Polyoma Virus Infections in Kidney Transplantation

1
Polyoma Virus Infections in Kidney Transplantation

• Emilio Ramos, MD
• Associate Professor of Medicine
• Division of Nephrology
• University of Maryland School of Medicine
• Baltimore, Maryland

2
Human Polyoma Virus (HPV) Background

• Double stranded DNA viruses (40-45 nm)
• The sub-group of polyoma includes
• JC
• BK
• SV40
• JC is primarily associated with progressive
  multifocal leukoencephalopathy
• JC and BK have been associated with pathological
  changes in the urinary tract
• SV40 can also co-infect renal transplants

3
The Viral Capside
The viral capside is formed by 72 pentameres of
VP1 protein
4
JCV Structure and Proteins
5
Viral Host Cell Interactions

• Virions attach to the surface.
• Surface membrane invaginates, forming smooth
  vesicles that enclose the virion.
• The vesicles fuse with a system of smooth tubules
  through which the virions reach the nucleus.
  

• Production of early proteins (mainly T antigen)
  regulates cellular functions leading to
  productive infection.
• At later stages, the transcription of late
  proteins results in production of capside
  components (VP1, VP2, VP3).

6
Viral Host Cell Interactions Advanced Stages

• Infected host cell shows an enlarged nucleus
  containing thousands of virions.
• Cellular functions are impaired.
• Sloughing of infected cells with this feature in
  urine is common (decoy cells).

• Viral cell lysis occurs as mechanisms to maintain
  integrity of cellular membranes fail.
• With cellular fragmentation virions shed in the
  extracellular space
• Adjacent cells may become infected

7
Polyomavirus Infection
Fishman JA. N Engl J Med. 2002347527-530.
8
Human Polyoma Virus Epidemiology

• HPV are ubiquitous
• Positive serology is found in 65-100 of the
  population depending on age group and
  geographical location
• Infection with BK occurs in childhood through the
  respiratory route
• In the latent stage the virus localizes in the
  renal epithelium
• Active infection and associated clinical disease
  have been demonstrated only in immunosuppressed
  patients

9
Viral Activation Risk Factors

• Viral reactivation occurs when cellular immunity
  is lowered
• Pregnancy
• Immunosuppression
• Uncontrolled diabetes
• AIDS
• Corticosteroid therapy
• Cytotoxic drugs

10
Human Polyoma VirusHistorical Background

• 1971, the first case of HPV in a renal transplant
  patient was described (BK initials of patient)1
• 1978, pathogenicity of BK and JC remained
  unclear2,3
• 1978-9, several studies confirmed the
  pathogenicity of PV in renal allografts
• increasing BK antibody titers correlated with
  progressive reduction in renal function in 45 of
  patients4
• 1980s (BK forgotten??)

1. Gardner SD, et al. Lancet. 197111253-1257.
2. Anonymous. Lancet. 19782876-877. 3.
Harrison P, et al. Lancet. 197821150. 4.
Andrews CA, et al. J Infect Dis. 1988158176-81
11
Human Polyoma VirusCurrent

• 1995-present, marked increase in the number of
  reported cases
• Of the many infectious processes that affect
  renal transplant patients, HPV currently
  attracts the most attention
• Probably secondary to the use of the more potent
  immunosuppressive drugs
• Mycophenolate mofetil (MMF)
• Tacrolimus (FK506)
• Cyclosporin (CSA)

12
Human Polyoma Virus Histology
Courtesy of St. Marys Hospital, London, UK
13
Clinical Significance

• Affects 2-8 of renal transplants
• Selective tendency to affect the transplanted
  kidney leading to allograft dysfunction and
  premature graft loss
• Up to 45 of patients with biopsy proven PV have
  been reported to lose their grafts prematurely
• No specific treatment available
• With decrease in immunosuppression, improvement
  in some patients
• Unpredictable course

14
Clinical Manifestation

• Asymptomatic viruria
• Pyuria
• Renal dysfunction
• Ureteral stenosis
• Hemorrhagic cystitis

15
Clinical Diagnosis

• Currently due to the lack of better markers of
  the disease, the observation of viral cytopathic
  changes in a renal biopsy with confirmation by
  immunohistochemistry, electron microscopy or PCR
  studies is considered as the only useful tool for
  the diagnosis of PVN in renal allografts

Randhawa PS, Demetris AJ. N Engl J Med.
20003421361-1363.
16
Latent Infection
17
Limited (Low Level) Viral Replication

• Mostly limited to the urothelium
• Common in immunosupressed patients
• May occur rarely in healthy individuals, i.e.
  pregnant women
• 20-65 of renal transplant patients
• Transient or intermittent viruria
• Decoy cells on urine cytology
• Viruria with PCR methods
• No viremia
• No clinical significance normal renal function

18
High Level Viral Replication With Tissue
Destruction

• Allograft nephropathy in a minority of renal
  transplant patients (5-10)
• Persistent viruria
• Decoy cells on urine cytology
• Significant viruria by quantitative PCR
• Viremia
• Abnormal renal function if parenchymal disease is
  extensive

19
Immunohistochemical Staining for SV-40, BK
Nephropathy
Courtesy of Dr. Cynthia Drachenberg, University
of Maryland.
20
Large Amount of Intranuclear Virons
Courtesy of Dr. Cynthia Drachenberg, University
of Maryland.
21
Nephritis PatternsDrachenberg Criteria
Courtesy of Dr. Cynthia Drachenberg, University
of Maryland.
22
Nephritis PatternsDrachenberg Criteria
Courtesy of Dr. Cynthia Drachenberg.
23
Nephritis PatternsDrachenberg Criteria
PATTERN C Rare viral cytopathic changes in
atrophic tubules, in a background of extensive
tubular atrophy/fibrosis and chronic inflammation
(end-stage PVAN)
Courtesy of Dr. Cynthia Drachenberg, University
of Maryland.
24
Clinical Diagnosis Urine Cytology

• Useful for the screening of immunosuppressed
  patients, ie., renal tx, bone marrow tx
• Up to 30 of renal transplant recipients have
  decoy cells in the urine, whereas the incidence
  of histologically proven BK nephritis is
  significantly lower
• Transient positivity is not important
• Persistent positivity is strongly predictive of
  BK nephritis

25
Usefulness of Urine Cytology in Patients With
Graft Dysfunction

• Negative predictive value 99-100
• Positive predictive value 90
• Sensitivity 96.7
• Specificity 97
• Accuracy 97
• (correct classification
• of patients as having PV or not)

26
Urine Sediment Decoy Cells
Courtesy of Dr. Cynthia Drachenberg, University
of Maryland.
27
HPV Nephritis Clinical Diagnosis

• Urine cytology
• Quantitative viral load in plasma
• Quantitative PCR in urine
• Quantitative viral load in tissue

28
Viral Load Quantification

• 78 renal transplant recipients
• 23 decoy cells shedding
• 10 BK viremia (2,000 copies per ml)
• 5 PVN (28,000 copies per ml)
• The viral load in plasma was higher in patients
  with PVN than in those without nephropathy
  (Plt.001)

Hirsch HH, et al. N Eng J Med. 2002347488-496.
29
The University of Maryland Experience

• 96 Patients with PVN (1997-2002) out of 2,212
  Renal Transplant Recipients
• 70 males (73)
• 26 females (27)
• 40 living donors (42)
• 56 cadaveric donors (58)
• Mean age 53 years (12-79)

Ramos E, et al. Clin Transpl. 2002143-153
30
The University of Maryland Experience

• Among recipients of cadaveric kidneys
• 44.6 DGF
• 23.2 acute rejection
• Among recipients of living donors
• 10 DGF
• 25 acute rejection
• No statistical difference in presence of DGF or
  acute rejection between the group with BKAN and
  the control group

BKANBK-associated nephropathy DGFdelayed graft
function
Ramos E, et al. Clin Transpl. 2002143-153
31
The University of Maryland Experience

• Immunosupression
• 89 patients FK506, MMF, prednisone
• 5 patients CSA, MMF, prednisone
• 1 patient CSA, azathioprine, prednisone
• 1 patient FK506, azathioprine, prednisone
• Baseline Cr mean 1.6 mg/dL (0.5-4)
• Cr at diagnosis mean 2.7 mg/dL (0.9-5.1)
• Follow-up after diagnosis Mean 16.8 months
  (range 2-61.7)
• Follow-up after transplantation Mean 31.3 months
  (range 5.8-78)

Cr creatinine Csacyclosporin
FK506tacrolimus MMFmycophenolate mofetil
Ramos E, et al. Clin Transpl. 2002143-153
32
Graft Outcome in Patients With BKAN
8
41
30
21
BKANBK-associated nephropathy
Ramos E, et al. Clin Transpl. 2002143-153
33
Incidence of BKAN Per Year of Transplant
Number of Patients (x100)
Year of Transplantation

January to October 2002
Ramos E, et al. Clin Transpl. 2002143-153
34
Graft Survival in Patients With BKAN
Kaplan Meier Analysis of Graft Survival in
patients with histological diagnosis of BK
associated nephritis (BKA-N) vs the group
without BKA-N. P0.000 by long-rank test
Ramos E, et al. Clin Transpl. 2002143-153
35
Algorithm For Early Diagnosis of PVN
Ramos E, et al. Clin Transpl. 2002143-153
36
Polyoma Virus Nephritis Treatment

• Judicious decrease in immunosuppression
• Tacrolimus levels (6-8 ng/ml)
• CSA levels (75-100 mg/ml)
• Sirolimus levels (12-15 ng/ml)
• Half or discontinue MMF
• Cidofovir
• Leflunomide
• Quinolones
• Careful monitoring for evidence of rejection

37
Graft Survival

• BK 67 patients with graft dysfunction and PV in
  biopsy and urine.
• Mean follow up 26 months.
• Control 162 patients with graft dysfunction and
  no evidence of PV in biopsy and urine.
• Mean follow up 25.3 months.

Ramos E, et al. J Am Soc Nephrol.
2002132145-2151.
38
PVN Summary

• New immunosuppressive drugs since the 1990s, have
  resulted in a significant decrease in acute
  rejection rates but PV-associated disease has
  reemerged
• Graft loss secondary to BKAN or a combination of
  rejection and BKAN is significant, occurring in
  up to 60 of patients in early reports
• Early diagnosis and decrease in
  immunosuppression, resulted in a less dire
  outcome with only 30 of patients with BKAN
  losing graft function after a mean follow-up of
  26 months1

1. Ramos E, et al. Clin Transpl . 2003 (in press.)
39
Retransplantation in Patients with Graft Loss Due
to PVN

• In 1996, a 40-year-old woman lost her cadaveric
  transplant kidney to PVAN 160 days following
  transplantation
• She had a transplant nephrectomy followed 4
  months later by a living related kidney
  transplant
• Three and a half years later, the kidney
  continued to function well on a combination of
  prednisone, azathioprine and tacrolimus
• She had negative quantitative and qualitative PCR
  assays for BK virus in blood and urine

Poduval R, et al. Transplantation
2002731166-1169.
40
Retransplantation in Patients with Graft Loss Due
to PVN

• Conversely, a 35 year old man who received a
  simultaneous pancreas-kidney transplant had
  recurrence of BKAN 5 months after
  retransplantation.
• Renal function gradually deteriorated and the
  patient returned to hemodialysis 12 months
  following the second transplant.
• In this patient preemptive cadaveric renal
  transplantation was done simultaneously with the
  removal of the first transplanted kidney.

Boucek P, et al. Transplantation. 2002 74 1478.
41
Current Retransplant Data

• Retrospective data on retransplanted patients
  from 5 US centers.
• University of California, San Francisco
• University of Tennessee, Memphis
• University of Pittsburgh, Pittsburgh
• Inova Hospital, Fairfax, Virginia
• University of Maryland, Baltimore

42
First Transplant

• Tx Nephrec

• Time from
• BK to ESRD

• Time from
• Tx to BK

• IS prior
• to BK

• Type of 1st Tx

• Pt

• No

• 12

• 94

• FK/MMF/Pred

• LRT

• 1

• No

• 42

• 2

• FK/MMF/Pred

• CRT

• 2

• No

• 18

• 15

• FK/MMF/Pred

• CRT

• 3

• Yes

• 9

• 11

• Aza/FK/MMF/Pred

• CRT

• 4

• Yes

• 6

• 9

• FK/MMF/Pred

• SPKT CRT

• 5

• Yes

• 7

• 29

• FK/MMF/Pred

• SPK CRT

• 6

• Yes

• 3

• 15

• CSA/MMF/Pred

• LRT

• 7

• Yes

• 12

• 8

• CSA/MMF/Pred

• SPK

• 8

• Yes

• 4

• 14

• CSA/MMF/Pred

• SPK

• 9

• Yes

• 12

• 12

• FK/MMF/Pred

• CRT

• 10

Ramos E, et al. Transplantation. 200477131-133.
43
Retransplant
44
Conclusion

• From the presented study, we can conclude that
  patients with graft loss due to BKAN can be
  safely re-transplanted.
• The risk of recurrence appears to be similar to
  that in the general renal transplant population.
  
• Neither nephroureterectomy of the infected graft
  prior the retransplantation, nor selection of a
  different immunosuppressive regime appear to
  influence the risk of recurrence of BKAN.
• An extended follow-up period is needed to
  definitively ascertain the long-term outcome in
  these patients

45
Acknowledgements

• Cinthia Drachenberg, MD
• Miguel Portocarrero, MD
• Matthew Weir, MD
• Hans Hirsch, MD
• Ravinder Wali, MD
• David Klassen, MD
• Stephen Bartlett, MD
• Eugene Schweitzer, MD
• Ann Wiland, PharmD
• The nurses and clinical coordinators of the
  transplant team