Case Report: Vancomycin-Associated Tubulointerstitial Nephritis in Clinical Practice-Case Report and Review of Literature

Nephrotoxicity is one of the major limiting factors for vancomycin use. The most common histological patterns of kidney injury are acute tubulointerstitial nephritis and acute tubular necrosis. Patients who develop acute tubulointerstitial nephritis are prone to develop acute kidney injury with vancomycin rechallenge and, in most cases, present alone or as a part of Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS). The purpose of the review study is to identify biopsy-proven vancomycin-associated-tubulointerstitial nephritis in literature, determine possible underlying pathophysiology and identify the consequences of vancomycin rechallenge in such patients.


INTRODUCTION
Vancomycin, famously known as "Mississippi Mud, " was first approved for use by the Food and Drug Administration in 1958 (1). It is the antibiotic of choice for gram-positive infections, mainly methicillin-resistant Staphylococcus aureus (MRSA). Despite significant nephrotoxicity associated with vancomycin, it still has widespread use, being the drug of choice in the emergency department/acute setting for initial broader coverage. Vancomycin-associated tubulointerstitial nephritis (VAIN) is a recognizable histopathological pattern observed in patients receiving vancomycin. We present a patient with biopsy proven vancomycin-associated tubulointerstitial nephritis who was re-introduced to the drug after a year of developing maculopapular rash and mild acute kidney injury. We identified 14 case reports with VAIN, nine of which were biopsy-proven. We found that the kidney injury was self-limiting and improved by discontinuing vancomycin; however, steroids were used in some cases. Only three studies showed rapid recurrence of maculopapular rash and/or acute oligo-anuric kidney injury with vancomycin rechallenge.

CASE PRESENTATION
We present the case of a 56-year-old man with hypertension, poorly controlled type II diabetes mellitus (DM) and hyperlipidemia who presented to the Emergency Room with generalized fatigue, fever and an open draining ulcer on his right heel. Laboratory work up showed elevated white blood cell count of 18.95 K/µL (3-11.3 K/µL), initial blood urea nitrogen of 18 mg/dL (6-24 mg/dL) and creatinine of 1.0 mg/dL (0.6-1.10 mg/dL) and rest of the blood work as shown in Table 1. His blood pressure was controlled with lisinopril 40 mg daily, hyperlipidemia with atorvastatin 40mg daily and his DM with insulin therapy. The patient was started on initial broad-spectrum antibiotics with vancomycin 1 g every 12 h (70-kilogram male) and piperacillin-tazobactam 4.5 g every 8 h after drawing blood cultures. On Hospital Day 1, his blood culture was positive for gram positive cocci, so Piperacillin was stopped. Two days later, he developed pitting pedal edema, reduced urine output (250 ml/day) and serum creatinine increased up to 5.8 mg/dL as shown in Table 1 and creatinine trend shown in Figure 1. His vancomycin trough was 17 mcg/ml. Urinalysis showed moderate hematuria with 10-20 red blood cells and 3 + protein. Microscopic examination of the sediment showed a single white blood cell cast. Given concern for acute tubulointerstitial nephritis, vancomycin was immediately stopped, kidney biopsy was obtained which confirmed the presence of eosinophils in the interstitium and interstitial cells within the tubules as shown in Figure 2. After this event, his previous hospital records were reviewed and it was discovered that the patient was hospitalized a year back with a diabetic foot ulcer and at that time, he had received vancomycin which resulted in him developing maculopapular rash and mild acute kidney injury. Vancomycin was stopped due to concern for an allergic reaction and his symptoms had resolved with a short course of prednisone (500 mg of intravenous methylprednisolone for 3 days followed by oral prednisone at 1 mg/kg tapered over 14 days).

DISCUSSION
One of the limiting factors of vancomycin use is kidney injury. Vancomycin related acute kidney injury (AKI) is defined as at least two or three consecutive elevations in serum creatinine by 0.5 mg/dl or at least a 50% increase from the baseline, whichever is greater; the increase must be documented after several days of vancomycin therapy, and no alternative explanation for the impairment in glomerular filtration rate is identified (2).
Vancomycin can cause varied immune-mediated reactions or hypersensitivity reactions (HSR)-immediate, type I IgE mediated HSR, type II antibody-mediated HSR, and type IV cell-mediated delayed HSR. These HSR include Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), IgA bullous dermatosis, and Steven-Johnson Syndrome/Toxic Epidermal   Necrolysis (SJS/TEN). Acute tubulointerstitial nephritis (AIN) is a part of type II antibody-mediated HSR.
Another histological pattern seen with vancomycin is ATN-Animal studies demonstrated that vancomycin leads to tubular damage and interstitial inflammation related to oxidative stress in the proximal tubular cells and vasoconstriction by free oxygen radicals (6). It can also alter mitochondrial function. Oxidative phosphorylation by vancomycin induces free oxygen radicals, thereby reducing the activity of defensive antioxidative enzymes, including superoxide dismutase and catalases. Vancomycin superoxide production causes mitochondrial membrane potential depolarization with the release of cytochrome C and subsequent activation of caspases 9 and 3, leading to apoptotic cell death.
Vancomycin, in addition, causes immunological injury by acting as an exogenous antigen that can be directly trapped within the interstitium or circulate as an immune complex that gets deposited subsequently within the interstitium. Alternatively, it can bind to tubular antigens and act as haptens or perform molecular mimicry of the tubules and/or interstitium. Both cellmediated and humoral immunity can be involved in the process, but it is initiated when an antigen-presenting lymphocyte is activated. This results in the formation of activated T-cells that promote differentiation and proliferation of other T-cells resulting in cytokine and chemokine production, including TGFβ, PDGF-β, EGF-β, and fibroblast growth factor-2. Over time, tubulointerstitial inflammation and edema transition to fibrosis and tubular loss (7). In the case of vancomycin, the clinical presentation is quite variable. It comes to attention when there is an unexplained rise in serum creatinine after exposure to vancomycin. Nevertheless, the clinical picture is often complicated by multiple processes ongoing during hospitalization or otherwise, such as systemic infection, bouts of hemodynamic instability, and concomitant use of other nephrotoxic medications. Most often, the suspicion for vancomycin-associated tubulointerstitial nephritis is low as symptoms are non-specific and the classic triad of fever, rash, and eosinophilia suggestive of hypersensitivity are present only in a minority of patients (> 5-10%) (7).
Objectively, there is no one laboratory test that can be used to diagnose VAIN. Most commonly observed laboratory abnormalities are eosinophilia, increased serum IgE levels, elevated erythrocyte sedimentation rate, and anemia. Urinalysis can show hematuria, pyuria, and proteinuria on dipstick testing. Urine eosinophils are neither sensitive nor specific for the diagnosis of VAIN as it is seen in cystitis or prostatitis, pyelonephritis, atheroembolic disease, acute tubular necrosis, and rapidly progressive glomerulonephritis. White blood cell casts seen on urine microscopy in a patient with AKI without pyelonephritis are highly suggestive of VAIN.
Since vancomycin-associated tubulointerstitial nephritis represents a hypersensitivity reaction, sometimes with systemic symptoms and dermatological manifestations, a kidney biopsy can provide diagnostic information regarding exact etiology, decision toward discontinuation of the drug, corticosteroid administration, and prediction of long-term prognosis. Nonetheless, it is often difficult to establish causality due to confounders/risk factors as seen from the literature review (including presence of other antibiotics, nonsteroidal anti-inflammatory drugs, severe sepsis) and biopsy timing in relation to the use of vancomycin. In patients who cannot undergo kidney biopsy, scanning with 67Ga scintigraphy or positron emission tomography scanning may be utilized to differentiate VAIN from acute tubular necrosis (ATN) (20).

CONCLUSION
Vancomycin-associated tubulointerstitial nephritis is presumed to be more frequent than we encounter in clinical practice, and hence the reported literature has been regarded as the tip of the iceberg. Survival analysis has linked the presence of acute tubulointerstitial nephritis to a worse prognosis. Hence, performing a timely kidney biopsy is paramount to diagnosing and treating tubulointerstitial nephritis. Furthermore, for biopsyproven AIN, future rechallenges with vancomycin should be avoided, and such patients should be listed as having had an adverse reaction to vancomycin.

DATA AVAILABILITY STATEMENT
The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.

ETHICS STATEMENT
Ethical review and approval was not required for the study on human participants in accordance with the local legislation and institutional requirements. The patients/participants provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.

AUTHOR CONTRIBUTIONS
LK: conception, design of the study, review of literature, and analysis of data. RR: drafting of the manuscript and review of the final manuscript. Both authors contributed to the article and approved the submitted version.