Adenovirus and graft versus host disease in the kidney

A young man with a myelodysplastic syndrome status post allogeneic bone marrow transplant was recently found to have graft-versus-host disease (GVHD) of the skin and presumed liver involvement which was treated with tacrolimus and methotrexate. The increased immunosuppression was complicated by an upper respiratory tract infection which was treated with empiric cefepime; also, at that time,  a nasopharyngeal swab culture tested positive for rhinovirus.

The patient was discharged on amoxicillin-clavulanate to complete a 14-day course. A few days later, the patient presented to the hospital with dysuria and hematuria. Kidney function was within normal limits (creatinine 0.6-0.8 mg/dL) on admission and he was diagnosed with rhinovirus infection again. Additionally,  he was found with a concomitant adenovirus infection, confirmed with culture and DNA PCR amplification test (2,250,000 copies/ml). Also, the patient developed acute kidney injury (AKI) with a rise in creatinine up to 1.32 mg/dL. He had 5.6 grams of proteinuria on 24 hour urine collection and he was presumed to have adenovirus related hemorrhagic cystitis.

A renal biopsy was performed for further management of the acute kidney injury, revealing signs of both GVHD and adenovirus infection. In order to treat the patient’s GVHD of the native kidney he was given methylprednisolone and was continued on tacrolimus. Furthermore, for the hemorrhagic cystitis due to adenovirus infection, he was given intravesicular and intravenous cidofovir, probenecid, in addition to hyperbaric oxygen. The patient’s kidney function improved, however, he had recurrent AKI due to obstructive nephropathy due blood clots, for which he underwent bilateral stent placement. At the time of discharge, the patient was hemodynamically stable and kidney function was almost at his baseline.

According to the National Institute of Health (NIH) consensus criteria, Acute GVHD usually happens within the first 100 days after transplant, then it becomes chronic.  Classification is based mostly on clinical findings, rather than period of time. Acute GVHD is characterized by maculopapular rash, nausea and vomiting, diarrhea, ileus or hepatitis;  persistent, recurrent, or late-onset GVHD have symptoms of acute GVHD but it presents after 100 days, without features of chronic GVHD. Overlap GVHD happens when the patient has both symptoms of acute and chronic GVHD. It has been reported that patients with overlap syndrome have increased morbidity and mortality. GVHD rarely affects the kidney and usually presents after decreasing immunosuppressive therapy. In the chronic form it usually causes nephrotic syndrome such as membranous glomerulonephropathy and minimal change disease; less commonly it can cause focal segmental glomerulosclerosis, IgA nephropathy, and membranoproliferative glomerulonephritis.

First line therapy includes corticosteroids either topical or intravenous, depending on the stage. When the GVHD is grade I limited to the skin, it is treated with topical corticosteroids and possible adjustments of the patient's methotrexate and tacrolimus . Grade II GVHD or higher is treated with high-dose systemic corticosteroids- usually 2 mg/kg/day of intravenous methylprednisolone or oral steroids. Finally, extensive GVHD is treated with high-dose systemic corticosteroids, and occasionally with cyclosporine with trough levels of 200-450 ng/ml. Tacrolimus has been used in some case reports.

Adenovirus may cause an upper respiratory tract infection. It can cause a tubulointerstitial nephritis and hemorrhagic cystitis which affects the kidney as well, usually seen after a renal transplant. Diagnosis can be made by viral culture, viral antigen assay and PCR. Renal biopsy is needed for definitive diagnosis of renal involvement. On light microscopy, we can see necrotizing granulomas with interstitial nephritis and electron microscope shows icosahedral virions that form large paracrystalline aggregates with the nuclei of infected cells. Current treatment is with cidofovir with probenecid to decrease its nephrotoxic effects. Concurrently, if the patient is on immunosuppressive therapy, it should be decreased to promote immune recovery. Hyperbaric oxygen has been shown to treat radiation and cyclophosphamide induced hemorrhagic cystitis, and according to several small case reports, it has been used to treat adenovirus-induced hemorrhagic cystitis.

In conclusion, this is a unique case not commonly encountered in which a patient suffered from adenovirus infection and GVHD, concomitantly. Renal biopsy is generally required for diagnosis and when both diseases are present, there is a challenge on how to manage immunosuppression.

Cassiopia Lippold, MD
Second year Nephrology Fellow
University of Maryland Medical Center