Q:

9/11/2013
I am seeing a 7 year old patient with seasonal allergies and steroid-responsive nephrotic syndrome (suspected MCNS but never biopsied at parent's refusal). She seems to flare every summer, as grass pollens peak. Previous skin testing was + for grass and cat. The family had a cat, but removed it after testing confirmed allergy (>2 years ago). Her seasonal symptoms are very mild, but she has been on oral steroids to control her nephrotic syndrome. The question of immunotherapy has been raised, primarily as an attempt to control the nephrotic flares. A review of the literature was unable to find any evidence linking allergy triggers to nephrotic flares, but the summer flares and the + skin testing raises the question of association.

Because we have grass pollen SLIT (OralAir) available in Canada, I am questioning its use. Although traditional SIT is contra-indicated in autoimmune disorders, I am unable to find any safety data for SLIT in this setting. Would you have any comments on its use (or its contraindications) in this setting? Is there anectdotal European data, given its extensive use in Europe? I am not comfortable starting grass SLIT in this setting, but if it can help control her flares without placing her at any additional risk, it may be worth considering.

A:

Thank you for your inquiry.

The line of reasoning you are following is logical and actually has been a consideration amongst allergists for many years. There is a significant body of literature linking atopy, elevated IgE, allergic rhinitis, and nephrotic syndrome (specifically steroid resistant nephrotic syndrome). Articles discussing this issue date back to the 1970’s, and also there has been at least one attempt to treat nephrotic syndrome with allergen immunotherapy (in this instance, subcutaneous immunotherapy). I have copied below a select group of references and abstracts that illustrate the type of literature dealing with this issue. Thus, although there are some articles to the contrary, the weight of evidence seems to support a link between atopic disease, specifically allergic rhinitis, and nephrotic syndrome. In addition, flares of nephrotic syndrome during the pollen season have been reported.

The difficulty, however, is deciding on whether or not immunotherapy would be potentially beneficial, and more so, whether it could possibly be detrimental. As you know, there are a number of anecdotal reports that immunization can cause or exacerbate nephrotic syndrome. I have copied below an abstract of one such report for your interest.

Thus, although there is a theoretical possibility that immunotherapy could be of benefit, there is also an argument to avoid immunizations of any sort. I do not believe that one can make a distinction in this regard for sublingual immunotherapy. The reason for this is that when one looks at the immunologic changes associated with sublingual immunotherapy (the production of specific IgG against the allergen involved, a temporary rise in specific IgE to the allergen involved, and a shift from TH2 to TH1 cytokine production), the changes for both forms of immunotherapy appear to be identical. In addition, as you know, the dose of pollen is considerably higher when one administers it sublingually. Thus, I do not believe the issue is the form of immunotherapy per se, but rather whether any form of allergen immunotherapy would be helpful versus harmful.

I wish I could give you a definitive answer to this question, but one is simply not available. There are no studies that would allow us to come to a conclusion, and therefore the decision as to whether to administer immunotherapy would be entirely left to one’s clinical judgment.

In summary, the profile of your patient is one that has been described in the past, and there are a number of articles dealing with the issues you have brought forth. The novel feature of course is the present availability of sublingual immunotherapy, but, as noted, I do not think there is a clinically significant difference based on the route of administration in regards to whether or not the result would be beneficial or harmful. That is, I would approach the problem in light of whether or not allergen immunotherapy, regardless of the route of administration, would be of help. And unfortunately, there is no evidence in the literature to allow us to answer this question with any confidence.

Thank you again for your inquiry.

J Investig Allergol Clin Immunol. 1992 May-Jun;2(3):136-40.
Nephrotic syndrome and respiratory allergy in childhood.
Florido JF, Díaz Pena JM, Belchi J, Estrada JL, García Ara MC, Ojeda JA.
Source
Servicio de Alergia, Hospital La Paz, Madrid, Spain.
Abstract
The etiology and pathogenesis of idiopathic nephrotic syndrome remain obscure. Several investigations have reported a role for allergy in the development and maintenance of this disease, especially in childhood. We have studied 20 pediatric patients with relapses of nephrotic syndrome related in time to respiratory symptoms. Sensitization was demonstrated to one or more allergens in 7 patients with episodes of proteinuria of seasonal tendency. Preventive management with disodium cromoglycate was successful in preventing new relapses in 3 patients; specific immunotherapy was assayed in another 2 without beneficial outcome. There appears to be a pathogenic relationship between respiratory allergy and proteinuria in some cases of nephrotic syndrome.

Clin Allergy. 1975 Jun;5(2):121-37.
Seasonal nephrotic syndrome. Description and immunological findings.
Reeves WG, Cameron JS, Johansson SG, Ogg CS, Peters DK, Weller RO.
Abstract
Three cases are described showing a seasonal exacerbation of their nephrotic syndrome in association with an atopic trait and grass pollen allergy. The first patient has a history of four consecutive seasonal relapses each requiring steroid therapy. Following a course of desensitization injections he has now been free of relapse for 3 consecutive years. The second patient has also had a recurrent steroid-sensitive nephrotic syndrome often associated with the pollen season and allergic rhinitis. In this patient a course of cyclophosphamide has reduced his tendency to relapse. The third patient who has been on continuous prednisone therapy shows a seasonal increase in proteinuria. Serum changes in the first two patients include: a seasonal rise in total and grass pollen specific IgE; the continued presence of grass pollen specific IgG throughout the year but with a reduction during the pollen season in association with a more pronounced fall in the total IgG level; a depression in the C3 level in association with each major relapse; a mild rise in the I-K titre and a positive result in the Clq test for circulating complexes. A renal biopsy performed on the first patient when in relapse showed minor histological changes only and IgG, IgM, IgA, IgD, IgE, C3 and fibrinogen were undetectable by immunofluorescent examination. The probable mechanism for the development of proteinuria in these patients is discussed.

Lancet. 1970 Mar 14;1(7646):542-3.
Nephrotic syndrome associated with inhaled allergens.
Wittig HJ, Goldman AS.

Lancet. 1978 Jun 24;1(8078):1365-1365.
Antiallergic drugs in idiopathic nephrotic syndrome of childhood.
Freed DL.

J Int Med Res. 2011;39(6):2307-13.
Elevated levels of immunoglobulin E may indicate steroid resistance or relapse in adult primary nephrotic syndrome, especially in minimal change nephrotic syndrome.
Tan Y, Yang D, Fan J, Chen Y.
Source
Department of Laboratory Medicine, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.
Abstract
Immunoglobulin E (IgE) antibodies may play a role in the development of kidney diseases that are related to hypersensitivity reactions. Patients with idiopathic nephrotic syndrome often exhibit increased serum IgE levels and this may be related to sensitivity to steroid treatment. In the present study, the serum IgE levels in 120 patients with different types of primary nephrotic syndrome (PNS) were analysed and found to be significantly elevated in cases of minimal change nephrotic syndrome (MCNS) compared with membranous nephropathy or membrano-proliferative glomerulonephritis. No difference in serum IgE level was observed between cases of steroid-sensitive nephrotic syndrome (SSNS) or steroid-resistant nephrotic syndrome, although the serum IgE level was significantly elevated in SSNS patients in relapse compared with SSNS patients in remission. In MCNS patients, 73.6% exhibited SSNS regardless of their serum IgE level at diagnosis. It is concluded that elevated levels of IgE may be a feature of steroid resistance or relapse, indicating prognostic significance in adult PNS, particularly in MCNS.

Acta Paediatr. 2007 Apr;96(4):561-6. Epub 2007 Feb 26.
Atopy in childhood idiopathic nephrotic syndrome.
Salsano ME, Graziano L, Luongo I, Pilla P, Giordano M, Lama G.
Source
Department of Paediatrics, Unit of Paediatric Nephrology, Second University of Naples, Naples, and Unit of Nephrology and Paediatrics Dyalisis, Paediatrics Hospital Giovanni XXIII, Bari, Italy.
Abstract
Aim: Aim of the study was to evaluate the immunoallergic pattern and their modulating serum cytokines in children with primary manifestation of nephrotic syndrome, in order to analyse the correlation with disease activity and the outcome of childhood NS.
Materials and Methods: We have evaluated 72 children: 58 steroid-sensitive and 14 steroid-resistant; 42 subjects were the healthy controls. In all were measured serum: T cell-subset, cytokines by Th-1, Th-2, total IgE levels and specific IgE antibodies.
Results: Of the 72 children investigated, 35 (48.6%) had either a history of atopy and/or elevated serum IgE; 14 of these children (40%) had clinical sign of an atopic disease (asthma, rhinitis, dermatitis) and 21 (60%) had elevated sIgE. The atopy was more frequent among SS than SRNS patients (52% versus 36%, p<0.05). The CD19 were significantly increased in nephrotic patients compared with controls. IL-4 levels were not different from those in normal control both in SS and SRNS patients, either in relapse than in remission. There was no correlation between the sIgE and IL-4 levels. Therefore, IL-5 and Il-13 levels were significantly higher in SSNS compared to controls, in both pre than posttreatment, and higher in atopic patients. Interestingly, IL-6 and IL-10 levels were significantly increased in SRNS pretreatment compared to posttreatment and controls and, only for IL-10, significantly higher in atopic patients.
Conclusion: In our study, only 40% of atopic children had a positive allergic history and 51.4% of the nephrotic children had normal sIgE levels, both pre and posttreatment, indicating different aetiologies, as immune mechanisms, in the pathogenesis of NS. Therefore, specific IgE antibodies were not related to disease activity, suggesting that IgE production might be co-incident in childhood NS. However, the increased production of IL-5 and IL-13 in atopic SSNS may indicate that these cytokines are involved in the enhanced production of sIgE while IL-4 have a role as controlling cytokine.

Pediatr Nephrol. 2004 Jun;19(6):627-32. Epub 2004 Apr 3.
Atopy, serum IgE, and interleukin-13 in steroid-responsive nephrotic syndrome.
Cheung W, Wei CL, Seah CC, Jordan SC, Yap HK.
Source
Department of Pediatrics, National University of Singapore, 5 Lower Kent Ridge Crescent, 119074 Singapore.
Abstract
Earlier studies have demonstrated a strong association of steroid-responsive nephrotic syndrome (SRNS), atopy, and elevated serum IgE levels. Interleukin (IL-13) gene expression is significantly increased in children with SRNS in relapse. As interferon (IFN)-gamma, IL-13, and IL-4 have regulatory effects on IgE synthesis, we examined the relationship between intracellular cytokine production and serum IgE levels in children with SRNS, in order to further define the reported association with atopy. The median serum IgE levels in nephrotic patients in relapse with (492 U/ml) or without atopy (561 U/ml) were significantly higher than those in remission (221 U/ml, P<0.002 or 90 U/ml, P<0.001, respectively) and non-atopic controls (177 U/ml) (P<0.001). The percentage of CD3+ IL-13-producing cells was significantly higher in nephrotic children in relapse, and correlated with the serum IgE levels during the active phase of the disease (r=0.90, P<0.001). These data suggest that the elevated serum IgE levels during relapses of SRNS were the result of upregulation of IL-13. This probably reflects some common immune activation following various stimuli, rather than a direct association with atopy.

Am J Kidney Dis. 2009 Nov;54(5):945-53. doi: 10.1053/j.ajkd.2009.03.019. Epub 2009 Jun 25.
Idiopathic nephrotic syndrome and atopy: is there a common link?
Abdel-Hafez M, Shimada M, Lee PY, Johnson RJ, Garin EH.
Source
Division of Pediatric Nephrology, University of Florida, Gainesville, FL 32610, USA.
Abstract
Numerous reports during the last 60 years have reported a strong association between idiopathic nephrotic syndrome and atopic disorders. Idiopathic nephrotic syndrome can be precipitated by allergic reactions and has been associated with both aeroallergens (pollens, mold, and dust) and food allergies. Patients with idiopathic nephrotic syndrome also may show increased serum immunoglobulin E (IgE) levels. A review of the literature suggests that although some idiopathic nephrotic syndrome cases may be associated with allergies, evidence that it is a type of allergic disorder or can be induced by a specific allergen is weak. Rather, it is likely that the proteinuria and increased IgE levels in patients with idiopathic nephrotic syndrome are caused by increased levels of interleukin 13 observed in these patients. Recent studies suggest that interleukin 13, a known stimulator of IgE response, may mediate proteinuria in patients with minimal change disease because of its ability to directly induce CD80 expression on the podocyte.

Minimal change nephrotic syndrome in an 82 year old patient following a tetanus-diphteria-poliomyelitis-vaccination.
Clajus C, Spiegel J, Bröcker V, Chatzikyrkou C, Kielstein JT.
Source
Department of Nephrology and Hypertension, Medical School Hannover, Hannover, Germany.
Abstract
Background: The most common cause of idiopathic nephrotic syndrome in children and younger adults is the minimal change nephrotic syndrome (MCNS). In the elderly MCNS is relatively uncommon. Over the last decade some reports suggest a rare but possible association with the administration of various vaccines.
Case Presentation: A 82-year old Caucasian female presented with pronounced nephrotic syndrome (proteinuria of 7.1 g/d, hypoproteinemia of 47 g/l). About six weeks prior to admission, she had received a combination vaccination for tetanus, diphtheria and poliomyelitis as a booster-vaccination from her general practitioner. The renal biopsy revealed typical minimal change lesions. She responded well to the initiated steroid treatment. As through physical examination as well as extensive laboratory and imaging studies did neither find any evidence for malignancies nor infections we suggest that the minimal change nephrotic syndrome in this patient might be related to the activation of the immune system triggered by the vaccination.
Conclusion: Our case as well as previous anecdotal reports suggests that vaccination and the resulting stimulations of the immune system might cause MCNS and other severe immune-reactions. Increased awareness in that regard might help to expand the database of those cases.

Sincerely,
Phil Lieberman, M.D.

AAAAI - American Academy of Allergy Asthma & Immunology