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Letter to the Editor
DOI: 10.1016/j.nefro.2019.06.005
Open Access
Disponible online el 23 de Octubre de 2019
Basophil activation test in interstitial nephritis. Some comments
Test de activación de basófilos en la interstitial nephritis. Algunos comentarios
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Salvatore Chirumboloa,
Autor para correspondencia
salvatore.chirumbolo@univr.it

Corresponding author.
, Geir Bjørklundb, Antonio Vellac
a Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona, Verona, Italy
b Council for Nutritional and Environmental Medicine (CONEM), Mo i Rana, Norway
c Unit of Immunology and Cytofluorimetry-AOUI, Policlinico GB Rossi piazzale AL Scuro 10, 37134 Verona, Italy
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Dear Editor:

The recent paper by Lara Belmar Vega and coworkers introduced the role of a CD123pos/HLADRneg basophil activation test (BAT) in a case report of interstitial nephritis, suggesting the occurrence of an interstitial nephropathy secondary to the use of omeprazole.1 Omeprazole is well known from past reports to cause interstitial nephritis.2 The renal oedematosus interstitium having a massive infiltration of leukocytes and eosinophils, suggested the author to assess an immune response, due to the omeprazole therapy. This case report should assess the optimal use of BAT in omeprazole hypersensitivity.3 Despite the fact that the authors were not endowed with further allergic tests, such as skin prick test (SPT) or serum IgEs to assess their evidence, they moved on the clinical suspicion of an allergy-driven nephropathy caused by an hypersensitivity response to omeprazole and found a CD63 stimulation index (SI) ≥4.1 and ≥10% respect the basal, non activated level.1 The analytical performance of a BAT based on the CD123pos/HLADRneg gating protocol allowed the authors to easily capture basophils in a flow cytometry (FC) approach and to assess cell activation by evaluating the CD63 membrane upregulation upon the activation from omeprazole-caused drug hypersensitivity. Yet, the activation is only slightly higher (i.e. 10.25%) than the indicated cut off, which is ≤5% and did not reach the much more encouraging level of an fMLP-mediated activation (34.9%).1 Causes underlying this moderate, poor activation may be further elucidated by introducing in the test a polyclonal anti-IgE agonist, to probe the level of releasability and activation of basophils in the IgE-mediated mechanism.4 Furthermore, a CD203c marker to assess also a possible involvement of non IgE-mediated reactions might be useful to better comprehend the observed reaction to omeprazole.1 Noteworthy, omeprazole targets H2-receptors, so hampering the counter-regulation of basophil activation by histamine, their costitutive activation and the subsequent down-regulation of the FcɛRI/IgEs complexes, causing therefore a desensitized cell and/or a CD63 exhausted pool.5–8 The apparently low level of activation can be also explained by the same gating strategy used by the authors. As already reported in our labs, capturing basophils as SSClow/CD123pos cells, results in the inclusion of further non basophilic CD123pos cells.9 These cells can be differentiated as CD45pos cells and/or CD203cneg leukocytes, while basophils are notoriously CD45dim/CD123bright cells.9 The inclusion of more CD123pos events in the gate, while basophils are only Cd123bright cells, underestimates the CD63%, because a possible apparet “cellular loss”, as previously reported, actually caused by a biased gating protocol.10,11

Therefore, the enthusiastic conclusion about the use of BAT in drug hypersensitivity, should be softened by introducing some bias-preventing warnings:

  • a)

    basophils should be optimally captured in FC as CD45dim/CD123bright/HLA-DRneg cells, without starting in the FSC/SSC dot plot;

  • b)

    the introduction of a CD203c activation marker may be particulaly useful to discern non IgE from IgE-mediated responses.

In the case report described by the authors one cannot exclude the hypothesis that the effect of omeprazole on basophils may be of immune, pharmacological origin, rather than allergic. The interaction with H2 and H4-receptors may block the histamine-mediated loop to deactivate basophils, causing the ongoing release of IL-4 from these leukocytes and the activation of a Th-mediated response, an effect that can increase the production of IgGs, with consequent nephritis onset.12,13

This paper is interesting because permits to focus onto the major effect exerted by a BAT in the clinics.

Conflict of interest

The authors state they have no conflict of interest.

References
[1]
L. Belmar Vega, M. López Hoyos, D. San Segundo Arribas, J. Irure Ventura, G. Fernández Fresnedo, J.C. Ruiz San Millán, et al.
Basophil activation test. Tool for the diagnosis of interstitial nephritis.
Nefrologia, 39 (2019), pp. 436-438
[2]
D. Yip, S. Kovac, M. Jardine, J. Horvath, M. Findlay.
Omeprazole-induced interstitial nephritis.
J Clin Gastroenterol, 25 (1997), pp. 450-452
[3]
J.J. Laguna, G. Bogas, M. Salas, C. Mayorga, J. Dionicio, R. Gonzalez-Mendiola, et al.
The basophil activation test can be of value for diagnosing immediate allergic reactions to omeprazole.
J Allergy Clin Immunol Pract, 6 (2018), pp. 1628-1636
[4]
S. Chirumbolo, A. Vella, R. Ortolani, M. De Gironcoli, P. Solero, G. Tridente, et al.
Differential response of human basophil activation markers: a multi-parameter flow cytometry approach.
Clin Mol Allergy, 6 (2008), pp. 12
[5]
S. Chirumbolo.
Basophil activation test in allergy: time for an update?.
Int Arch Allergy Immunol, 158 (2012), pp. 99-114
[6]
S. Chirumbolo, M. Brizzi, R. Ortolani, A. Vella, P. Bellavite.
Inhibition of CD203c membrane up-regulation in human basophils by high dilutions of histamine: a controlled replication study.
Inflamm Res, 58 (2009), pp. 755-764
[7]
S. Mommert, S. Kleiner, M. Gehring, B. Eiz-Vesper, H. Stark, R. Gutzmer, et al.
Human basophil chemotaxis and activation are regulated via the histamine H4 receptor.
Allergy, 71 (2016), pp. 1264-1273
[8]
A. Tedeschi, M. Lorini, M. Arquati, A. Miadonna.
Regulation of histamine release from human basophil leucocytes: role of H1, H2 and H3 receptors.
Allergy, 46 (1991), pp. 626-631
[9]
S. Chirumbolo, G. Bjorklund, A. Vella.
Using a CD45dim/CD123bright/HLA-DRneg phenotyping protocol to gate basophils in FC for airway allergy. CD123 does not decrease.
Adv Respir Med, 85 (2017), pp. 193-201
[10]
A.F. Santos, N. Bécares, A. Stephens, V. Turcanu, G. Lack.
The expression of CD123 can decrease with basophil activation: implications for the gating strategy of the basophil activation test.
Clin Transl Allergy, 6 (2016), pp. 11
[11]
S. Chirumbolo.
Major pitfalls in BAT performance may be caused by gating protocols and CD63% cut off evaluation.
Cytometry A, 85 (2014), pp. 382-385
[12]
A.K. Moharana, S.K. Bhattacharya, P.K. Mediratta, K.K. Sharma.
Possible role of histamine receptors in the central regulation of immune responses.
Indian J. Physiol Pharmacol., 44 (2000), pp. 153-160
[13]
M. Jutel, K. Blaser, C.A. Akdis.
The role of histamine in regulation of immune responses.
Chem Immunol Allergy., 91 (2006), pp. 174-187
Copyright © 2019. Sociedad Española de Nefrología
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