific immunoassay
§Invasive CMV disease : specific organ involvement –
pneumonitis, hepatitis, colitis, enteritis, involvement
of the graft itself

40. Risk factors for CMV
infection
§Net stage of immunosuppression
§CMV donor-recipient mismatching
§Use of lymphocyte depleting agent
§Comorbid illnesses, neutropenia
§Coinfection with HHV6,7
§Donor age > 60 years
§Acute rejection episode
San Juan, Clin Infect Dis 2008Oct 1;47(7):875-82. doi: 10.1086/591532.

41. San Juan, Clin Infect Dis 2008Oct 1;47(7):875-82. doi: 10.1086/591532.

45. CMV IgG antibody
Donor Recipient
CMV Antibody status
Terminology Infection % Disease % Pneumonitis %
+ - Primary infection 70-88 56-80 30
- + Reactivation 0-20 0-27 rare
+ + Reinfection or superinfection 70 27-39 3-14
- - - 0 - -
Pretransplant Serologic testing

46. Diagnosis of CMV infection
§Histopathology
§Viral culture
§Serology
§Molecular assay - nucleic acid detection, antigen
detection *** (Viral load testing )

47. Diagnosis of CMV infection
§Histopathology
§Tissue invasive CMV
§ Microscopic examination of tissue for nuclear inclusion body
§ Insensitive – inclusion body may be positive only in advance infection
§Immunohistochemical staining with labeled monoclonal CMV
antibody
§Electron microscopic examination of CMV in biopsy specimen

48. Diagnosis of CMV infection
§Histopathology

49. Diagnosis of CMV infection
§Viral culture
§Culture of urine, buffy coat, throat, BAL fluid
§Conventional culture – take weeks to process
§Detect typical cell cytopathic effect
§Rapid shell-vial culture technique : can be processed in 24
to 48 hours
§fluorescence tagged monoclonal antibody is used to
detect a CMV antigen expressed early in viral replication
§Not as sensitive as conventional culture

50. Diagnosis of CMV infection
§Serology
§Acute/convalescent
§CMV IgG or single IgM titer
§fourfold increase in CMV-IgG titer or a markedly
positive CMV-IgM titer may be used to suggest
recent infection
• Useful for screening but less useful for diagnosis of
CMV disease
• Serologic response may be delayed or absent in
primary infection

51. Diagnosis of CMV infection
§Nucleic acid detection, antigen detection
§pp65 antigenemia assay – detect CMV pp65 antigen
in peripheral blood lymphocytes

52. Diagnosis of CMV infection
§Level of viral load and CMV disease
Gregory D. Hart et al ,Transplantation 1999; 68:1305

53. Diagnosis of CMV infection
§Clinical utility of quantitative molecular CMV assays
§Monitoring response to therapy
§>90 percent reduction in viral load after therapy for
CMV infection
§Patients with documented ganciclovir resistance
have persistently elevated viral load (20,000 to
70,000 copies/mL ) after 2 weeks

54. administration of
antiviral medication either to all
patients or to a selected cohort
of ‘at-risk’ patients. antiviral
medications are
usually started in the first 10
days after Tx
and continue for approximately
100 days after Tx
Universal prophylaxis
Kotton, C. N. Nat. Rev. Nephrol. 6, 711–721 (2010)
Pre-emptive therapy
-laboratory tests: regular
intervals (often weekly) to
detect early, asymptomatic.
-viral replication reaches a
certain assay
-ideally before the
development of symptoms,
-antiviral therapy-- initiated to
prevent the progression to
clinical disease.
Strategies for CMV prevention

55. §Monitor whole blood quantitative CMV-PCR weeklyx12-16
wks
§CMV PCR+,>500-2000 copies/ml to do
1. stop antimetabolite drugs
2. evaluate&f/u weekly quantitative PCR
3. treat with valganciclovir at least 21d in asymptomatic or
mildly disease
4. iv ganciclovir for invasive disease
Preemptive strategy

56. Indirect effect

57. Multicenter, RCT, double-blindD+/R-
Valganciclovir : 900 mg/day
Primary efficacy : develop CMV disease in 52 wk
Secondary : BPAR, CMV Disease at : 6 & 9 mo, OI, PTDM
Background : Prophylaxis 3 mo à
increase late CMV infection--- prolong duration??

58. This study demonstrates valgancyclovir prophylaxis (900mg/
day) to 200 days significantly reduces the incidence of CMV
disease and viremia through to 12 mo compared with 100 days’
prophylaxis,
-----The NNT : avoid CMV disease = 5.

59. Oral Valganciclovir Is Non-inferior to Intravenous
Ganciclovir :VICTOR TRIAL
§Randomized multicenter trial : 42 center (N=321)
§IV Gancyclovir 5mg/kg twice daily (D1-21 ) then valgancyclovir 900mg/day Vs
valgancyclovir 900mg/day BID
§Primary outcome : eradicated CMV viremia-- D21
A. A sberga: American Journal of Transplantation 2007; 7: 2106–2113
CMV disease Viremia

60. A. A sberga:American Journal of Transplantation 2007; 7: 2106–2113
Oral valgancyclovir = IV gancyclovir
Inclusion : Mild to moderate CMV disease
Reduction in CMV viral load with time

61. Prophylaxis of CMV disease
American Journal of Transplantation 2009; 9 (Suppl 3): S44–S58
§ CMV prophylaxis:
§ We recommend that KTRs (except when donor and recipient both have
negative CMV serologies) receive chemoprophylaxis for CMV infection
with oral ganciclovir or valganciclovir
§ for at least 3 months after transplantation (1B)
§ for 6 weeks after treatment with aT-cell–depleting antibody. (1C)

62. Treatment of CMV disease
American Journal of Transplantation 2009; 9 (Suppl 3): S44–S58
§ All patients with serious (with tissue invasive) CMV disease be treated
with IV ganciclovir. (1D)
§ CMV disease in adult KTRs that is not serious (e.g. episodes that are
associated with mild clinical symptoms) be treated with either IV
ganciclovir or oral valganciclovir. (1D)
§ Continuing therapy until CMV is no longer detectable by plasma NAT
or pp65 antigenemia. (2D)
§ Suggest reducing immunosuppressive medication in life-threatening
CMV disease, and CMV disease that persists in the face of treatment,
until CMV disease has resolved. (2D)

63. Treatment of CMV disease
§Standard treatment
§Intravenous Ganciclovir 5 mg/kg every 12 hours
continue for 2-3 weeks
§Valganciclovir 900 mg twice daily for 21 day
§Reduction of immunosuppressive drugs if disease is
severe
§Patients with ongoing risk factors should receive
maintainance immunosuppressive therapy

64. §Leucopenia,granulocytopenia***
§Thrombocytopenia
§Azoospermia
( due to direct inhibit sperm-producting cells)
§Mild elevation serum Cr
• Usually reversible after reducing dose or stop drug
• Prevent with concomitant recombinant G-CSF
Ganciclovir : Toxicity

65. Monitoring of CMV disease
American Journal of Transplantation 2009; 9 (Suppl 3): S44–S58
§ In patients with CMV disease, we suggest weekly monitoring of CMV by NAT
or pp65 antigenemia. (2D)

66. Intelligence dialysis center
Nephrology Unit
Phramongkutklao Hospital and College of Medicine