Etiology

Published causes of acute interstitial nephritis (AIN) are diverse and may be grouped into drugs, systemic autoimmune diseases, and infections.[1][3][4]​​​ Drug-induced acute interstitial nephritis is the commonest type, and over 250 medications have been implicated.[8][10][11]​​ Drug-induced AIN accounts for over 70% of AIN cases in developed countries.[4] Polypharmacy means it may be unclear which drug is responsible in some patients. The most common drugs implicated in AIN include:[1][3][8][12][13]

  • Antibiotics: virtually all penicillins and cephalosporins, as well as many sulfonamides, rifampin, and some fluoroquinolones

  • Proton-pump inhibitors

  • Nonsteroidal anti-inflammatory drugs (NSAIDs; virtually all): trigger a unique reaction consisting of AIN with a concurrent nephrotic syndrome

  • Immune checkpoint inhibitors including the monoclonal antibodies programmed death (PD)-1 agents such as pembrolizumab, nivolumab, and cemiplimab; PD-L1 agents such as atezolizumab, avelumab, and durvalumab; and cytotoxic T-lymphocyte- associated antigen (CTLA)-4 inhibitors such as ipilimumab and tremelimumab

  • Diuretics (several classes)

  • H2 antagonists: cimetidine and ranitidine

  • Other medications: allopurinol, phenytoin, mesalamine, and warfarin.

Infection-related AIN makes up 40% to 50% of cases in developing countries.[4] Bacterial, mycobacterial, viral, fungal, rickettsial, and parasitic infections may all cause AIN.[1] Patients with HIV are vulnerable to AIN through multiple mechanisms, including: hypersensitivity to antiretroviral drugs; direct tubulointerstitial damage by antiretroviral drugs; infections such as tuberculosis, cryptococcus, candida, or viruses; and immunologic syndromes.[4]

AIN can also occur in the context of inflammatory diseases such as sarcoidosis, Sjogren syndrome, IgG4-related syndrome, or systemic lupus erythematosus.[4] It may occur as part of the tubulointerstitial nephritis with uveitis (TINU) syndrome.[14] In some patients, there is no discernible cause.

Pathophysiology

Antigen-initiated cell-mediated injury is implicated in the pathogenesis of AIN.[1][15]​ Drug-induced AIN is a drug hypersensitivity reaction.[4][10]​ Kidney biopsy reveals interstitial edema and an inflammatory infiltrate with variable numbers of eosinophils, lymphocytes, mast cells, and plasma cells.[1][11][16]​ Often these inflammatory cells infiltrate into the tubules and cause tubular injury, a phenomenon termed "tubulitis." If nephrotic syndrome is present such as in AIN caused by NSAIDs, the pattern is usually minimal change disease, although membranous nephropathy has also been reported.

Several features point to involvement of an allergic-hypersensitivity mechanism:

  • Only a small proportion of patients receiving the triggering medications develop the reaction, a classic pattern for drug allergies.

  • The presence of rash, eosinophilia, eosinophiluria, and eosinophils on the renal biopsy specimen suggests an allergic mechanism.

  • Some patients have elevated circulating IgE levels and IgE-containing cells that react to the triggering drug.

  • Some patients have a recurrence of the disease when rechallenged by the same or a similar triggering medication.

  • CD4+T cells isolated from the peripheral blood of patients with AIN can be activated ex-vivo upon rechallenge with culprit medication.[17]

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