Management of Drug-Associated Acute Interstitial Nephritis

Abstract

Drug-associated acute interstitial nephritis (AIN) is characterized by acute or subacute loss of kidney function, interstitial infiltrates, edema, and tubulitis on kidney biopsy, with a relative sparing of the glomerulus and vasculature (1). Estimates indicate that AIN is the primary finding in 2%–5% of all native kidney biopsies. In those biopsied for acute kidney dysfunction, the frequency of AIN is closer to 10%–30%, although the true burden of AIN likely remains underestimated (1). Due to procedural risk, biopsies are often deferred in favor of empirical discontinuation of the suspected offending agent. Several AIN etiologies have been identified, but the majority of cases (60%–70%) have been linked to drugs and toxins. Pathophysiology and Presentation Drug-associated AIN is thought to be a cell-mediated immune response, akin to a type 4 (delayed-type) hypersensitivity reaction (2). Mechanistic explanations for AIN include that drugs could act as haptens to modify the endogenous response to native renal proteins or induce an autoimmune reaction to the tubular basement membrane through molecular mimicry. Drugs could also rarely lead to systemic immune activation that contributes to deposition or sequestration of immune complexes in the renal interstitium (2,3). As early as 7 days after drug exposure, the early inflammatory lesions in AIN can begin to evolve into irreversible interstitial fibrosis. This likely explains why, even with the best available management, only 40%–50% of patients with AIN experience complete renal recovery (4). As more and diverse cases of drug-associated AIN have been reported, it is apparent that the “classic triad” of extrarenal manifestations—which include fever, rash, and eosinophilia—only occur in about 10% of patients (5,6). Rather, drug-associated AIN has a highly variable presentation. In 133 cases of biopsy-confirmed AIN (95 of which were drug-related), fever, rash, and eosinophilia individually occurred in 20%–23% of patients. Microscopic hematuria, sterile pyuria, and non-nephrotic range proteinuria were present in 34%, 47%, and 91% of patients, respectively. Importantly, eosinophiluria was only present in 38% of drug-associated AIN cases (4). Recently, Moledina, et al. (7) identified urinary TNF-α and IL-9 as independently predictive of AIN. After accounting for the clinician’s prebiopsy suspicion of AIN, as well as standard available laboratory markers, urinary TNF-α and IL-9 significantly increased AIN prediction model performance (area under the curve, 0.84). Although many questions remain, these tools represent an exciting, new, noninvasive diagnostic approach to increase the probability of detecting AIN. Ideally, such biomarkers could sufficiently increase the post-test probability of AIN such that a kidney biopsy may be avoided. Drug Causes Several drugs and drug classes have been associated with AIN (Table 1). β-Lactam antibiotics, including penicillins and cephalosporins, are among the leading etiologies for drug-associated AIN. Time to onset of β-lactam AIN is typically over days to a few weeks, and it is often accompanied by extrarenal manifestations of hypersensitivity to the β-lactam (such as a rash). Other non–β-lactam antibiotics implicated in cases of AIN include sulfonamides, rifampin, and ciprofloxacin (1,2,4). Table 1. - Select agents with reported risk of drug-associated acute interstitial nephritis (1,2,4,10) Drug Type/Class Select Agents Antimicrobials β-Lactam antibacterials Penicillins (e.g., methicillin, nafcillin, amoxicillin) Cephalosporins Other antimicrobials Sulfonamides (e.g., sulfamethoxazole/trimethoprim) Rifampin Fluoroquinolones (e.g., ciprofloxacin) Vancomycin Acyclovir Antiretrovirals (e.g., abacavir, indinavir) Anti-inflammatory NSAIDs (e.g., ibuprofen, nabumetone) COX-2 inhibitors (e.g., celecoxib) 5-ASA derivatives (e.g., sulfasalazine, mesalamine) Acid-suppressive therapy PPIs (e.g., omeprazole, lansoprazole) Immune checkpoint inhibitors Anti-PD1 antibody (e.g., pembrolizumab, nivolumab) Anti-PD-L1 antibody (e.g., durvalumab) Anti-CTLA-4 antibody (e.g., ipilimumab) Anticonvulsants Phenytoin Carbamazepine Phenobarbital Others Allopurinol Furosemide NSAIDs, nonsteroidal anti-inflammatory drugs; COX-2 inhibitors, cyclooxygenase-2 inhibitors; 5-ASA, 5-aminosalicylic acid derivatives; PPI, proton-pump inhibitor; anti-PD1 antibody, anti–programmed cell death-1 (PD-1) antibody; anti-PD-L1, anti–programmed cell death ligand-1; anti-CTLA-4 antibody, anti–cytotoxic T lymphocyte-associated antigen 4. Nonsteroidal anti-inflammatory drugs (NSAIDs) and proton-pump inhibitors (PPIs) account for the bulk of the remaining drug-associated AIN cases. NSAIDs elicit nephrotoxicity through several mechanisms. Indirect nephrotoxicity may result from altered intraglomerular hemodynamics. Direct nephrotoxicity most commonly presents as AIN, but more rarely can also include minimal change disease, glomerulopathies, and papillary necrosis. (8) With PPIs,