Approach
Acute interstitial nephritis (AIN) should be suspected in all patients who develop non-oliguric acute kidney injury (AKI), and particularly those taking multiple medications. Other causes of AKI, including acute tubular necrosis, acute glomerulonephritis, and acute vascular changes, should be excluded. Referral to a nephrology specialist is advisable.
Clinical assessment
Patients present with non-oliguric loss of kidney function (AKI) or slower loss of kidney function (acute kidney disease). Some patients will also have rash, fever, or eosinophilia of the peripheral blood (the 'hypersensitivity triad'), but few will have all three at the time of presentation.[1][4][11] Arthralgia is sometimes seen as an associated symptom.
Over 250 medications are known to trigger AIN; the use of any of these should raise suspicion of AIN.[3][8][10] Antibiotics, particularly beta-lactams, are commonly implicated. Almost all penicillins and cephalosporins, many sulfonamides, rifampicin, and a variety of fluoroquinolones are known triggers. Other triggers include diuretics, non-steroidal anti-inflammatory drugs (NSAIDs), proton-pump inhibitors, immune checkpoint inhibitors, H2 antagonists (cimetidine and ranitidine), allopurinol, phenindione, phenytoin, sulfadiazine, mesalazine, and warfarin.
Uncommonly, patients with Sjogren syndrome, sarcoidosis, IgG4-related syndrome, and systemic lupus erythematosus can also develop AIN. Patients with AIN occurring as part of the tubulo-interstitial nephritis with uveitis (TINU) syndrome will also have uveitis; this is extremely rare.
Clinical examination is usually unremarkable. Fever may be present, but is non-specific and may reflect an underlying infection (for which the antibiotic is prescribed). The associated rash is usually macular or maculopapular. Costovertebral angle tenderness may be present in some patients. NSAIDs may trigger a unique reaction consisting of AIN with a concurrent nephrotic syndrome; these patients develop oedema secondary to hypoalbuminaemia.
Initial investigations
Blood tests[1]
Serum urea and serum creatinine are required to detect and assess the severity of AKI or acute kidney disease. Patients may also present with worsening kidney function in the setting of pre-existing chronic kidney disease.
Full blood count with white blood cell (WBC) differential reveals significant eosinophilia in some cases. Blood testing may also reveal the presence of anaemia and acidosis.[19]
Anti-neutrophil cytoplasmic antibody (ANCA), anti-nuclear antibody (ANA), anti-double stranded DNA (anti-ds DNA), and complement profile if associated systemic disease suspected. ANCA is associated with systemic vasculitis, and ANA and anti-ds DNA are associated with systemic lupus erythematosus.
Often shows sterile pyuria (leukocytes with a negative urine culture for bacteria). WBC casts are highly suggestive of AIN diagnosis, although these were present in <15% of AIN cases in one study.[20] Urine microscopy may also reveal granular casts and renal tubular epithelial cells due to accompanying tubular injury.[19]
Absence of dysmorphic red blood cells (RBCs) and RBC casts excludes acute glomerulonephritis in many but not all cases.
Presence of urine eosinophils may be suggestive. However, evidence shows that this test is neither specific nor sensitive.[21][22] This test should not be ordered to evaluate for AIN.
Heavy proteinuria suggests the presence of nephrotic syndrome. If the patient has nephrotic syndrome but is not taking NSAIDs, other causes should be investigated. Low grade ('tubular', <1 g/day) is often seen due to accompanying tubular damage.
AIN diagnostic model
A combination of four commonly available tests may provide probability of AIN in patients in whom a biopsy is being considered (serum creatinine, urea to serum creatinine, urine specific gravity, and urine protein) and is available as an online calculator.[23]
Trial of discontinuation of triggering medication
Symptoms may resolve following discontinuation of the triggering medication; a retrospective diagnosis of AIN can be made if this occurs.
If symptoms do not resolve, other diagnoses should be excluded.
Subsequent investigations
Kidney biopsy
The only test that provides a definitive diagnosis.
Performed in patients who have not responded to discontinuation of the triggering medication, where diagnosis is unclear, or if corticosteroid treatment is being considered.[11]
Requires a careful risk-benefit assessment in consultation with a nephrologist including assessment of bleeding risk. Patients with AKI have a higher rate of bleeding complications than those without AKI.[24][25] Antiplatelet and anticoagulant medications must be discontinued and not re-started for at least 48 hours after biopsy.
Typical findings are of an interstitial or tubulo-interstitial inflammatory infiltrate with variable numbers of eosinophils, lymphocytes, and plasma cells, with no bacteria, fungi, or other organisms found on special stains of the biopsy. Non-caseating granuloma may be seen in drug-induced AIN, sarcoidosis, and some other causes of AIN.
Kidney biopsy will also provide prognostic information: high degree of interstitial fibrosis indicates poor chances of recovery of kidney function whereas higher degree of infiltrate may be associated with better recovery of kidney function.
If nephrotic syndrome is present, the pattern is usually minimal change disease, although membranous nephropathy has also been reported.
Kidney ultrasound[11]
Shows large swollen kidneys that are often echogenic due to the inflammatory interstitial infiltrates and interstitial oedema.
Main use is to exclude hydronephrosis, renal calculi, or shrunken kidneys (a sign of chronic renal failure).
Gallium scan[26]
Findings are often non-specific and cannot be used to establish the diagnosis. The test has poor sensitivity and specificity.
Might be useful when negative to exclude the diagnosis, but it is only resorted to when biopsy is not an option.
Urine cytokines[27]
Urine interleukin-9 and tumour necrosis factor-alpha are higher in patients with AIN than with other renal diseases (e.g., acute tubular necrosis, glomerulonephritis, diabetic kidney disease) and AKI, and may help avoid a kidney biopsy in a subset of patients.
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