Identification of the Causative Drug in Drug-induced Acute Interstitial Nephritis

Acute interstitial nephritis (AIN) is a nosological entity characterized by the presence of an inflammatory infiltrate and edema in the renal interstitium responsible for acute renal failure. AIN represent 1-3% of all renal biopsies in some studies and up to 20% of diagnosis in acute renal failure. There are several etiologies of AIN: drug-induced (DAIN), immunological, infectious and idiopathic. In a North American single-center retrospective study of 133 patients with histologically proven AIN between 1993 and 2001, the most common cause was drug-induced (70%). The involved drugs were mainly antibiotics (49%), proton pump inhibitors (14%) and non-steroidal anti-inflammatory drugs (11%). More than 250 drugs can cause DAIN and it is established that any drug can be responsible for DAIN.

The clinical presentation of DAIN is aspecific and variable depending on the drug class involved. It usually occurs 7 to 10 days after the introduction of the causative drug, but this delay may be one day with some antibiotics or several months with non-steroidal anti-inflammatory drugs or proton pump inhibitors. The only consistent manifestation is acute or subacute renal failure, requiring extra-renal epuration in 40% of cases. Clinically, patients may be asymptomatic or present aspecific clinical manifestations such as arthralgias (45%), fever (36%), and skin rash (22%). Biological examinations systematically reveal elevated creatinine levels and, to varying degrees, eosinophilia (35%), microhematuria (67%), leukocyturia (82%) and non-nephrotic proteinuria (93%). The classic triad of fever, rash and eosinophilia is highly suggestive of DAIN and type IV hypersensitivity reaction but is present in only 10-15% of cases. The diagnosis of DAIN should therefore be systematically evoked in the presence of unexplained acute renal failure associated with recent drug exposure.

The pathophysiology of DAIN remains poorly understood. It would involve a drug hypersensitivity reaction. This pathophysiological hypothesis is based on several observations:

(1) DAIN is an idiosyncratic and non-dose-dependent pathology, (2) the presence of eosinophils in the inflammatory infiltrate is frequent (3) it may be accompanied by a systemic hypersensitivity reaction (skin rash, liver damage, eosinophilia), (4) there is usually a 7-10 day interval between the onset of drug exposure and the onset of acute renal failure. Delayed hypersensitivity (Gell and Combs type IV) in which T cells play a central role is the current hypothesis in the pathophysiology of DAIN. Moreover, the preponderance of T lymphocytes in the interstitial inflammatory infiltrate, the absence of immunoglobulin and complement deposits in direct immunofluorescence in the majority of cases also pleads in favour of a delayed hypersensitivity of type IV mediated by T lymphocytes.

The kidney is a target organ for delayed hypersensitivity for 2 main reasons. First, blood flow is high in the kidneys where potential antigens are filtered, secreted, metabolized and/or concentrated. On the other hand, the kidney plays a central role in the excretion of most drugs. These 2 mechanisms explain the particular susceptibility of the kidneys to delayed hypersensitivity due to the exposure of the renal parenchyma to numerous antigens from pharmacological agents and their metabolites.