Infectious mononucleosis is caused by the Epstein-Barr virus and most commonly causes a febrile illness with pharyngitis and lymphadenopathy. Complications involve the central nervous system, liver, heart, and blood. Hematuria and proteinuria have been reported in 10% to 15% of cases, but the development of acute renal failure during infectious mononucleosis is rare. In cases where renal biopsies have been performed, the most common pathology found is interstitial nephritis. There is some evidence linking Epstein-Barr virus to chronic interstitial nephritis. Steroid therapy and hemodialysis have been used, but some cases can resolve spontaneously. We wish to report a case of acute renal failure associated with an acute Epstein-Barr infection and discuss the possible pathogenesis.
*Microbiology and Infectious Diseases, †Pathology and ‡Nephrology, St Mary's, Hospital, Montreal, Quebec, Canada.
Address correspondence and reprint requests to Joe Dylewski, MDCM, Microbiology and Infectious Diseases, St Mary's, Hospital, 3830 Lacombe, Montreal, Quebec, Canada H3T 1M5. E-mail: firstname.lastname@example.org.
Infection with Epstein-Barr virus (EBV) can result in a wide spectrum of diseases ranging from classic infectious mononucleosis (IM) to fatal lymphoproliferative disease. Abnormalities in the urinalysis occur in 5% to 15% of cases, with proteinuria and microscopic hematuria being the most frequent findings.1 Renal biopsies have been performed on IM patients without clinical evidence of renal disease and have revealed glomerular swelling and focal interstitial inflammation.2 The development of acute renal failure during EBV-induced IM is rare, and the etiology is unclear.3 Most cases undergoing a renal biopsy have demonstrated an interstitial nephritis.3 We report a new case of EBV-induced acute renal failure and discuss the possible pathogenesis.
A 28-year-old man was seen complaining of a 2-week history of fatigue, anorexia, and a decrease in urinary output. He also noted a low-grade fever and chills starting 2 days before his admission to hospital. He was not on any medications, and his medical history was unremarkable. His temperature was 37.5°C, blood pressure was 102/60, and pulse rate was 102/min. There were palpable nontender anterior cervical and right axillary lymph nodes and an enlarged spleen. The pharyngeal examination was normal. His initial laboratory tests showed elevated alkaline phosphatase of 203 IU/L (reference range, 13-113 IU/L), serum alanine transaminase of 185 IU/L (reference range, 5-60 IU/L), and serum aspartate aminotransferase 87 IU/L (reference range, 10-42 IU/L). The serum sodium, potassium, chloride, and carbon dioxide were normal, but creatinine (494 μM/L; reference range, 44-123 μM/L) and urea (12.5 mM/L; reference range, 1.7-8.9 mM/L) were significantly elevated. The creatine phosphokinase level was normal. The urine had a specific gravity of 1.025 and tested positive for ketones and protein. On microscopic examination, hematuria with granular casts was present. The total white blood count was elevated at 16.7 × 109/L, with 4.5 × 109/L neutrophils, 9 × 109/L lymphocytes, and 3.1 × 109/L monocytes. Variant lymphocytes were noted but were less than 10% of the total. The hemoglobin and platelets were normal. A slide test for heterophile antibodies and an immunoglobulin M test for EBV viral capsid antigen were positive, but antibodies for EBV nuclear antigen were negative. Tests for acute hepatitis A, B, and C; human immunodeficiency virus, rheumatoid factor, and antinuclear antibody were negative. An antistreptolysin titer was not elevated. The serum complement levels were normal, but the C-reactive protein was high at 49.3 mg/L (reference range, 0-8 mg/L).
The patient was started on intravenous pulse methylprednisolone 1 g daily that he received for 3 days, and then, he was switched to oral prednisone 70 mg daily. On the second day of hospitalization, the serum creatinine had risen to 831 μM/L and 1 hemodialysis treatment was given. Within 24 hours, his urine output began to increase, and the serum creatinine dropped, so the planned renal biopsy was canceled. In hospital over the next week, the patient's condition continued to improve, and he was discharged on the ninth hospital day on tapering doses of prednisone. The serum creatinine had returned to normal when he was tested again 1 month later.
Infectious mononucleosis is caused by EBV and usually is a self-limited illness causing fever, pharyngitis, and adenopathy. Complications involving the hematopoietic, hepatic, cardiac, and central nervous systems may occur and can confound the diagnosis.1 Renal involvement was first described in 1946 when 17 of 556 military personnel with IM were noted to have microscopic hematuria and proteinuria.4 In another study, an 11% incidence of hematuria and 14% incidence of proteinuria were found.5 Renal biopsies performed in acute IM from 12 of 13 patients without clinically apparent renal disease demonstrated enlargement of the glomeruli and focal interstitial infiltrates of mononuclear cells.2
Acute renal failure associated with EBV-induced IM is a very rare occurrence. A review article in 1996 could find only 27 cases over a 30-year period.3 In 5 of these cases, myoglobinuria, caused by acute rhabdomyolysis, was the most likely cause of the renal failure. There was 1 case of hemolytic-uremic syndrome that may, in fact, have been associated with a recent diarrheal illness and not acute IM. One patient had minimal-change glomerulopathy, and 2 patients had evidence of immune-complex glomerulonephritis. Of the 18 remaining patients, 13 underwent renal biopsy, and 10 had interstitial nephritis. In a pediatric series of 165 previously healthy children with primary EBV infection, 8 had acute renal failure.6 Two underwent renal biopsies and demonstrated interstitial nephritis.
There are 2 possible explanations for the interstitial nephritis. One is that the kidney is an innocent bystander injured by activated T lymphocytes reacting to EBV antigens from infected lymphocytes passing through the kidney. Another possibility is that EBV directly infects the kidney, triggering an immune response that produces the renal failure.6-8 A predominance of cytotoxic/suppressor T cells is found in the interstitium of biopsied cases.3 The uncertainty arises from the inconsistent finding of EBV DNA from renal biopsy specimens. Early biopsy studies using in situ hybridization failed to demonstrate EBV DNA in the kidney. More recent work using polymerase chain reaction technology in patients with idiopathic chronic interstitial nephritis and in a case of acute EBV-induced renal failure demonstrated the presence of EBV DNA.7-9 As well, the receptor for EBV in B lymphocytes, CD21, was detected in proximal renal tubule cells. There was also evidence of up-regulation of CD21 in the EBV-infected cells. These studies are more supportive of a direct role for EBV infection of the kidney, provoking an immunologic response resulting in the interstitial nephritis. However in one report, a patient with chronic active EBV infection was found to have EBV-infected lymphocytes infiltrating the renal epithelium but sparing the renal tubular cells.10 These processes may lead to chronic renal disease in some patients.7,8 Our patient did not undergo a renal biopsy because he improved rapidly after receiving systemic corticosteroids and a single hemodialysis treatment. However, the laboratory findings and clinical course are in keeping with other reported IM patients with acute renal failure, many of whom did not undergo biopsy.3,6 The prognosis is usually excellent, although there are reports of death, and 1 patient required a renal transplantation.3 Corticosteroids have usually been given, but some patients have improved without any form of treatment. Acyclovir has also been used in treatment, but there are no controlled studies to demonstrate benefit.3,6
Proteinuria and hematuria seem to be common complications of acute IM, but the development of acute renal failure is unusual. Clinicians should be aware of this complication and the possible therapeutic options available.
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