—  SPECIALTY CONFERENCE  —

Infectious Disease Pathology

Case 1 - Tubulointerstitial Nephritis Secondary to Adenovirus Infection

Amy L. Adams, Emory University, Atlanta, GA





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Clinical History
The patient is a 63 year old man who underwent deceased donor renal transplant for end-stage renal disease secondary to presumed systemic arterial hypertension. He received anti-thymocyte globulin induction, followed by a maintenance immunosuppressive regimen of tacrolimus, mycophenolate mofetil, and prednisone. On post-operative day (POD) 12 he presented to clinic complaining of poor p.o. intake, dizziness, decreased urine output, dysuria, occasional hematuria, and watery diarrhea since his discharge on POD 3. He reported no history of fever. Upon examination he was found to be hypotensive with a blood pressure of 66/44 mmHg. Initial labs revealed a serum creatinine of 5.7 mg/dl, increased from a nadir of 2.4 mg/dl (normal range 0.7-1.2 mg/dl). Urinalysis showed 100 mg/dl protein, large blood, and trace leukocyte esterase. He was admitted to the Inpatient Transplant Service for treatment and evaluation. With no improvement in his renal function after aggressive IV hydration, the patient underwent renal biopsy which was interpreted as acute cellular rejection, Banff grade I-B. He was started on a 3-day steroid pulse. Urine and blood cultures, as well as stool samples for culture, ova and parasites, and Clostridium difficile toxin, were all negative. His creatinine had improved to 4.41 mg/dl at the time of discharge on POD 15. On POD 20 the patient again presented to clinic with a 2-day history of decreased p.o. intake, chills, diffuse body aches, nausea, and soft stools. He had been unable to tolerate his medications in the 2 days prior to admission. Laboratory analysis showed a persistently elevated creatinine of 4.77 mg/dl and a subtherapeutic tacrolimus level. He was admitted and treated with a 10-day course of anti-thymocyte globulin, given the previous history of rejection and lapse in his immunosuppressive medications. With no significant improvement in creatinine despite this, a second renal biopsy was performed.

Pathological/Microscopic Findings and any Immunohistochemical or Other Studies:
Histologic sections reveal two cores of renal parenchyma, predominantly cortex, with essentially unremarkable glomeruli. The interstitium contains a marked degree of inflammation, consisting mainly of plasma cells and lymphocytes. Severe tubulitis is present, with occasional tubules exhibiting obliterative tubulitis. Focally, the tubules display a distinctive coagulative necrosis of the tubular epithelium. A few tubular epithelial cell nuclei appear enlarged with "smudgy" chromatin. Occasional poorly formed granulomas are identified around the injured tubules. Immunoperoxidase stains for C4d, polyomavirus, and cytomegalovirus are negative; however, an immunoperoxidase stain for adenovirus is strongly positive.

Follow-up laboratory analysis demonstrates positive direct immunofluorescence staining for adenovirus in a urine sample which is subsequently culture-positive for adenovirus. Quantitative real-time PCR for adenovirus is positive in serum (2,856 copies/ml) and urine (399,376 copies/ml) (reference range < 500 copies/ml).


Case 1 - Figure 1
Biopsy #1, overview (H&E, 2X)
Case 1 - Figure 2
Biopsy #1, localized severe tubulitis (H&E, 10X)
Case 1 - Figure 3
Biopsy #1, severe tubulitis (H&E, 20X)
Case 1 - Figure 4
Biopsy #2, marked interstitial inflammation and tubular dropout (H&E, 2X)

Case 1 - Figure 5
Biopsy #2, vaguely granulomatous interstitial inflammation (H&E, 10X)
Case 1 - Figure 6
Biopsy #2, necrosis of tubular epithelium, (H&E, 20X)
Case 1 - Figure 7
Biopsy #2, coagulative necrosis of tubular epithelium (H&E, 20X)
Case 1 - Figure 8
Biopsy #2, necrosis of tubular epithelium with "smudgy" intranuclear inclusions, (H&E, 40X)

Case 1 - Figure 9
Adenovirus immunoperoxidase stain (10X)
Case 1 - Figure 10
Adenovirus immunoperoxidase stain (20X)

Differential Diagnoses:
The differential diagnosis of acute renal failure status-post renal transplant is broad but commonly includes acute cellular or antibody-mediated rejection, acute tubular necrosis, bacterial or viral infection, or recurrent disease. Adverse drug reactions, such as calcineurin-inhibitor toxicity or acute interstitial nephritis, may occasionally occur as well.

Final Diagnosis:
Tubulointerstitial nephritis secondary to adenovirus infection

Case Discussion:
Acute renal failure in a renal transplant patient may be the end result of a variety of disease processes, and the appropriate treatment rests on determination of the correct etiology. Commonly, the differential diagnosis in this setting includes acute cellular or antibody-mediated rejection, infection, acute tubular necrosis (ATN), recurrent disease, or drug-related injury. As the clinical symptoms of each may overlap significantly, renal biopsy is often required for definitive diagnosis. As illustrated by the current case, distinguishing between acute rejection and infection on biopsy can sometimes be difficult, given that the key pathologic features of each, namely interstitial inflammation and tubulitis, are similar. However, there are often clinical and histologic clues which may point to the correct diagnosis.

In the current case the initial biopsy showed primarily acute tubular injury with mild interstitial inflammation and focally severe tubulitis. While some degree of interstitial inflammation may be present in the setting of ischemic or toxic ATN, tubulitis is not typical; thus, while the tubular injury is likely contributing to the clinical picture in this case, a diagnosis of ATN does not explain all the biopsy findings. The two most likely diagnoses in this setting are acute rejection versus infection.

Acute rejection in the renal transplant patient may be T cell- (cellular) or antibody-mediated. Histologic hallmarks of acute cellular rejection include interstitial inflammation, consisting primarily of lymphocytes and macrophages, and tubulitis of at least 5 or more mononuclear cells per tubular cross-section. More severe cellular rejection may also show intimal arteritis or fibrinoid necrosis of arterioles and small arteries. A diagnosis of acute antibody-mediated rejection requires that three criteria must be met: (1) morphologic evidence of tissue injury including ATN, peritubular capillary inflammation, or arterial fibrinoid necrosis, (2) evidence of complement component C4d deposition in the peritubular capillaries, and (3) circulating anti-donor antibodies. Bacterial or viral infections involving the renal allograft may also result in a biopsy which shows interstitial inflammation and tubulitis.

Bacterial pyelonephritis can occur in transplant patients, often resulting from the same organisms as seen in the non-transplant population, including Enterococcus sp., Escherichia coli, Enterobacter cloacae, Klebsiella sp., Pseudomonas sp., and Proteus mirabilis. In the case of bacterial pyelonephritis neutrophils, rather than lymphocytes, predominate in the interstitium and tubules. While neutrophilic inflammation and tubulitis can occur in acute rejection, neutrophils are more common in antibody-mediated rejection, in which case the presence of C4d and anti-donor antibodies along with a negative urine culture, should help distinguish it from bacterial pyelonephritis.

Viral infections of particular significance in the renal allograft include polyomavirus, cytomegalovirus, and adenovirus. Polyomaviruses, which include BK, JC, and SV-40 strains, are ubiquitous, double-stranded, non-encapsulated DNA viruses which do not produce disease in non- immunocompromised hosts. However, in renal transplant recipients the BK strain, which is the most common strain involved in these cases, may reactivate due to immunosuppression, resulting in interstitial inflammation, tubulitis, and fibrosis. Some cases of polyomavirus nephropathy exhibit characteristic amorphous, basophilic, "ground-glass" nuclear inclusions, but in others the nuclear changes are more subtle. The diagnosis can be confirmed by the presence of nuclear reactivity with an immunoperoxidase stain utilizing antibody to the SV-40 large T antigen, which cross-reacts with both the BK and JC strains.

Cytomegalovirus (CMV), a member of the herpesvirus family, is a significant pathogen in the solid organ transplant population, where disease may occur due to a new infection or reactivation of a latent infection, often in the first 3 months post-transplant. While symptoms generally include a flu-like syndrome, some patients also develop tissue- invasive disease which may involve the gastrointestinal tract, liver, heart, pancreas, lungs, or kidneys. Fortunately, CMV nephritis in the renal allograft has become quite rare, due to careful serologic screening and effective antiviral therapy. Histologic features of CMV infection involving the kidney include focal viral cytopathic effect involving the tubular epithelium and occasionally the endothelium. The infected cells are enlarged and contain the typical "owl's eye" nuclear inclusion, a central round nuclear inclusion surrounded by a halo. Other inclusions which may be seen include homogenous, smudgy nuclear inclusions and small basophilic cytoplasmic inclusions. These features may be accompanied by a nodular mononuclear inflammatory infiltrate, which sometimes can be vaguely granulomatous. When the typical histologic features are present, the diagnosis can be confirmed with an immunoperoxidase stain for CMV.

Adenovirus has become an increasingly recognized pathogen in renal allografts, often producing a dramatic histologic picture best characterized as necrotizing tubulointerstitial nephritis. Microscopic features include marked interstitial inflammation, severe destruction of tubules, and foci of tubular (and even cortical) necrosis. The inflammatory infiltrate, which consists primarily of mononuclear and plasma cells with prominent neutrophils in areas of necrosis, can also sometimes be granulomatous. The tubular epithelial cells may display viral cytopathic effect including nuclear enlargement and smudgy, "ground-glass" nuclear inclusions. As with polyomavirus and CMV, the diagnosis is confirmed with immunohistochemistry.

In our index case, the findings of severe tubulitis, vaguely granulomatous interstitial inflammation, coagulative necrosis of the tubular epithelium, and "smudgy" nuclear inclusions are characteristic of adenovirus nephritis. Immunohistochemical staining for adenovirus, which was also subsequently performed on the initial biopsy, was positive in both samples, confirming the diagnosis of adenovirus nephritis. The patient improved with ribavirin therapy. Upon follow-up 24 months later, he was doing well with no episodes of rejection and a stable baseline creatinine of 2.64 mg/dl.

Review of the Literature/Treatment Options :
Adenovirus is a large, non-enveloped, double-stranded DNA virus. Currently, fifty-three human adenovirus serotypes have been identified, belonging to species A-G. The virus can be transmitted by way of respiratory droplets or fecal- oral contamination. In the immunocompetent host, infections are relatively common, primarily occurring in children under the age of five. Clinical manifestations in this population include mild, self-limited upper and lower respiratory tract infections, gastroenteritis, or conjunctivitis. The various serotypes each show some predilection for a particular organ or tissue; for example, upper respiratory tract infection is primarily caused by serotypes from subgroup C, while lower respiratory tract infection is often caused by serotypes from subgroup B. Gastrointestinal infection is often due to subgroups D and F, and conjunctivitis is typically associated with serotypes of subgroup D. Infection usually results in antibody production and subsequent immunity to the responsible serotype; however, some patients may continue to shed the virus in their stool for months after initial infection, and others may develop persistent asymptomatic infection due to the virus residing in lymphoepithelial tissues, a scenario which may have implications for patients requiring transplant or immunosuppression.

In the transplant population, adenovirus infection has long been identified as an important complication in stem cell transplant recipients where it affects up to 40% of pediatric and 10% of adult patients. Infection in solid organ transplant (SOT) patients is somewhat less common, involving approximately 5-10% of cases. In this latter population, adenovirus infection has been identified in liver, intestine, renal, lung, and heart transplant patients. Mirroring the pattern observed in immunocompetent patients, adenovirus infection in SOT recipients is more frequent in children. Infection most commonly occurs in the first few months post-transplant, and most are asymptomatic or mild and self-limited. More severe infection often shows a predilection for involving the transplanted organ, i.e., hepatitis in the liver allograft, colitis in the case of the intestinal transplant, and hemorrhagic cystitis/nephritis in the renal allograft.

Hemorrhagic cystitis due to adenovirus, involving both immunocompetent and immunocompromised patients, has long been documented, but reports of adenovirus nephritis in renal allograft recipients have emerged more recently, perhaps due, in part, to the current use of potent lymphocyte-depleting induction agents. Subclinical, asymptomatic adenovirus infection is not uncommon in renal transplant patients, where the incidence of viremia is 6.5%. While reports of adenovirus nephritis in the kidney are still relatively uncommon, awareness of this pathogen in the renal transplant population is of the utmost importance to allow for appropriate diagnosis and treatment. In addition to the characteristic histopathologic features with supporting immunohistochemistry as outlined above, the diagnosis may be also confirmed by polymerase chain reaction performed on urine or serum. Viral culture and direct antigen identification using radioimmunoassay, immunofluorescence, or ELISA are less sensitive for detecting low levels of virus and may miss early cases.

There is no definitively established treatment for adenovirus nephritis in renal transplant recipients. Reduction of immunosuppression is the mainstay of treatment. Antiviral therapy with agents such as ribavirin and cidofovir has shown somewhat mixed results. While cidofovir has perhaps demonstrated greater efficacy, renal toxicity due to the drug remains a concern. Despite a variety of therapeutic approaches, in general published reports of adenovirus nephritis in the renal allograft describe resolution of infection with a favorable outcome. Occasional cases complicated by subsequent episodes of rejection have resulted in graft loss.

Conclusion(s):
  1. A detailed clinical history is important in the assessment of the post-transplant renal biopsy, as the pathologic features of acute rejection and infection may be similar.

  2. Adenovirus is an important viral pathogen which may involve the renal allograft, and awareness of the characteristic histologic features is important to allow for accurate diagnosis.

  3. Treatment of adenovirus nephritis in the renal transplant patient involves supportive care, reduction of immunosuppression, and in some cases antiviral therapy.

  4. Based upon the limited number of case reports in the literature, the prognosis of adenovirus nephritis in the renal transplant setting overall appears favorable.


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