From the Guidelines
Penicillin and NSAIDs can cause acute interstitial nephritis (AIN) through immune-mediated hypersensitivity reactions and direct cytotoxic effects, leading to significant morbidity and mortality if not promptly addressed. The most recent and highest quality study on this topic is from 2017 1, which highlights the importance of considering the mechanism of nephrotoxicity when selecting medications for patients with acute kidney disease (AKD). According to this study, NSAIDs can cause AIN through both direct cytotoxic effects and immune-mediated mechanisms, disrupting prostaglandin synthesis in the kidney and forming reactive metabolites that act as haptens. Penicillin antibiotics, on the other hand, trigger AIN by acting as haptens, binding to proteins in the kidney to form immunogenic complexes that the immune system recognizes as foreign. The resulting immune response in both cases involves infiltration of T lymphocytes, monocytes, and eosinophils into the renal interstitium, causing tubular damage, edema, and potentially fibrosis if not addressed promptly. Symptoms typically include fever, rash, eosinophilia, and declining kidney function, often with sterile pyuria and proteinuria. Other studies, such as those from 2009 1 and 2014 1, also support the idea that NSAIDs and penicillin can cause AIN, and emphasize the importance of avoiding these medications in patients with preexisting renal disease or those at risk of AKI. For example, a study from 2015 1 recommends temporary discontinuation of potentially nephrotoxic and renally excreted drugs, including NSAIDs, in people with a GFR < 60 ml/min/1.73 m2 who have serious intercurrent illness that increases the risk of AKI. Key points to consider when managing patients with AIN include:
- Avoiding NSAIDs and penicillin in patients with preexisting renal disease or those at risk of AKI
- Monitoring kidney function and adjusting medication regimens accordingly
- Considering alternative medications that are less likely to cause nephrotoxicity
- Providing prompt treatment for AIN, including withdrawal of the offending medication and supportive care.
From the FDA Drug Label
ADVERSE REACTIONS ... nephropathy are infrequent reactions and usually associated with high doses of parenteral penicillin. The FDA drug label does not answer the question.
From the Research
Mechanisms of Penicillin and NSAIDs Leading to Acute Interstitial Nephritis (AIN)
- Penicillin and NSAIDs are known to cause AIN through immune-allergic reactions, as reported in studies 2, 3, 4, 5, 6
- The exact mechanisms are not fully understood, but it is believed that these drugs trigger an immune response, leading to inflammation and damage to the kidney tissue
- NSAIDs, in particular, have been shown to inhibit the synthesis of prostaglandins, which can lead to vasoconstriction of the afferent arteriole and a decrease in glomerular filtration rate (GFR) 3
Clinical Presentation and Diagnosis
- AIN can present with a range of symptoms, including acute kidney injury, elevated serum creatinine, and eosinophiluria 2, 4
- Renal biopsy is often necessary to confirm the diagnosis of AIN, and certain histologic features may help to identify the underlying condition 4, 5, 6
- The presence of mononuclear leukocytes, including T cells and monocytes, in the kidney tissue is a common finding in AIN, and may play a role in the pathogenesis of the disease 5
Treatment and Management
- Early withdrawal of the culprit drug is essential in the treatment of AIN, and corticosteroid therapy may be necessary to reduce inflammation and promote recovery 2, 4, 6
- Prolonged treatment with corticosteroids beyond 8 weeks may not provide additional benefit in terms of kidney function recovery 6
- Monitoring of renal function and adjustment of medication are crucial in preventing and managing AIN, particularly in patients with pre-existing kidney disease or those taking multiple medications 3, 4