Drug-Induced Acute Interstitial Nephritis

Abstract

Drug-induced acute interstitial nephritis (DI-AIN) is a common cause of AKI, affecting about 20% of patients with unexplained AKI, and leads to CKD and ESRD (1). Although any drug can potentially cause DI-AIN, antibiotics, non-steroidal anti-inflammatory drugs, and proton pump inhibitors, are the most frequent offenders (1). Diagnosis of DI-AIN is obvious when the classic triad of rash, fever, and eosinophilia occur within a few days of the initiation of a culprit drug. However, these findings occur in <10% of patients, and the onset of DI-AIN may be delayed by weeks or months after drug initiation (2). Moreover, only half of all patients with biopsy-proven DI-AIN present with AKI, whereas the rest have a slow, progressive loss of kidney function not meeting the AKI criteria (3). Urinary abnormalities such as eosinophiluria, pyuria, and white blood cell (WBC) casts, considered typical of DI-AIN, are also unreliable (2). Diagnosis of DI-AIN relies on maintaining a high index of suspicion in those at risk for this disease and obtaining a kidney biopsy to establish the diagnosis. As challenging as diagnosing DI-AIN is for clinicians, formulating an evidence-based treatment plan is equally difficult. Given the underlying immune mechanism of DI-AIN, corticosteroid administration has been considered the treatment of choice along with early withdrawal of the culprit drug. However, there is no randomized controlled trial of corticosteroids in DI-AIN. The literature is fraught with case reports, case series, and retrospective studies examining corticosteroid therapy for this inflammatory kidney lesion (4–8). Review of this literature reveals that there is no definitive answer for DI-AIN treatment except that early drug withdrawal is imperative. We present two patients to illustrate the frustrating nature of this issue and offer DI-AIN treatment recommendations on the basis of current literature. Patient 1 A 25-year-old woman with acute pyelonephritis from Escherichia coli was treated with oral double-strength trimethoprim/sulfamethoxazole. On day 11 of 14 of antibiotic treatment, the patient developed a maculopapular rash, low-grade fever, and eosinophilia. Serum creatinine (SCr) was 1.9 mg/dl (baseline SCr 0.7 mg/dl). Urine sediment microscopy revealed 1–3 WBC casts per low power field (LPF). Acute interstitial nephritis (AIN) due to sulfamethoxazole was presumed and the drug was discontinued. Treatment was completed with 3 days of daily levofloxacin. Over the next week, her symptoms resolved, and SCr returned to baseline. Patient 2 A 69-year-old man with coronary artery disease, atrial fibrillation, and hypertension was admitted to the intensive care unit for pneumonia complicated by hypotension. After clinical improvement with ceftriaxone and azithromycin therapy, he was transferred to a medical floor. On day nine, the nephrology service was consulted to evaluate his SCr rise from 1.2 to 2.1 mg/dl. Urine sediment microscopy demonstrated 5–10 isomorphic red blood cells per high power field (HPF), 10–15 WBCs per HPF, 3–5 renal tubular epithelial cells per HPF, and 1–3 granular casts per LPF. Acute tubular injury, acute infectious GN, and DI-AIN were considered in the differential diagnosis of AKI. Antibiotics were discontinued for clinical suspicion of DI-AIN. However, because the SCr continued to rise to 5.7 mg/dl on day 13, kidney biopsy was performed. Light microscopy revealed diffuse AIN, acute tubular injury, and 30% interstitial fibrosis. Ceftriaxone was the most likely culprit. After consultation with infectious diseases specialists, therapy with intravenous methylprednisolone 500 mg daily for 3 days was initiated, followed by oral prednisone, 60 mg daily for 4 weeks with subsequent taper. Two weeks after starting therapy, a gradual decrease in SCr was observed. At 6-month follow-up, the patient’s SCr was 1.9 mg/dl. Discussion These patients illustrate two important features of DI-AIN: (1) the varied clinical presentation, and (2) the divergent response to culprit drug discontinuation alone. The first patient developed classic “allergic DI-AIN” with systemic and kidney manifestations, whereas the second patient had only kidney manifestations that did not allow DI-AIN to be easily differentiated from other causes of AKI. Furthermore, the first patient had resolution of DI-AIN solely with drug discontinuation, whereas the second patient had worsening AKI, presumably from ongoing tubulointerstitial inflammation and injury despite drug discontinuation. In response to worsening AKI, corticosteroid therapy was initiated and kidney function eventually improved (albeit incompletely) over the next several weeks. An obvious first step in the treatment of DI-AIN is early identification and discontinuation of the culprit drug, which should not be delayed while a kidney biopsy is being contemplated. Longer duration of exposure to the culprit drug is associated with worse chance of recovery of kidney function (6). After t