Kidney and Liver Transplant - Update and Issues
Case 7 -
Renal and Hepatic Transplant Infections
Arthur H. Cohen, Juan Lechago and Cynthia C. Nast
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Allografts are susceptible to the same infections as are native organs, and such abnormalities as
acute infectious interstitial nephritis, xanthogranulomatous pyelonephritis, and hepatitis B and C will
not be covered in this part of the course. Excluding these, the most common viral infections impacting
kidney and liver allografts will be addressed herein. Viral infections occur in approximately 35% of
renal allografts, resulting in significant short and long term graft dysfunction. The viral agents
discussed below are those most likely to confront the transplant pathologist with unique features ,
disease of major consequence to the organ recipient.
Cytomegalovirus (CMV) is one of the most frequent infectious agents in both
liver and kidney transplant recipients, accounting for more than one-third of renal allograft viral
infections, and both organs can harbor latent viral infections, which are asymptomatic in up to 75% of
. In recipients of both organs , serologic evidence of disease is observed to a greater
degree compared with parenchymal injury, the latter associated with primary infection. When there is
active renal infection, the kidney may show tubulo-interstitial nephritis with
interstitial edema and a mononuclear inflammatory infiltrate. Tubular inflammation is present to varying
degrees with associated tubular epithelial cell injury simulating acute cell mediated rejection. The
presence of viral inclusions in tubular epithelium, endothelial cells, or interstitial or circulating
monocytes is crucial in distinguishing these disease processes, while the identification of vascular
inflammation is diagnostic for acute rejection . Immunohistochemical staining can contribute to virus
identification, but PCR may induce over-expression of latent inactive virus. CMV infection can initiate
or follow acute rejection episodes
and the two entities may co-exist ; in fact CMV may induce more renal injury through initiation of
rejection than by direct viral-associated damage and may be linked to chronic vascular rejection or
chronic allograft nephropathy
. Glomerular capillary luminal monocytic inflammation was
previously thought to represent CMV infection , but in the absence of CMV inclusions is now thought
to be acute allograft glomerulopathy, a form of acute rejection [10 ]. Hepatic
allografts involved with active CMV infection have parenchymal inflammatory changes, which may
take the form of microabscesses or microgranulomas
often containing cells with CMV inclusions.
Liver biopsies also show heterogeneous inflammatory foci throughout the hepatic lobule [12 ] and chronic
injury may result . Immunohistochemical staining again aids in virus detection.
Patients with CMV infection usually present within one to four months of transplantation and may have
any of the signs and symptoms of this viral disease including fever, mononucleosis-like syndrome,
gastroenteritis, pneumonia, and neutropenia
. There may be allograft failure or hepatitis. CMV
infection may initiate reactivation of Epstein-Barr virus (EBV) infection in patients with latent EBV,
inducing additional graft injury as described below. Treatment for CMV is with appropriate anti-viral
agents such as ganciclovir.
| CMV Renal Pathology || CMV Hepatic Pathology|
| Tubulo-interstitial nephritis|
plasma cells, mononuclear cells
tubular cells, monocytes,
infected monocytes in capillaries
| Microabscess formation |
Patchy lobular inflammation
Focal hepatocyte destruction
Hepatocyte CMV inclusions
EBV occurs in transplant patients as primary infection or as a latent
infection that is reactivated. Reactivation can occur within the first week post-engraftment, and in
some patients induces a T cell response which may induce acute rejection [13 ]. However,t he primary
importance of this virus is its role in the transformation of lymphocytes and induction of a post-transplant lymphoproliferative disorder (PTLD). PTLD is found in 1-2% of renal
and 2-5% of liver allograft recipients, usually occuring between 2 and 5 years postengraftment
}. In 5-15% of cases
where malignancy develops there is a T cell lymphoma. In the kidney, the
abnormal lymphocytes are often large, with cleaved, non-cleaved, immunoblastic and plasmacytoid cells
with mitotic activity. These cells occur in dense infiltrates or nodular aggregates [18 ]. There may be
irregular patchy parenchymal necrosis, and the interstitium may lack edema or there may be concurrent
acute cell mediated rejection, which can make diagnosis more challenging particularly in the earlier
lesions [19 ]. The liver contains similar lymphoid cells in portal tracts
without eosinophils or prominent cholangitis .
EBV secondarily infects B-lymphocytes, which then undergo malignant transformation. The coincident
diminished T-cell surveillance due to immunosuppression allows the outgrowth of the transformed cells,
which then develop into the lymphoproliferative disorder
. In some cases the transformed
cells themselves may be immunosuppressive through release of viral IL-10 . Risk factors include
primary EBV infection and the intensity of the immunosuppressive regimen. The more undifferentiated the
lymphocytes become the more aggressive the lesion, with mortality rates of up to 80% for monoclonal
monomorphic PTLD. There are EBV negative PTLDs and these lesions are increasing in frequency with a
later onset at 50-60 months after transplantaton . Treatment includes reduction of
immunosuppression and anti-viral agents. Newer theraPies such as anti-CD20 are being evaluated as
adjuvant treatment. For less well-differentiated and more aggressive lesions, primary lymphoma treatment
may be indicated.
| EBV+ PTLD Diagnosis ||PTLD Classification|
| Two of 3 features required |
Oligoclonal or monoclonal population
plasma cell hyperplasia
polyclonal or monoclonal
Plasma cell rich
Polyoma virus is a member of the papovavirus family; the BK virus is
primarily the cause of polyoma-induced nephropathy following transplantation although JC virus causes
disease to a lesser extent . There are 3 distinct forms of genito-urinary injury caused by polyoma
virus, only one of which involves the renal parenchyma. In this type, which may affect up to 5% of renal
transplant recipients, polyoma infects the tubular epithelium particularly of the collecting ducts, with
resulting cytopathic changes . Infected tubular cells are enlarged with basophilic intranuclear
inclusions occasionally surrounded by halos; ultrastructurally the viral inclusions are composed of 40-45
nm paracrystalline arrays. The tubulo-interstitium may contain a minimal inflammatory infiltrate or
display a patchy or diffuse brisk tubulo-interstitial nephritis with plasma cells and tubulitis [27-29].
Immunostains for BK or SV40 (simian polyoma) are helpful in confirming the diagnosis. BK virus also
resides in ureteric epithelium and has been reported in association with ureteral stenosis in transplant
recipients . Patients with the more common tubular infection and tubulo-interstitial nephritis
present with renal dysfunction and may be on more intense triple immunosuppressive regimens with
tacrolimus and mycophenolate [31 ]. Patients can be monitored by measuring viral plasma load [32 ].
Treatment consists of reduction of immunosuppression although careful monitoring for superimposed acute
rejection is required and the virus may persist leading to early graft loss
Human herpesvirus-6 (HHV-6) infects almost all
individuals by the age of 4, and shows evidence of replication due to reactivation in approximately 30%
of liver allograft recipients. HHV-6 often replicates together with CMV in doubly infected patients,
with infection more severe than with either virus alone, and CMV may actually reactivate HHV-6
HHV-6 has been reported to worsen recurrent hepatitis C infection [38 ]. HHV-6 predominantly
infects CD4+ lymphocytes and lesser numbers of CD8+ lymphocytes, natural killer cells and macrophages,
but not hepatocytes. Following clinically relevant reactivation a systemic syndrome resembling CMV
infection is produced. The exact role HHV-6 plays in liver and renal transplantation remains to be
determined, but there are suggestions that it may cause immune reactions initiating rejection episodes in
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