The patient in question was a woman with rapidly-progressive, oliguric, acute renal failure. She had just been hospitalized with infectious mononucleosis and her Epstein Barr Virus (EBV) DNA viral load was >11,000 copies/mL. Her symptoms resolved with intravenous hydration, and she was discharged in two days. Unfortunately, the patient returned two weeks later with fevers, flank pain, and anorexia. Her exam was normal apart from mild edema. Urinalysis revealed 100 mg protein, trace ketones, 21 white blood cells, and three red blood cells. A urine protein/creatinine ratio was 0.62. Serum creatinine was 2.58 mg/dL, total CO2 was 14 mmol/L, and she had no peripheral eosinophilia. The patient was initially treated with hydration and antibiotics for presumed pyelonephritis. When a urine culture revealed no organisms and her renal function continued to deteriorate, Nephrology was consulted.
Our differential diagnoses included pre-renal azotemia, acute tubular necrosis from sepsis or hypoperfusion, post-infectious glomerulonephritis, and AIN. My sediment analysis only revealed a few granular casts. Given the patient’s normal renal function at baseline, absence of diuretic use, and oliguria, we interpreted her fractional excretion of 1.1% to indicate intrinsic renal pathology. A renal ultrasound revealed mildly enlarged kidneys with increased echogenicity. Serum complements as well as anti-nuclear and anti-neutrophil cytoplasmic antibody levels were all normal. Her EBV DNA viral load was now 220 copies/mL. The patient’s creatinine continued to rise in spite of adequate hydration and discontinuation of nephrotoxic agents, peaking at 4.04 mg/dL. By this time, she was found to have an elevated urinary eosinophil count. Despite having a positive predictive value for AIN of only 30%, the patient’s urinary eosinophils increased our post-test probability for AIN in this clinical situation. As she had no comorbidities, took no home medications, and had only received antibiotics for a few days, Epstein-Barr Virus (EBV) was presumed to be the cause.
Our patient was hesitant to undergo a renal biopsy, and as the potential benefit of corticosteroids outweighed any risks, she was empirically started on 1 mg/kg po prednisone daily. Her renal function began to improve the following day and was ultimately restored to premorbid levels at her two-week follow-up visit.
Though viral infections have long been described in textbooks as known causes of AIN, few case reports of it exist in the current literature. EBV-associated AIN was first reported in 2000 when a 17-year old patient presented with jaundice, hemolytic anemia, and acute renal failure. Serology revealed elevated EBV IgM and IgG viral capsid antibody titers, elevated IgG early antigen titers, and negative IgG nuclear antigen titers. Renal biopsy and subsequent light microscopy revealed a patchy, interstitial infiltrate comprised of lymphocytes, plasma cells, eosinophils, and neutrophils. In-situ hybridization for EBV mRNA was positive. Serum creatinine returned to normal one month after treatment with prednisone. Other cases were published with similar presentations and outcomes, but reports of EBV-associated AIN continue to be scarce.
Two competing theories exist which seek to explain the pathogenesis of EBV-associated interstitial nephritis. One suggests that kidney injury is simply collateral damage from activated T lymphocytes responding to the infection. Another theory indicates that direct toxicity from the virus itself plays a role. Is EBV-associated AIN then, a result of direct viral infection or is it a consequence of an immunologic response? The literature is conflicting. Biopsied cases of EBV-associated interstitial nephritis do reveal a predominance of cytotoxic T cells. However, Mayer et al failed to identify EBV RNA in renal biopsy tissue and instead suggested that the EBV antigens in infiltrating lymphocytes activated a massive T-cell mediated immune response. This was demonstrated once more in a 2011 study that detected no EBV DNA in renal biopsy specimens of patients with suspected AIN.
In contrast, both Bao’s and Cataudella’s analyses reported the detection of the EBV genome using polymerase chain reaction (PCR) techniques in renal biopsy samples. However, EBV DNA has since been inconsistently found in other renal biopsy specimens, and EBV DNA has been found in biopsies of patients with IgA Nephropathy and Membranous Nephropathy as well.
EBV’s direct role in infection is less debated in patients with chronic interstitial nephritis. Becker et al used in-situ hybridization and PCR techniques to show that renal biopsies of patients with “idiopathic” chronic interstitial nephritis actually had EBV genomes expressed in their proximal tubule epithelia. It is now known that asymptomatic EBV can persist within B lymphocytes and that reactivation can result in a robust, pro-inflammatory cytokine cascade.
Without more invasive testing, it is impossible to determine whether our patient’s acute renal failure was a result of the virus’s direct nephrotoxicity as opposed to a consequence of cytokine-mediated inflammation. Though she was not prescribed any antiviral agents, these are not routinely recommended in immunocompetent persons infected with EBV. In the same vein, we cannot assume her rapid improvement with corticosteroids supports the pro-inflammatory hypothesis of EBV-associated AIN.
Further studies analyzing the presence or absence of EBV DNA in patients with both AIN and chronic interstitial nephritis are needed. Such studies may provide basis for the use of corticosteroids, determine baseline characteristics of latent EBV, and help to develop our understanding of the pathogenesis of AIN in general. Cases like that of our patient’s also serve to remind us of less common causes of AIN to bear in mind when in clinic or on the wards.
Posted by Devika Nair, Vanderbilt Nephrology Fellow
