Skip to main content

Main menu

  • Home
  • Content
    • Published Ahead of Print
    • Current Issue
    • Podcasts
    • Subject Collections
    • Archives
    • ASN Meeting Abstracts
    • Saved Searches
  • Authors
    • Submit a Manuscript
    • Author Resources
  • Trainees
    • Peer Review Program
    • Prize Competition
  • About CJASN
    • About CJASN
    • Editorial Team
    • CJASN Impact
    • CJASN Recognitions
  • More
    • Alerts
    • Advertising
    • Feedback
    • Reprint Information
    • Subscriptions
  • ASN Kidney News
  • Other
    • JASN
    • Kidney360
    • Kidney News Online
    • American Society of Nephrology

User menu

  • Subscribe
  • My alerts
  • Log in
  • My Cart

Search

  • Advanced search
American Society of Nephrology
  • Other
    • JASN
    • Kidney360
    • Kidney News Online
    • American Society of Nephrology
  • Subscribe
  • My alerts
  • Log in
  • My Cart
Advertisement
American Society of Nephrology

Advanced Search

  • Home
  • Content
    • Published Ahead of Print
    • Current Issue
    • Podcasts
    • Subject Collections
    • Archives
    • ASN Meeting Abstracts
    • Saved Searches
  • Authors
    • Submit a Manuscript
    • Author Resources
  • Trainees
    • Peer Review Program
    • Prize Competition
  • About CJASN
    • About CJASN
    • Editorial Team
    • CJASN Impact
    • CJASN Recognitions
  • More
    • Alerts
    • Advertising
    • Feedback
    • Reprint Information
    • Subscriptions
  • ASN Kidney News
  • Visit ASN on Facebook
  • Follow CJASN on Twitter
  • CJASN RSS
  • Community Forum
Editorials
You have accessRestricted Access

Urinary Eosinophils in AIN: Farewell to an Old Biomarker?

Mark A. Perazella and Andrew S. Bomback
CJASN November 2013, 8 (11) 1841-1843; DOI: https://doi.org/10.2215/CJN.08620813
Mark A. Perazella
*Section of Nephrology, Yale University School of Medicine, New Haven, Connecticut; and
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Andrew S. Bomback
†Division of Nephrology, Columbia University Medical Center, New York, New York
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • Article
  • Figures & Data Supps
  • Info & Metrics
  • View PDF
Loading

Urinary biomarkers of kidney injury are an area of ongoing research in nephrology. For years, urinary eosinophils have been used as biomarkers for acute interstitial nephritis (AIN). The characteristics that would make eosinophiluria a useful biomarker for AIN include that (1) eosinophils are consistently present in the urine of patients with AIN (i.e., AIN is characterized by an eosinophilic interstitial infiltrate), (2) eosinophils are absent in the setting of another etiology of AKI (i.e., other renal and extrarenal diseases are not associated with eosinophiluria), and (3) a predetermined percentage of eosinophils is easily visualized in the urine when present (i.e., excellent stain performance).

As early as 1967, urinary eosinophils were reported in rejection episodes after kidney transplantation, suggesting that they were associated with “kidney inflammation” (1). The earliest description of this test as a biomarker for AIN was by Galpin et al. (2) in 1978. Using the Wright stain, nine of nine cases of methicillin-associated AIN had urinary eosinophils. Six of nine cases had biopsy-proven AIN, with eosinophils within the renal interstitium and occasionally, tubular lumens; 0 of 43 patients with AKI from another diagnosis had eosinophiluria. These data implied that eosinophiluria was a sensitive and specific test for AIN. Linton et al. (3) subsequently described eosinophiluria in six of nine patients with drug-induced AIN. Eight patients had biopsy-proven AIN, with five patients having prominent interstitial eosinophils. Overall, these two small studies suggested that eosinophiluria might be a reasonably good biomarker for AIN.

Additional work on this subject by Corwin et al. (4) examined the clinical correlates of eosinophiluria using the Wright stain in 65 patients. AIN was diagnosed in 9 of 65 patients, with eosinophiluria noted in 8 of 9 of these cases, replicating previous data. However, urinary eosinophils were also shown in 27 of 56 patients with diagnoses other than AIN (Table 1), suggesting that the test was rather nonspecific. Corwin et al. (4) concluded that using a >5% eosinophil cutoff might identify a group with higher probability of having AIN. However, 6 of 56 non-AIN patients and only 4 of 9 AIN patients met this cutoff, which (not unexpectedly) improved specificity but reduced sensitivity. The lack of sensitivity of urinary eosinophils was further emphasized in a review paper based on data from 10 studies examining drug-induced AIN showing that eosinophiluria was present in only 59% (19/32) of biopsy-proven AIN cases (5).

View this table:
  • View inline
  • View popup
Table 1.

Urinary eosinophils in the diagnosis of acute interstitial nephritis

Because low sensitivity was the major concern, Nolan et al. (6) renewed interest in eosinophiluria as an AIN biomarker with a New England Journal of Medicine publication that hailed the Hansel stain as a better method to visualize urinary eosinophils. This stain was chosen based on its use in identifying eosinophils in nasal, bronchial, and ocular secretions of patients with allergy-related diseases; 92 patients with an active urine sediment were identified by the nephrology consult service, of which 11 patients had AIN (proven by biopsy in 2 patients). Hansel stain was positive in 10 of 11 AIN cases, whereas Wright stain was positive in only 2 of 11 cases. Hansel stain was also positive in other diagnoses but negative in all 30 acute tubular necrosis cases (Table 1). Overall, the Hansel stain provided a sensitivity of 91% and positive predictive value of 45%. Nolan et al. (6) concluded that the Hansel stain improved the sensitivity of eosinophiluria in AIN but that the test was not specific. Nolan et al. (6) emphasized that it was useful when the differential diagnosis of AKI boiled down to AIN versus acute tubular necrosis. Additionally, Nolan et al. (6) argued that a positive test in the setting of high pretest probability for AIN tends to confirm the diagnosis, whereas negative eosinophiluria in patients with low pretest probability can reasonably exclude AIN. However, lack of biopsy confirmation of AIN was a major flaw of the paper.

In the face of these data, a study was undertaken to more completely define the significance of eosinophiluria (7). Urine for eosinophils was examined in 183 patients assigned a clinical diagnosis using blinded chart review, with AIN based on biopsy or clinical diagnosis. Eosinophiluria was documented in 20 patients, with Hansel stain positive in 18 of 20 patients and Wright stain positive in 8 of 20 patients. Hansel and Wright stains were positive in five of eight and two of eight AIN cases, respectively. Clearly, Hansel stain improved urinary eosinophil detection compared with Wright stain, confirming the data in the work by Nolan et al. (6). Although Hansel stain was also positive in other diagnoses, it still had a very good specificity and negative predictive value of 98% (Table 1). Corwin et al. (7) concluded that Hansel stain improved detection of urinary eosinophils, but its use for diagnosis of AIN remained unclear.

A study directed at patients suspected of having an acute kidney process who also had urine eosinophils measured was conducted by Ruffing et al. (8). AIN was noted in 15 patients, of which Hansel stain was positive in 6 patients. Eosinophiluria was also present in 10 of 36 patients with other diagnoses; overall, the test underperformed in this selected group compared with previous studies (Table 1). Ruffing et al. (8) felt that eosinophiluria was not suitable as a stand-alone test to make a diagnosis of AIN. It is also worth noting that, in addition to these studies, numerous case reports have described eosinophiluria in various diseases, including atheroembolic disease, allergic granulomatosis, bladder tumors, ileal conduits, and asthma.

Despite the unclear utility of eosinophiluria, with its varying ranges of sensitivity and specificity, the test has been widely used to evaluate for the possibility of AIN. Our experience is that many clinicians automatically order this test in the workup of hospital-acquired AKI. A positive result is then incorrectly used to support a diagnosis of AIN (and discontinuation of potential culprit medications), whereas negative urinary eosinophils often lead to inappropriate exclusion of AIN as the cause of AKI. A letter to the New England Journal of Medicine highlighted the common and concerning clinical practice of ordering urinary eosinophils for AIN workup (9).

In this issue of CJASN, Muriithi et al. (10) seem to strike, perhaps, the final blow against the use of eosinophiluria in diagnosing AIN. Using data over an 18-year period, Muriithi et al. (10) identified 566 patients with both urinary eosinophil testing and kidney biopsies performed within the same week. Approximately two thirds (63 of 91) of the biopsy-confirmed AIN cases in this cohort tested negative for any urinary eosinophils. When urinary eosinophils≥1% were used as a cutoff for a positive test, this assay identified only 28 of 91 AIN cases (30.8%), with a similar positive rate in acute tubular necrosis (20 of 69 cases or 29.0%). A 5% urinary eosinophil cutoff only slightly improved specificity but with a concomitant decreased sensitivity.

The study by Muriithi et al. (10) is not without its limitations, chief among them the selection bias inherent in any biopsy-based cohort. Most diagnoses of AIN are made clinically using history, physical examination, and laboratory findings; renal biopsy is generally performed if either the diagnosis of AIN is unclear or the diagnosis is likely but confirmation is needed before modifying therapy or in select cases, starting steroids. In theory, a large number of nonbiopsied patients with AIN and urinary eosinophils could have been excluded from this cohort. Nonetheless, such clinical diagnoses of AIN are themselves flawed given lack of confirmation by biopsy, which remains the gold standard for diagnosing AIN. Manual inspection of the urinary sediment by a treating nephrologist is likely the next best option after kidney biopsy in diagnosing AIN. A sediment replete with white blood cell casts and urinary eosinophils, in the setting of an appropriate clinical history, may be sufficient to diagnose AIN. Notably, the results presented by Muriithi et al. (10) highlight the poor performance of the Hansel stain in AIN and do not necessarily apply to manual sediment analysis.

Although the lack of specificity of eosinophiluria for AIN is understandable, why is the test insensitive, even with use of Hansel stain? Possible explanations are that (1) eosinophils are not always shed into the urine at a high enough number to reach >1% of white blood cells, (2) urinary eosinophils lyse before visualization, or (3) the cause of AIN is not characterized by a prominent eosinophilic interstitial infiltrate. The last point is true in many systemic diseases associated with AIN, such as sarcoidosis, Sjogren’s syndrome, and various infections. In contrast, drug-induced AIN is considered to be allergic and marked by an eosinophilic infiltrate. In fact, many pathologists raise the specter of drug-induced AIN when eosinophils are present. However, although β-lactam drugs are classically associated with this finding, not all medications promote an eosinophilic infiltrate (i.e., nonsteroidal anti-inflammatory drugs). In fact, four studies focusing on drug-induced AIN showed that only 24 of 40 (60%) patients had a significant eosinophilic interstitial infiltrate on biopsy (2,3,11,12). Regardless of the explanation, the paper by Muriithi et al. (10) should signal the end of urinary eosinophils as a useful biomarker for AIN and provide nephrologists with data to definitively recommend against this test.

This end of an era is particularly important, because we have entered a new era of greater use of steroids in confirmed cases of AIN. Although no prospective, randomized controlled trials have emerged to support the use of steroid therapy for AIN, over the last two decades, data showing the benefits of steroid therapy for AIN have improved from anecdotal case reports to larger cohort series with favorable outcomes in treated versus nontreated patients (13). Appropriate use of steroids, along with removal of the offending agent, can potentially reverse AIN lesions, restore kidney function, and minimize risk of progression to CKD and/or ESRD. This potential, however, seems to rest primarily on how quickly the lesion is identified and how early steroid therapy is introduced. Urinary eosinophils clearly are inadequate biomarkers for such crucial identification.

Disclosures

A.S.B. has received royalties from UptoDate.

Footnotes

  • Published online ahead of print. Publication date available at www.cjasn.org.

  • See related article, “Utility of Urine Eosinophils in the Diagnosis of Acute Interstitial Nephritis,” on pages 1857–1862.

  • Copyright © 2013 by the American Society of Nephrology

References

  1. ↵
    1. Spencer ES,
    2. Petersen VP
    : The urinary sediment after renal transplantation. Quantitative changes as an index of the activity of the renal allograft reaction. Acta Med Scand 182: 73–82, 1967
    OpenUrlPubMed
  2. ↵
    1. Galpin JE,
    2. Shinaberger JH,
    3. Stanley TM,
    4. Blumenkrantz MJ,
    5. Bayer AS,
    6. Friedman GS,
    7. Montgomerie JZ,
    8. Guze LB,
    9. Coburn JW,
    10. Glassock RJ
    : Acute interstitial nephritis due to methicillin. Am J Med 65: 756–765, 1978
    OpenUrlCrossRefPubMed
  3. ↵
    1. Linton AL,
    2. Clark WF,
    3. Driedger AA,
    4. Turnbull DI,
    5. Lindsay RM
    : Acute interstitial nephritis due to drugs: Review of the literature with a report of nine cases. Ann Intern Med 93: 735–741, 1980
    OpenUrlCrossRefPubMed
  4. ↵
    1. Corwin HL,
    2. Korbet SM,
    3. Schwartz MM
    : Clinical correlates of eosinophiluria. Arch Intern Med 145: 1097–1099, 1985
    OpenUrlCrossRefPubMed
  5. ↵
    1. Sutton JM
    : Urinary eosinophils. Arch Intern Med 146: 2243–2244, 1986
    OpenUrlCrossRefPubMed
  6. ↵
    1. Nolan CR 3rd.,
    2. Anger MS,
    3. Kelleher SP
    : Eosinophiluria—a new method of detection and definition of the clinical spectrum. N Engl J Med 315: 1516–1519, 1986
    OpenUrlPubMed
  7. ↵
    1. Corwin HL,
    2. Bray RA,
    3. Haber MH
    : The detection and interpretation of urinary eosinophils. Arch Pathol Lab Med 113: 1256–1258, 1989
    OpenUrlPubMed
  8. ↵
    1. Ruffing KA,
    2. Hoppes P,
    3. Blend D,
    4. Cugino A,
    5. Jarjoura D,
    6. Whittier FC
    : Eosinophils in urine revisited. Clin Nephrol 41: 163–166, 1994
    OpenUrlPubMed
  9. ↵
    1. Fletcher A
    : Eosinophiluria and acute interstitial nephritis. N Engl J Med 358: 1760–1761, 2008
    OpenUrlCrossRefPubMed
  10. ↵
    1. Muriithi AK,
    2. Nasr SH,
    3. Leung N
    : Utility of urine eosinophils in the diagnosis of acute interstitial nephritis. Clin J Am Soc Nephrol 8: 1857–1862, 2013
    OpenUrlAbstract/FREE Full Text
  11. ↵
    1. Kleinknecht D,
    2. Vanhille P,
    3. Morel-Maroger L,
    4. Kanfer A,
    5. Lemaitre V,
    6. Mery JP,
    7. Laederich J,
    8. Callard P
    : Acute interstitial nephritis due to drug hypersensitivity. An up-to-date review with a report of 19 cases. Adv Nephrol Necker Hosp 12: 277–308, 1983
    OpenUrlPubMed
  12. ↵
    1. Pusey CD,
    2. Saltissi D,
    3. Bloodworth L,
    4. Rainford DJ,
    5. Christie JL
    : Drug associated acute interstitial nephritis: Clinical and pathological features and the response to high dose steroid therapy. Q J Med 52: 194–211, 1983
    OpenUrlPubMed
  13. ↵
    1. González E,
    2. Gutiérrez E,
    3. Galeano C,
    4. Chevia C,
    5. de Sequera P,
    6. Bernis C,
    7. Parra EG,
    8. Delgado R,
    9. Sanz M,
    10. Ortiz M,
    11. Goicoechea M,
    12. Quereda C,
    13. Olea T,
    14. Bouarich H,
    15. Hernández Y,
    16. Segovia B,
    17. Praga M
    ; Grupo Madrileño De Nefritis Intersticiales: Early steroid treatment improves the recovery of renal function in patients with drug-induced acute interstitial nephritis. Kidney Int 73: 940–946, 2008
    OpenUrlCrossRefPubMed
PreviousNext
Back to top

In this issue

Clinical Journal of the American Society of Nephrology: 8 (11)
Clinical Journal of the American Society of Nephrology
Vol. 8, Issue 11
November 07, 2013
  • Table of Contents
  • Table of Contents (PDF)
  • Index by author
View Selected Citations (0)
Print
Download PDF
Sign up for Alerts
Email Article
Thank you for your help in sharing the high-quality science in CJASN.
Enter multiple addresses on separate lines or separate them with commas.
Urinary Eosinophils in AIN: Farewell to an Old Biomarker?
(Your Name) has sent you a message from American Society of Nephrology
(Your Name) thought you would like to see the American Society of Nephrology web site.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Citation Tools
Urinary Eosinophils in AIN: Farewell to an Old Biomarker?
Mark A. Perazella, Andrew S. Bomback
CJASN Nov 2013, 8 (11) 1841-1843; DOI: 10.2215/CJN.08620813

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
Request Permissions
Share
Urinary Eosinophils in AIN: Farewell to an Old Biomarker?
Mark A. Perazella, Andrew S. Bomback
CJASN Nov 2013, 8 (11) 1841-1843; DOI: 10.2215/CJN.08620813
del.icio.us logo Digg logo Reddit logo Twitter logo CiteULike logo Facebook logo Google logo Mendeley logo
  • Tweet Widget
  • Facebook Like

Jump to section

  • Article
    • Disclosures
    • Footnotes
    • References
  • Figures & Data Supps
  • Info & Metrics
  • View PDF

More in this TOC Section

  • Growing Understanding of the Antigenic Basis for Membranous Nephropathy
  • Measuring Patient Experience with Home Dialysis in the United States
  • The Promise and Challenge of Aerobic Exercise in People Undergoing Long-Term Hemodialysis
Show more Editorials

Cited By...

  • Diagnosis and Management of Immune Checkpoint Inhibitor-Associated Renal Toxicity: Illustrative Case and Review
  • Rare allergic reaction of the kidney: sitagliptin-induced acute tubulointerstitial nephritis
  • Google Scholar

Similar Articles

Related Articles

  • Utility of Urine Eosinophils in the Diagnosis of Acute Interstitial Nephritis
  • PubMed
  • Google Scholar

Articles

  • Current Issue
  • Early Access
  • Subject Collections
  • Article Archive
  • ASN Meeting Abstracts

Information for Authors

  • Submit a Manuscript
  • Trainee of the Year
  • Author Resources
  • ASN Journal Policies
  • Reuse/Reprint Policy

About

  • CJASN
  • ASN
  • ASN Journals
  • ASN Kidney News

Journal Information

  • About CJASN
  • CJASN Email Alerts
  • CJASN Key Impact Information
  • CJASN Podcasts
  • CJASN RSS Feeds
  • Editorial Board

More Information

  • Advertise
  • ASN Podcasts
  • ASN Publications
  • Become an ASN Member
  • Feedback
  • Follow on Twitter
  • Password/Email Address Changes
  • Subscribe to ASN Journals

© 2021 American Society of Nephrology

Print ISSN - 1555-9041 Online ISSN - 1555-905X

Powered by HighWire