Aetiology

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 most common 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, rifampicin, and some fluoroquinolones

  • Proton-pump inhibitors

  • Non-steroidal anti-inflammatory drugs (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, phenindione, phenytoin, sulfadiazine, mesalazine, 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 tubulo-interstitial damage by antiretroviral drugs; infections such as tuberculosis, cryptococcus, candida, or viruses; and immunological 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 tubulo-interstitial 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 oedema 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.

A number of 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 re-challenged 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 re-challenge with culprit medication.[17]

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