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Drug-induced acute interstitial nephritis (DI-AIN), also called allergic acute interstitial nephritis, is the most common cause of acute interstitial nephritis (AIN) in developed countries. DI-AIN is associated with a sharp decline in renal function, often requiring dialysis, and has the potential for permanent renal insufficiency, especially if left untreated. Differentiating from other causes of acute kidney injury and discontinuing the causative medication is key to early reversibility. Renal biopsy is the definitive diagnostic test for AIN, and barring chronic changes seen on biopsy or contraindications, steroid therapy is the preferred treatment. This activity discusses the etiology, pathophysiology, clinical symptomatology, and treatment while emphasizing the interprofessional team's role in managing allergic interstitial nephritis. Objectives: Identify potential allergic and drug-induced acute interstitial nephritis cases by recognizing varied presentations and conducting a thorough medication history review. Differentiate allergic and drug-induced acute interstitial nephritis from other causes of acute kidney injury through clinical assessment, laboratory investigations, and renal biopsy if indicated. Apply evidence-based guidelines for the treatment of allergic and drug-induced acute interstitial nephritis, including the judicious use of corticosteroids when indicated, weighing the potential benefits against risks. Coordinate care and follow-up for patients with allergic and drug-induced acute interstitial nephritis to monitor renal function, medication adjustments, and potential long-term consequences, aiming for optimal outcomes. Access free multiple choice questions on this topic.

Drug-induced acute interstitial nephritis (DI-AIN), also called allergic acute interstitial nephritis, is the most common cause of acute interstitial nephritis (AIN) in developed countries. DI-AIN is associated with a sharp decline in renal function, often requiring dialysis, and has the potential for permanent renal insufficiency, especially if left untreated. Differentiating from other causes of acute kidney injury and discontinuing the causative medication is key to early reversibility. Interstitial nephritis was first described in 1898 by William Thomas Councilman, chief pathologist at Brigham Hospital, who noted nonsuppurative interstitial lesions on autopsies of patients with streptococcal infections, and this term is used to describe various immune-mediated kidney disorders that cause significant inflammatory cell infiltration of the renal interstitium and tubules while sparing the glomeruli.[1][2][3] The most common form of AIN in developed countries is caused by drug exposure, estimated at 70% to 75% of cases. DI-AIN is a frequent causative agent of acute kidney injury (AKI), responsible for about 20% of renal biopsies performed for unexplained AKI.[1] AIN is associated with an acute decline in renal function and may progress to permanent renal insufficiency or even end-stage renal disease (ESRD).[3] AIN has been defined as an increase of 0.5 mg/dL or 50% in serum creatinine over a 24- to 72-hour period starting 24 to 48 hours after exposure to a potential triggering medication.[4][5] The classic clinical presentation of AIN characterized by fever, rash, and eosinophilia was prominently associated with methicillin use, which occurred in about 17% of cases. However, this specific presentation is less common with other medications known to cause AIN.[6] Identification and discontinuation of the offending medication are the mainstays of treatment, with conflicting evidence regarding the benefit of steroid treatment.[7][8][9][10] With early recognition and proper treatment, AIN and its associated renal failure are generally reversible.[7]

The classic clinical presentation of AIN characterized by fever, rash, and eosinophilia was prominently associated with methicillin use, which occurred in about 17% of cases. However, this specific presentation is less common with other medications known to cause AIN.[6] Identification and discontinuation of the offending medication are the mainstays of treatment, with conflicting evidence regarding the benefit of steroid treatment.[7][8][9][10] With early recognition and proper treatment, AIN and its associated renal failure are generally reversible.[7] For information on other causes of interstitial nephritis (genetic, idiopathic, infectious, immune-mediated, and associated with various systemic inflammatory disorders), as well as anti-tubular basement membrane disease and tubulointerstitial nephritis and uveitis syndrome (TINU), see our companion StatPearls reference article on Tubulointerstitial Nephritis. Autosomal dominant tubulointerstitial kidney disease is also described elsewhere.[11][12]

NSAIDs are the most common class of drugs causing DI-AIN, responsible for 44% of cases.[7][10][13][14][15] Antibiotics such as penicillins, cephalosporins, rifampin, sulfonamides, and ciprofloxacin account for about 33% of DI-AIN.[13] Different medication classes causing DI-AIN have distinct presentations and are associated with specific patient demographics. NSAIDs are very commonly used both as a prescription and over-the-counter. Patients with NSAID-induced AIN tend to be older than 50 years and are frequently chronic users with significant comorbidities or some degree of preexisting renal dysfunction.[15] Associated characteristics of Allergic Interstitial Nephritis (AIN) include significant proteinuria, which may even reach nephrotic range levels (3 grams or more of urinary protein per day), longer latency periods, less complete renal recovery, and minimal change disease. Clinical presentation is less likely to show eosinophilia, eosinophiluria, rashes, fevers, hematuria, or arthralgias than patients with AIN from other triggering drugs.[15][16][17] All NSAIDs can produce AIN, but nonselective agents, such as aspirin, ibuprofen, and sulindac, tend to produce less DI-AIN.[18][19] Proton pump inhibitors are an increasing cause of AIN, with an estimated 12/100,000 population incidence.[20] In some studies, they are the second most common underlying trigger for DI-AIN.[21][22] The severity of AIN from proton pump inhibitors is somewhat less than from other medications, such as antibiotics, but the likelihood of recovery is also reduced.[23][24] Beta-lactams are the class of drugs most likely to demonstrate the classic triad of symptoms (fever, rash, and arthralgias), produce eosinophilia, and develop a pure form of allergic/hypersensitivity reaction histologically. Patients with a prior penicillin or cephalosporin reaction are more likely to develop this.[25]

Beta-lactams are the class of drugs most likely to demonstrate the classic triad of symptoms (fever, rash, and arthralgias), produce eosinophilia, and develop a pure form of allergic/hypersensitivity reaction histologically. Patients with a prior penicillin or cephalosporin reaction are more likely to develop this.[25] Immune checkpoint inhibitors are monoclonal antibodies used for cancer therapy and are an increasingly significant cause of AIN.[26] Clinical and histological presentations are similar to other cases of AIN, but patients tend to have a longer latency period, reduced level of AKI, and a slower recovery of renal function.[15][27] There also appears to be an association with the simultaneous use of proton pump inhibitors.[28][29][30][31] AIN from immune checkpoint inhibitors poses a significant therapeutic dilemma since there are no reasonable alternative medications for many cancer patients, making it difficult or impossible to discontinue the offending drug safely.[15][32][15] Other drug classes that have demonstrated a tendency to produce AIN include sulfa drugs, tyrosine kinase inhibitors, antiepileptics (phenytoin), antivirals, and histamine-2 antagonists.[4] Numerous case reports in the literature regarding other medication culprits demonstrate the need for ongoing consideration of DI-AIN as a potential cause of worsening renal function after initiation of drug therapy. More than 250 drugs have been described as triggering agents for DI-AIN.[33] Polypharmacy, particularly in the older population, can make identification of the causative agent challenging in many cases.[34][35][36][37]

The frequency of AIN and DI-AIN is likely underestimated, as the diagnosis can only be definitively confirmed with the histological evaluation from a renal biopsy.[15] In practice, renal biopsies are often deferred as clinical suspicion often guides therapy, especially if the patient's symptoms and renal function improve within 7 days of drug discontinuation.[15] Given the lack of solid evidence to pursue immunosuppressant therapy, a biopsy often does not change the treatment plan beyond discontinuing the likely offending agent. The increased use of NSAIDs, antibiotics, and proton pump inhibitors in most countries globally has contributed to a worldwide increase in DI-AIN diagnosis, even though it represents less than fifteen percent of all reported adverse drug reactions.[15][33] Older patients are particularly susceptible to AIN due to chronic use of triggering medications, preexisting renal disorders, and polypharmacy.[15][38] The most common triggers are NSAIDs, proton pump inhibitors, and penicillins, while systemic causes are less likely in older AIN patients.[23][38] Older patients with AIN are more likely to have preexisting chronic kidney disease, higher baseline creatinine levels, increased levels of proteinuria, and a greater need for dialysis than younger patients.[23][39] Although more likely to develop AIN, older patients may not be considered good candidates for a renal biopsy for various reasons, which may cause the overall prevalence to be further underestimated in this population group.

Renal parenchyma is prone to cellular damage for many reasons, including high metabolic activity with a relatively limited blood supply, greater exposure to higher concentrations of drugs than other organs, active tubule transport systems further increasing drug exposure, and a high osmotic environment.[7][40] Several mechanisms of inflammatory pathway activation appear to be involved, including hapten-mediated immune activation, direct drug stimulation of T-cells, medication-induced renal tubular cell damage, tubular crystallization of medications, and antibody-mediated cellular injury.[15] The underlying pathophysiology of DI-AIN is thought to be a type IV idiosyncratic T-cell–mediated delayed hypersensitivity reaction.[15][41] It is primarily a cell-mediated immunological process, as evidenced by high numbers of activated T-cells in renal biopsies of DI-AIN patients.[42] Drug-specific T-cells have also been identified in the renal interstitium of biopsy-proven DI-AIN patients in research settings.[43][44] Haptens are small molecules that become immunogenic only when attached to a larger molecule, most often a protein. Drugs causing AIN are endocytosed by interstitial or tubular cells, becoming haptens.[15][33][42][43][45] As the tubular epithelial cells process the drug haptens, adjacent renal interstitial dendritic cells near the basolateral basement membrane are mobilized and migrate to the regional lymph nodes to activate T-cells further.[15][46] These activated T-cells eventually reach the damaged renal tubular cells and produce cytokines and proinflammatory chemokines.[15][47] The initiation of the inflammatory process results in fibroblast proliferation, macrophage migration, and localized edema, producing AIN's characteristic inflammatory interstitial infiltrate.[15][47] Several drugs can also directly cause local and regional T-cell stimulation and activation.[15][45][48] Others may cause kidney tubular damage directly or indirectly via cross-reactivity between some medications, the renal tubular basement membrane (TBM), and interstitial antigens.[15][49][50][51]

Haptens are small molecules that become immunogenic only when attached to a larger molecule, most often a protein. Drugs causing AIN are endocytosed by interstitial or tubular cells, becoming haptens.[15][33][42][43][45] As the tubular epithelial cells process the drug haptens, adjacent renal interstitial dendritic cells near the basolateral basement membrane are mobilized and migrate to the regional lymph nodes to activate T-cells further.[15][46] These activated T-cells eventually reach the damaged renal tubular cells and produce cytokines and proinflammatory chemokines.[15][47] The initiation of the inflammatory process results in fibroblast proliferation, macrophage migration, and localized edema, producing AIN's characteristic inflammatory interstitial infiltrate.[15][47] Several drugs can also directly cause local and regional T-cell stimulation and activation.[15][45][48] Others may cause kidney tubular damage directly or indirectly via cross-reactivity between some medications, the renal tubular basement membrane (TBM), and interstitial antigens.[15][49][50][51] Some medications or their metabolites are relatively insoluble in the urine, resulting in drug crystal precipitation in the distal tubular lumens. This causes renal tubular obstruction and injury, as well as localized inflammation resulting in AKI and AIN.[52] Examples of drugs with poor urinary solubility include antibiotics (ampicillin, ciprofloxacin, sulfonamides), antivirals (acyclovir, indinavir), methotrexate, and triamterene.[4] Although the predominant pathophysiology of AIN is related to cytotoxic T-cell activity, antibody-mediated cellular injury is sometimes involved.[15] Methicillin, for example, is associated with granular immune complex deposition on the tubular basement membrane and a TBM-specific hapten.[15][53] Similarly, AIN from rifampin demonstrates anti-rifampin antibodies.[15] There also appears to be an association between some human leukocyte antigen (HLA) histocompatibility genotypes and AIN.[54] Specifically, individuals with greater HLA-DR and HLA-DQ expression showed a positive correlation with the risk of AIN, DI-AIN severity, and increased interstitial T-lymphocyte infiltration.[54][55]

There also appears to be an association between some human leukocyte antigen (HLA) histocompatibility genotypes and AIN.[54] Specifically, individuals with greater HLA-DR and HLA-DQ expression showed a positive correlation with the risk of AIN, DI-AIN severity, and increased interstitial T-lymphocyte infiltration.[54][55] In severe, chronic cases, extensive fibroblastic infiltration is associated with increased extracellular matrix production, which promotes further renal tubular cellular damage, ultimately leading to tubulointerstitial fibrosis, tubular atrophy, and chronic kidney disease.[15][43]

DI-AIN can be definitively diagnosed only by renal biopsy, characterized by an inflammatory infiltrate in the renal interstitium and tubules that typically does not involve the glomeruli.[7][15][41] Light microscopy shows interstitial inflammation with a predominance of T-lymphocytes, both CD4+ and CD8+, along with eosinophils, whose presence near the tubular basement membrane is diagnostic of AIN. Neutrophils and plasma cells may also be present. The inflammatory infiltrate is typically associated with interstitial edema and tubulitis. An altered brush border, prominent nucleoli, cytoplasmic vacuolization, tubular dilation, and disruption of the tubular basement membrane characterize Tubulitis. Immunofluorescence will usually not show a specific immunoglobulin or complement pattern, and electron microscopy is useful in diagnosing NSAID-induced AIN, causing a minimal change in disease.[43][56] The glomeruli and renal vasculature are usually not involved, and fibrosis is minimal unless exposure has been ongoing and chronic interstitial nephritis has developed. Older AIN patients tend to have more tubular atrophy, fibrosis, and sclerotic glomeruli.[23] The presence of fibrosis or tubular atrophy indicates that steroids may not be helpful, as the acute inflammatory phase (which steroids suppress) has been completed.[57] [58] Granulomatous interstitial nephritis is a less common presentation of DI-AIN. It is associated with NSAIDs and antimicrobials like vancomycin or ciprofloxacin. Granulomas are formed by macrophages and multinucleated giant cells, often due to the inability to eradicate the offending antigen.[15]

The initial workup should include a thorough history and physical examination with particular attention to over-the-counter medications such as NSAIDs, proton pump inhibitors, and any recently introduced drugs. Symptoms may appear within a few days or be delayed weeks or months after exposure to the triggering medication.[15] Earlier presentation is typically associated with prior exposure to the offending drugs.[59][60][61] Patients with DI-AIN may present with the classic triad of rash, fever, and eosinophilia (in 10% of cases) but more often present with nonspecific symptoms such as fatigue, malaise, and nausea.[7][41][62] When present, rashes or skin eruptions are highly suggestive of DI-AIN. Skin manifestations are variable but most often described as a maculopapular or morbilliform rash, although diffuse erythroderma or even toxic epidermal necrolysis may be present.[15][38] Many patients will demonstrate hypertension due to increased angiotensin II activity from interstitial inflammation, causing arterial vasoconstriction and increased water and sodium retention.[63][64][65][66][67] Patients are not usually oliguric until advanced AKI develops and may even be polyuric due to impaired tubular concentrating ability.[2]

AIN and DI-AIN should be considered in the differential diagnosis of any patient with worsening renal function, especially if they have recently been exposed to new medications. Worsening renal function, eosinophilia, increased levels of serum IgE, eosinophiluria, sterile pyuria, proteinuria, WBC casts in the urine, and microscopic hematuria are common laboratory findings.[7][2] While traditionally considered diagnostic of DI-AIN, eosinophiluria can no longer be considered a reliable test due to a sensitivity of 40% with a positive predictive value of just 38%.[15][25] Proteinuria is frequently found in DI-AIN (40% of cases) due to the release of a cytokine-like permeability-enhancing factor from interstitial inflammatory cells, preexisting underlying glomerular disease, or new glomerular injury from AIN-related cytokines.[2][68] Nephrotic-range proteinuria (3 grams or more per day) is often encountered in NSAID-induced AIN.[16] One study found that glucosuria in patients without diabetes highly suggests tubular injury related to AIN and is often associated with low serum phosphorus, uric acid, and bicarbonate levels from impaired tubular reabsorption.[2] There is no available imaging test that will reliably diagnose patients for AIN. Ultrasound or CT scans are frequently used to identify and exclude hydronephrosis or obstructive uropathy in cases of newly discovered azotemia but may show nonspecific kidney enlargement or enhanced echogenicity of the renal cortex in AIN.[3][25][42] Investigational Tests A higher ratio of urinary proinflammatory to anti-inflammatory macrophages has been suggested to help distinguish AIN from other renal disorders.[69] The lymphocyte transformation test measures the degree of lymphocytic proliferation in the presence of a specific medication. This can help identify the critical triggering drug in challenging situations such as cancer treatment, where discontinuing a critical chemotherapy agent can have serious consequences.[15][70] Several urinary biomarkers are being investigated for possible use in diagnosing and monitoring AIN. These include monocyte chemotactic peptide-1, alpha1-microglobulin, β2-microglobulin, KIM-1, sC5b-9, TNF-α, IL-9, and CXCL9.[7][57][71][72][73][74][75] Of these, the most clinically promising appears to be the following:

Several urinary biomarkers are being investigated for possible use in diagnosing and monitoring AIN. These include monocyte chemotactic peptide-1, alpha1-microglobulin, β2-microglobulin, KIM-1, sC5b-9, TNF-α, IL-9, and CXCL9.[7][57][71][72][73][74][75] Of these, the most clinically promising appears to be the following: TNF-α and IL-9 are consistently elevated in patients with interstitial nephritis compared to other forms of kidney disease and normal controls.[75][58] CXCL9, an interstitial nephritis-promoting chemokine associated with lymphocytic chemotaxis, also appears quite promising as a biomarker for AIN, with urinary levels more than 7-fold higher in patients with the disorder than controls.[7][73][76]

In patients with suspected or confirmed AIN or drug-induced interstitial nephritis, the mainstay of treatment is the withdrawal and discontinuation of the offending agent.[15][77][15] If the withdrawal of the likely offending drug does not result in a substantial improvement in renal function after 5 to 7 days, the consensus recommendation is to start the patient on corticosteroids.[7][15][41][57] It is thought that AIN patients with high urinary biomarkers like IL-9, greater levels of interstitial inflammation, and lower degrees of chronic changes, such as fibrosis and tubular atrophy, on renal biopsy are likely to show the best response.[57][58] Short-term dialysis is often needed in 30% to 69% of patients with DI-AIN, regardless of initial treatment.[15] Treatment should also be directed at concurrent potentially nephrotoxic factors such as anemia, hyperglycemia, and hypertension to preserve renal function optimally.[5] Small case series have evaluated mycophenolate mofetil, cyclophosphamide, infliximab, azathioprine, and cyclosporine as therapeutic options in glucocorticoid-dependent and steroid-resistant AIN patients.[78][79][80][81][82][83][84] Mycophenolate has been the most studied, but further investigations are needed before this alternative approach can be generally recommended.[78][85]

The differential diagnosis of DI-AIN includes acute tubular necrosis; autoimmune-induced AIN; tubulointerstitial nephritis and uveitis syndrome (TINU); underlying systemic diseases, eg, sarcoidosis, SLE, Sjogren; lead or toxic metal exposure; glomerulonephritis, vasculitis; and pyelonephritis. Urine sediment, urine chemistries, and serum markers can be useful in distinguishing the above etiologies; however, the definitive diagnosis is a renal biopsy, which should be performed unless contraindicated in all patients without imminent renal recovery after medication discontinuation.

The prognosis of AIN is favorable in cases where a diagnosis has been made promptly, and exposure to the offending medication is minimized. AIN with renal failure for greater than 3 weeks portends a worse prognosis, likely due to the development of interstitial fibrosis and tubular damage. NSAID-related AIN is also associated with a somewhat worse outcome. AIN due to proton pump inhibitors has been linked to lower severity of acute kidney injury but with a reduced likelihood of recovery at 6 months. This has been attributed to the possibility of prolonged drug exposure. One series revealed that 26% of patients with AIN ultimately returned to their baseline renal function, while 4% required long-term renal replacement therapy. It is estimated that 40% to 60% of patients with biopsy-proven AIN will not fully recover their baseline renal function when assessed six months after biopsy.[58] Lack of recovery is associated with lower GFR and albuminuria before DI-AIN, longer exposure to the attributable drug, and greater fibrosis, granulomas, or tubular atrophy on biopsy.[24][57][58][86]

In most instances, suspected DI-AIN resolves, as treating the underlying issue resolves the problem. Renal failure may persist for weeks or months, but recovery usually occurs within the first 3 months. AIN can progress into chronic kidney damage or even end-stage renal failure. This complication is more likely in older patients and those with preexisting kidney disorders. Hypertension may develop from increased angiotensin II production. [67] Anemia can be caused by decreased erythropoietin production, end-organ unresponsiveness, or hemolytic processes and should be monitored.[62]

Patients need to understand the underlying cause of their condition and strictly comply with all directions towards ameliorating the condition, usually by removing the offending agent. If started on steroids, they need to be aware of the need to taper the dosage over time and not stop the medication before the prescribed course duration. Patients should also be informed of the nature of their new "allergy" and that future lifetime avoidance of the triggering medication is necessary.

A BUN/creatinine ratio of 12 or less is a good, quick, easy test that suggests interstitial nephritis but not necessarily which type. An elevated IgE and a low BUN/creatinine ratio would strongly suggest AIN. Eosinophilia and eosinophiluria suggest AIN and DI-AIN, except in NSAID-induced disease, in which proteinuria is the predominant lab abnormality. Early steroid use appears to be beneficial.[15][87][88][89] If the differential diagnoses contain only disorders for which steroids would be therapeutic, there may be little reason to wait for the usual 5 to 7 days after medication withdrawal before starting therapy in the more severe cases.

AIN should be considered in the differential diagnosis of any patient with worsening renal function or newly discovered azotemia. A careful, focused, and comprehensive medication history, including OTC drugs, should be obtained, and a thorough physical examination should look for unexplained or new arthralgias, flank pain, fever, and rashes. Close cooperation and communication among the interprofessional healthcare team will help optimize patient outcomes. Clinicians who prescribe medications should be aware of those with a high potential for causing AIN and which patients might be at higher risk, such as older individuals. A careful and thorough medication history should be obtained and verified by all members of the clinical healthcare team, including nurses and pharmacists. Adverse reactions, including those associated with AIN, should be identified and reported. Patients should be aware of the importance of reporting possible adverse reactions so their healthcare team can take appropriate action. Nephrologists should be involved in any patient with newly discovered azotemia to advise on drug management, therapeutic steroid use, differential diagnoses for AKI, and the need and timing for a kidney biopsy. Interventional radiology or nephrology may need to be involved to perform the actual biopsy, while pathology will evaluate the specimen histologically to confirm the presence of AIN. Close coordination, communication, and cooperation within the interprofessional healthcare team (primary care physicians, nephrologists, pharmacists, dermatologists, histopathologists, nurses, and other professionals) will help improve patient care, preserve renal function, avoid end-stage renal disease, and optimize outcomes.