Urine eosinophils for acute interstitial nephritis

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Acute interstitial nephritis (AIN) is an important cause of acute kidney injury (AKI) in the hospital setting. However, the diagnosis of AIN is challenging because of its nonspecific clinical manifestations and the invasiveness of kidney biopsy, the gold standard for diagnosis. Urine eosinophils (UEs) emerged several decades ago as a noninvasive alternative for diagnosing AIN. Initial studies found UEs had a significant diagnostic value, but these studies had small sample sizes, and the diagnosis of AIN was made on clinical grounds only, without biopsy confirmation. In this article, we review the literature on the diagnostic value of UEs in the diagnosis of AIN.

A 62-year-old woman with type 2 diabetes mellitus, systemic hypertension, coronary artery disease, and obesity is admitted for AKI found on routine laboratory testing. She has been taking amoxicillin and doxycycline for left leg cellulitis the past 5 days, but improvement has been minimal. On admission, blood pressure is 120/74 mm Hg, and heart rate is 89 beats per minute. Serum creatinine level is increased, from 0.7 mg/dL at baseline to 3.6 mg/dL on admission. Complete urinalysis reveals 1+ protein and presence of white blood cells and isormorphic red blood cells. No casts or crystals are seen. Given the possibility of AIN, UE testing is ordered. UEs are positive at 25%. Does this result significantly increase the patient’s posttest probability of having AIN?

WHY YOU MIGHT THINK ORDERING URINE EOSINOPHILS IN THE EVALUATION OF AIN IS HELPFUL

AKI occurs in more than 1 in 5 hospitalizations and is associated with a more than 4-fold increased likelihood of in-hospital mortality at 21 days.¹ AIN is an important cause of AKI and has been found in 6% to 30% of AKI patients who had biopsies performed.^2-4 AIN is characterized by infiltration of inflammatory cells in the kidney interstitium and is more commonly caused by drugs, especially beta-lactam antibiotics, and less commonly by autoimmune or systemic diseases and infections. As the signs and symptoms of AIN are nonspecific, and the gold-standard test is renal biopsy, diagnosticians have sought a noninvasive test, such as UEs.

In 1978, Galpin et al.⁵ found that UEs comprised 10% to 60% of urine white blood cells in 9 of 9 patients with methicillin-induced interstitial nephritis; 6 of the 9 had biopsy-proven AIN. In 1980, Linton et al.⁶ found UEs in 6 of 9 patients with drug-induced AIN; 8 of the 9 had biopsy-proven AIN. In 1986, Nolan et al.⁷ reported that, compared with Wright stain, Hansel stain was more sensitive in visualizing UEs; they did not use biopsy for confirmation. Wright-stain detection of UEs is limited by the variable staining characteristics of “eosinophilic” granules in body fluids other than blood. With Hansel stain, UEs are readily identified by their brilliant red-pink granules. These 3 small studies helped make UEs the go-to noninvasive test for assessing for AIN.⁸

WHY THERE IS LITTLE REASON TO ORDER URINE EOSINOPHILS IN PATIENTS WITH SUSPICION FOR AIN

While initial studies indicated UEs might be diagnostically helpful, subsequent studies did not. In 1985, Corwin et al.⁹ used Wright stain and found UEs in 65 of 470 adults with AKI. Only 9 (14%) of the 65 had a diagnosis of AIN, which was made mostly on clinical grounds. These findings showed that UEs were produced by other renal or urinary tract abnormalities, such as urinary tract infections, acute tubular necrosis, and glomerulonephritis. In a second study, Corwin et al.¹⁰ found that Hansel stain (vs Wright stain) improved the sensitivity of UEs for AIN diagnosis, from 25% to 62.5%. Sensitivity was improved at the expense of specificity, as Hansel stain was positive in other diagnoses as well. The AIN diagnosis was not confirmed by kidney biopsy in the large majority of patients in this study. Lack of confirmation by biopsy, the gold-standard diagnostic test, was a methodologic flaw of this study and others.