Biopsy Proven Acute Tubular Necrosis Associated with Vancomycin in a Child: Case Report and Literature Review

Abstract

Vancomycin-related nephrotoxicity typically manifests as acute tubulointerstitial nephritis. The drug does appear, however, to increase the nephrotoxicity of concurrently administered aminoglycosides. The extent of direct tubular toxicity attributable to vancomycin, especially in the absence of aminoglycoside treatment, does not appear to have been previously described. We report a case of biopsy-proven acute tubular necrosis secondary to vancomycin toxicity in a 13-year-old boy where there was no likely alternate explanation for toxic or ischemic injury. No hemodialysis was required, and the patient made a full recovery with subsequently regained renal function.

Keywords:

• acute tubular necrosis
• acute renal failure
• drug-related toxicity

INTRODUCTION

Acute renal failure in children treated with vancomycin typically presents as interstitial nephritis.[1] Less commonly, vancomycin has been associated with acute tubular injury, particularly in cases of preexisting renal disease, septic or non-septic shock, or a combination treatment with aminoglycoside, which may also contribute to renal injury.[2–4] Herein, we describe a case involving a 13-year-old boy with systemic lupus erythematosus who developed acute renal failure in the presence of elevated vancomycin levels, where there was no definite explanation for acute tubular injury. Histologically, apparent acute tubular necrosis was discovered. Conservative treatment without hemodialysis was successful in improving the renal function. A subsequent renal biopsy found acute tubular necrosis to be in remission.

CASE REPORT

A previously healthy 13-year-old boy was admitted to a medical hospital complaining of arthralgia and a fever that had begun two weeks prior to admission. The boy also reported having had neck lymphadenopathy beginning at about the same time. Systemic lupus erythematosus was diagnosed, as antinuclear antibodies were positive (titer 1:1280) and homogenous and anti-double-stranded DNA antibody was positive (>3,200 IU/mL). The patient had malar rash and renal involvement. Serum concentration of urea nitrogen was 22 mg/dL and creatinine 1.2 mg/dL on day of admission. At that hospital, toxic skin syndrome was diagnosed and vancomycin (40 mg/kg per day) was prescribed for one week. After five days of vancomycin treatment, the 6 h trough vancomycin level was found to be 85.6 ug/mL. The patient was found to have general weakness, nausea, and poor appetite. He was referred to our hospital on day 7 of admission.

Upon admission, he was found to have a blood pressure of 138/56 mmHg, heart beat of 76 beats/min, respiratory rate of 18/min, and body temperature of 36°C. There was malar rash all over his face. His conjunctiva was not pale and both eyelids were not puffy. Breathing was coarse. Palpation of the abdomen showed no hepatomegaly.

Blood workup revealed hemoglobin to be 10.4 g/dL, white blood count 4.46×10⁹/L, and platelets 260×10⁹/L. The serum concentration of urea nitrogen was 82 mg/dL, creatinine 5.6 mg/dL, sodium 119 mg/dL, and calcium 5.7 mg/dL. Urinalysis disclosed microscopic hematuria and proteinuria (0.55 grams/24 hr). Clearance of creatinine was 13.8 mL/min per 1.73m². The initial clinical diagnosis of acute renal failure was made.

Other immunology studies found antinuclear antibodies to be positive (titer 1:640) and homogenous. The C3 and C4 levels were low at 16.5 mg/dL (normal: 90–180) and 6.4 mg/dL (normal: 10–40), respectively. The direct and indirect Coombs' test were both negative. Anti-SS-A and Anti-SS-B antibodies were present. The anti-double-stranded DNA antibody was positive (>400 IU/mL). The test for anticardiolipin IgG measured by enzyme-linked immnuosorbent assay was positive. A computed tomography-guided biopsy of the left kidney was performed on day 11 of admission. Histological examination of the renal specimen revealed focal tubular dilatation with attenuation of brush border and focal calcification, as well as mild hyaline cast and a neutrophil cast in a tubular lumen, but no widespread interstitial nephritis (see Figure 1). There was no tubular atrophy or interstitial fibrosis to suggest preexisting chronic renal injury, and blood vessels were not found to be remarkable affected. Immunofluorescent staining showed IgA, IgG, IgM, C3, C1q deposition in mesangium. Electron microscopic studies disclosed segmental electron dense deposits in subepithelial area. The pathologic findings were consistent with Class V lupus nephritis with changes compatible with acute tubular nephropathy.

Figure 1. Diffuse tubular dilatation, interstitial edema, and focal interstitial small lymphocyte cell infiltrate without tubulitis. (hematoxylin and eosin; original magnification: ×100). Periodic acid-Schiff stain also reveals attenuation of brush border.

The patient received prednisolone treatment. No hemodialysis was requested. One and one-half months later, he received renal biopsy again at another medical center. Pathologic findings revealed resolution of tubular and interstitial changes and Class II lupus nephritis (see Figure 2). His laboratory results were normal. The serum concentration of creatinine was 0.9 mg/dL, and creatinine clearance was 95 mL/min per 1.73m².

Figure 2. One and one-half months later, the histology displays mesangial proliferative lupus nephritis, Class II, with a resolution of tubular and interstitial changes. (Periodic acid-Schiff, original magnification: ×400.)

DISCUSSION

Herein, we report a case of acute renal failure due to acute tubular necrosis associated with vancomycin intoxication. This appears to be the first case with a series of histological evidences of acute tubular necrosis associated with vancomycin. The patient made a full recovery and regained renal function without requiring hemodialysis.

Vancomycin is a nephrotoxic drug associated with acute renal failure typically attributed to acute interstitial nephritis.[1],[5] There are few reports that present acute tubular necrosis secondary to vancomycin.[3],[6] With tubulointerstitial nephritis, clinical findings typically involve fever, rash, eosinophilia, and/or eosinophiluria. Although no anuria is induced, an elevation of serum creatinine is associated with tubulointerstitial infiltration.[2] However, our patient lacked these clinical findings. His renal pathologic findings classicly matched the criteria for acute tubular necrosis; however, there was no widespread interstitial inflammation or tubulitis, as should be seen in acute interstitial nephritis.

Most patients previously described have had risk factors contributing to their acute tubular necrosis, including sepsis, hemodynamic instability, a combination with nephrotoxic drugs as aminoglycoside therapy, and prolonged vancomycin therapy with a high cumulative dose.[7] Vancomycin nephrotoxicity has been reported in children, with elevated vancomycin levels preceding the onset of acute renal failure in these cases.[2],[4] Several studies have associated trough vancomycin concentrations >10–20 μg/mL with an increased rate of renal impairment, whereas peak serum concentrations did not affect outcome.[4],[8] The patient in this case report was prescribed the recommended dose of vancomycin (40 mg/kg per day) to treat toxic skin syndrome. It was astonishing that the serum trough vancomycin level was elevated and made acute renal failure. There were no indications of other nephrotoxic drug nor ischemic injury. A kidney biopsy was performed under the suspicion of systemic lupus erythematosus and acute renal failure. The pathologic findings were compatible with acute tubular necrosis and Class V lupus nephritis. One and one-half months later, he received a second kidney biopsy again, which revealed that his acute tubular necrosis had completely subsided.

Treatment with high-flux hemodialysis or charcoal hemoperfusion in patients with vancomycin overdose is known to result in the elimination of vancomycin from the circulation, and subsequent improvement in renal function had been reported.[6],[9] Our patient's renal function recovered quickly without hemodialysis. Gupta et al.[10] described that some types of cells contribute to the tubular regeneration that follows acute tubular necrosis. Thus, if the bone marrow is disabled, tubular regeneration may be impaired. Most cases with acute tubular necrosis, especially those resulting from drug toxicity, improve after three weeks, even if a return to normal renal function takes months.[7] It is controversial to perform the invasive hemodialysis procedure in patients with acute renal failure for vancomycin intoxication alone. Renal function should be monitored closely in patients receiving vancomycin therapy, and a continued need for therapeutic drug monitoring is necessary.

In summary, vancomycin-induced acute tubular necrosis was rarely seen. This case illustrates the need for continuing drug monitoring and close monitoring of renal function in patients receiving vancomycin therapy. Our case did not need treatment with high flux hemodialysis; nevertheless, he subsequently regained renal function.