Biopsy-proven granulomatous interstitial nephritis associated with vancomycin in an adult patient: a case report

Abstract

Acute kidney injury (AKI) caused by vancomycin mainly manifests as acute interstitial nephritis or acute tubular necrosis. Here, the rare case of a 71-year-old female patient with no history of kidney disease, who was diagnosed with granulomatous interstitial nephritis associated with vancomycin, is reported. The patient had been treated with vancomycin for over a month for an abscess in her right thigh. She presented to the emergency department with a history of fever, scattered rash, oliguria and elevated serum creatinine for >10 days. After hospitalization, the vancomycin trough concentration was confirmed to be >50 µg/ml. The patient received furosemide and continuous renal replacement therapy for AKI, teicoplanin and piperacillin/tazobactam for pulmonary infection, and urapidil, sodium nitroprusside and nifedipine for elevated blood pressure. Percutaneous ultrasound-guided kidney biopsy was performed. Light microscopy revealed granuloma formation, and diffuse infiltration of lymphocytes, monocytes, eosinophils, and some multinucleated giant cells. Finally, the patient was diagnosed with vancomycin-induced granulomatous interstitial nephritis and was treated with high-flux haemodialysis and 16 mg oral methylprednisolone, daily, for 3 weeks, which contributed to a significant recovery of renal function. This case suggests the need for regular vancomycin concentration testing during treatment. When AKI due to vancomycin occurs, a renal biopsy may be performed to help diagnose and treat the condition.

Introduction

Acute kidney injury (AKI) is the main adverse effect of vancomycin administration, with varying prevalence of vancomycin-associated AKI reported among published studies. In the meta-analysis by van Hal et al., ¹ the incidence of vancomycin-associated AKI ranged from 5% to 43%, which was similar to a more recent meta-analysis of 13 studies that reported the relative risk of AKI with vancomycin to be 2.45 (95% confidence interval, 1.69, 3.55), with an attributable risk of 59%. ²

To date, the main known pathological manifestations of vancomycin-induced AKI are acute interstitial nephritis and acute tubular necrosis. Here, a rare case of granulomatous interstitial nephritis associated with vancomycin is described.

Case report

The reporting of this study conforms to CARE guidelines. ³ Ethics approval is not required for this study in accordance with local and national guidelines. Written informed consent was obtained from the patient for treatment, and for publication of her medical case details and any accompanying images.

Approximately 2 months prior to presentation at the Emergency Department, a 71-year-old female patient with a history of abscess in her right thigh had received vancomycin treatment (1 g, every 12 h, i.v. glucose tolerance test [GTT]) for 54 days. The patient had experienced fevers and scattered rash on the body during treatment with vancomycin. She presented at the Emergency Department of the Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China, in April 2022, with oliguria and increased serum creatinine (1.1–9.2 mg/dl) for more than 10 days previously, and was admitted to hospital. Inpatient blood and renal function analyses revealed that her blood eosinophil count was 0.7 × 10⁹ cells/L (normal range, 0.02–0.52 × 10⁹ cells/L). Routine urinalysis revealed a blood cell count of 10 cells/µl; a positive leukocyte esterase result; glucose, 28 mmol/L; protein, 1.0 g/L; erythrocytes, 32.8 cells/µl (normal range, 0–30.7 cells/µl); leukocytes 25 cells/µl (normal range, 0–39 cells/µl); and bacteria 101.1 U/µl (normal range, 0–385.8 U/µl). Serum albumin level was found to be 31.4 g/L (normal range, 40–55 g/L). Blood results were negative for antineutrophil cytoplasmic antibody, anti-glomerular basement membrane antibody, and antinuclear antibody. The trough concentration of vancomycin was found to be >50 µg/ml. The patient was treated with furosemide (40 mg, intravenous [i.v.]) and continuous renal replacement therapy for AKI, teicoplanin and piperacillin/tazobactam (4.5 g, every 12 h, i.v. GTT) for pulmonary infection, and 200 mg urapidil in 50 ml 0.9% sodium chloride solution (1 ml/h i.v. infusion, dose adjusted according to blood pressure), sodium nitroprusside in 5% glucose solution (0.3 ml/h, i.v. infusion, dose adjusted according to blood pressure) and nifedipine controlled-release oral tablets for elevated blood pressure. Bifidobacterium bifidum was administered to replenish the intestinal flora and diarrhoea was controlled with montmorillonite powder. Human albumin and immunoglobulin supplements were also provided to support albumin levels and the body's immunity. Ultrasound examination demonstrated homogeneous echo in the kidney parenchyma and no obstruction of the urinary tract. Percutaneous ultrasound-guided kidney biopsy was performed. Analysis of the tissue sections by immunofluorescence showed that the biopsy tissue was negative for immunoglobulin (Ig)M, IgG, IgA, complement component C3, complement component C1q, fibrinogen, and albumin. Electron microscopy showed podocyte fusion, and no deposition of immune complex in the kidney. Light microscopy revealed granuloma formation, and diffuse infiltration of lymphocytes, monocytes, eosinophils, and some multinucleated giant cells (Figure 1). Finally, the patient was diagnosed with vancomycin-induced granulomatous interstitial nephritis. She was treated with high-flux haemodialysis and a 3-week course of 16 mg oral methylprednisolone, daily, contributing to a significant recovery of renal function: urinalysis revealed that the urine was negative for leukocyte esterase, glucose and blood, protein was 0.15 g/L, and serum creatinine was 75.5 µmol/L. The trough concentration of vancomycin decreased to 10.8 µg/ml during hospitalization, and serum creatinine level decreased to 0.9 mg/dl. At the latest follow-up, the patient was symptom free.

Figure. 1.

Representative photomicroscopy images of kidney biopsy findings from a 71-year-old female patient diagnosed with vancomycin-induced granulomatous interstitial nephritis, showing: (a) haematoxylin and eosin (H&E)-stained section demonstrating granuloma (arrows), and infiltration of lymphocytes, monocytes, eosinophils (original magnification, ×100); (b) H&E stained section demonstrating multinucleated giant cells (arrow, original magnification, ×400); (c) electron microscopy demonstrating podocyte fusion (original magnification, ×5000); (d) periodic acid–Schiff stained section exhibiting tubule brush border loss (arrows, original magnification, ×200; and (e) Masson trichrome stained section with no evidence of a fibrosis area (original magnification, ×200).

Discussion

Here, a case of biopsy-proven vancomycin-induced granulomatous interstitial nephritis has been presented. This case manifested as fevers, scattered rash, oliguria and increased serum creatinine during treatment with vancomycin, and highlights the usefulness of biopsy in the process of diagnosing and treating vancomycin-induced granulomatous interstitial nephritis. First, renal biopsy established the diagnosis of vancomycin-induced granulomatous interstitial nephritis. Secondly, renal biopsy helped determine the nature and extent of inflammation in granulomatous interstitial nephritis. The biopsy in this case suggested non-infectious pathological manifestations, such as diffuse infiltration of lymphocytes, monocytes, eosinophils and multinucleated giant cells. Thirdly, the presence of podocyte cell fusion under electron microscopy of renal biopsy tissue suggests glomerular injury. Fourthly, renal biopsy helps to determine the disease prognosis. An increase in the rate of interstitial fibrosis in cases of tubulointerstitial inflammatory infiltration suggests a worse prognosis. Finally, renal biopsy provides an indication for the use of steroids. In terms of timing of steroid administration, unnecessary delay may lead to renal fibrosis and development of interstitial scarring and irreversible renal insufficiency. In terms of the dose used, unreasonably high doses of steroids are not beneficial, and may be detrimental to the outcome of an underlying infection. ⁴

The mechanism of vancomycin-associated nephrotoxicity is unclear, but there are various known possible nephrotoxicity pathways. For example, acute tubular injury/necrosis is induced by oxidative stress, complement activation due to inflammatory injury, and mitochondrial damage. ⁵ Acute interstitial nephritis mainly manifests as what is thought to be primarily a T-cell-mediated type 4 delayed hypersensitivity response. ⁶ A recently-described novel and unique mechanism of vancomycin-associated kidney injury is drug-induced obstructive tubular cast formation. This was demonstrated by immunohistochemical staining techniques used to detect vancomycin in the renal tissue of patients; tubular cast obstruction consisting of amorphous, nano-spherical vancomycin aggregates entangled with urinary regulatory proteins was observed. ⁷ The mechanism of glomerular injury exhibited in the present case is unclear. One possible mechanism is an increase in tubular-glomerular feedback leading to afferent arteriole vasoconstriction, causing podocyte injury. Alternatively, sustained tubular injury with malfunctioning tubular-glomerular feedback may lead to arteriolar vasodilation, causing elevated glomerular pressure and sustained podocyte injury. ⁸

There is currently no standard treatment for granulomatous interstitial nephritis associated with vancomycin. Hong et al. ⁹ reported a case of acute vancomycin-induced granulomatous interstitial nephritis with poor corticosteroid treatment efficacy. Corticosteroid treatment was subsequently discontinued and the patient was treated with cyclosporine and mycophenolate mofetil. Fibrosis of the kidney was found in a follow-up biopsy. After discontinuation of haemodialysis, creatinine was maintained at 2.8 mg/dl. In 1989, Codding et al. ¹⁰ reported the case of a patient with vancomycin-induced acute interstitial nephritis who was not treated with corticosteroids and died of septic shock, concluding that renal function should be closely monitored in patients receiving vancomycin. In another reported case of vancomycin-induced pathology, the patient improved after treatment with prednisone. ¹¹ In the present case, the patient improved significantly after treatment with oral prednisone.

The present case suggests the need for regular testing of serum vancomycin concentration in patients treated with vancomycin. Published studies appear to correlate the risk of vancomycin-associated AKI with the area under the curve (AUC) and trough concentration of vancomycin. The latest guidelines recommend that an individualized goal of an AUC/minimum inhibitory concentration by broth microdilution (MICBMD) ratio of 400–600 (assuming a vancomycin MICBMD of 1 mg/L) should be advocated for patients with suspected or confirmed severe methicillin-resistant Staphylococcus aureus infection to achieve clinical efficacy while improving patient safety, and that trough concentration only is no longer recommended, with periodic vancomycin concentrations depending on the patient's condition. ¹²

Supplemental Material

sj-pdf-1-imr-10.1177_03000605231180052 - Supplemental material for Biopsy-proven granulomatous interstitial nephritis associated with vancomycin in an adult patient: a case report

Supplemental material, sj-pdf-1-imr-10.1177_03000605231180052 for Biopsy-proven granulomatous interstitial nephritis associated with vancomycin in an adult patient: a case report by Yong Lin, Liangbin Zhao, Dengpiao Xie, Lizeyu Lv, Yu Zhang, Ling Wu and Mingquan Li in Journal of International Medical Research