Atopic Disorder, Allergic Reaction and Nephrotic Syndrome

Pediatric nephrotic syndrome, also known as nephrosis, is defined by the presence of nephrotic-range proteinuria, edema, hyperlipidemia, and hypoalbuminemia. Nephrotic-range proteinuria in adults is characterized by protein excretion of 3.5 g or more per day. However, because of the great range of body sizes in children, the pediatric definition of nephrotic-range proteinuria is more cumbersome. 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.

Nephrotic-range proteinuria in children is protein excretion of more than 40 mg/m2/h. Because 24-hour urine collections are potentially unreliable and burdensome, especially in young children, many pediatric nephrologists instead rely on a single, first-morning urine sample to quantify protein excretion by the ratio of protein to creatinine

T he role of immune factors in idiopathic glomerulonephritis (GN) is well demonstrated, involving either the formation of antibodies to the glomerular basement membrane or the deposition or in situ formation of immune complexes.’ However, the role of immediate hypersensitivity in idiopathic GN has been seldom discussed. In the past 20 years, elevated serum IgE levels have been noted in primary GN and some reports have also described a few cases of lipoid nephrosis with atopic manifestations. For many years observers have noted an association between allergic diseases and nephrotic syndrome (NS), both in affected individuals and in family members. Indeed, several persons have had relapses of NS during asthma attacks or have undergone spontaneous remission
of both renal and respiratory symptoms with hyposensitization

With increasing knowledge of immunologic mechanisms, the pathogenesis ofsome forms ofrenal disease, and the association between allergic disease and NS in children, we have been prompted to investigate the serum IgE levels in children with various renal diseases, incidence of allergic disease in general, and specific IgE

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.

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,

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.

Cheung reported 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 study 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.

Lin also reported the incidence of atopic diseases in 206 children with nephrotic syndrome (NS) was studied. Boys with NS had three times higher incidence of bronchial asthma than the general population. There was no difference in the girls. Both boys and girls with NS had about three times more allergic rhinitis and ten times more atopic dermatitis than the general population. In NS patients with associated allergic disease, skin test and allergen-specific IgE antibodies by radioallergosorbent test (RAST) were performed. Most of the patients with dust mites (Dermatophagoides pteronyssinus, Dermatophagoides farinae), egg white, or cow’s milk protein-specific antibodies had positive skin tests. One hundred of the 206 children with NS received renal biopsies and serum IgE levels were measured. During the acute nephrotic phase the geometric mean serum IgE levels in minimal change nephrotic syndrome (MCNS), IgM mesangial nephropathy (IgMN), hepatitis B virus-associated membranous nephropathy, and treatment-responsive focal segmental glomerular sclerosis patients were all significantly elevated, in descending order of significance. These high serum IgE levels decreased in remission of NS and elevated again during relapse. The relationship between high serum IgE levels in NS patients and the incidence of allergic diseases showed that one third to one fourth of either IgMN or MCNS patients developed allergic diseases. These study suggest that NS patients had a higher allergic disease incidence. Serum IgE level may serve as one of the prognostic factors. However, an increase in the IgE level may be a reflection of body immunoregulatory imbalance that plays a direct pathogenic role in the occurrence of NS and proteinuria.

Salsani 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.

Study revealed 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.

In these 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.

The role of immediate-type allergic reactions in the pathogenesis of the nephrotic syndrome.

The study was made of 52 patients with various morphological forms of glomerulonephritis and history of allergy versus 22 healthy subjects. Most of the patients had lipoid nephrosis. Normal levels of IgE were more frequently associated with steroid-resistant nephrotic syndrome characterized by a progressive decline of renal function and severe damage to the glomeruli. A correlation existed between high IgE level and activation of antistreptococcal immunity. Two cases are reported of nephrotic syndrome onset following immediate allergic reaction to food allergen (1 case) and insect sting (1 case)

Reference

  • Abdel-Hafez M, et al. Idiopathic nephrotic syndrome and atopy: is there a common link? Am J Kidney Dis. 2009 Nov;54(5):945-53. Epub 2009 Jun 25.
  • Shishkin AN.. The role of immediate-type allergic reactions in the pathogenesis of the nephrotic syndrome. Ter Arkh. 1996;68(6):19-21. Article in.
    Cheung W, et al.Pediatr Nephrol. 2004 Jun;19(6):627-32.
  • Salsano ME, et al. Atopy in childhood idiopathic nephrotic syndrome.
    Acta Paediatr. 2007 Apr;96(4):561-6. Epub 2007 Feb 26.
  • Cheung W, Wei CL, Seah CC, Jordan SC, Yap HK. Atopy, serum IgE, and interleukin-13 in steroid-responsive nephrotic syndrome. Pediatr Nephrol. 2004 Jun;19(6):627-32. Epub 2004 Apr 3.
  • Lin CY, Lee BH, Lin CC, Chen WP. A study of the relationship between childhood nephrotic syndrome and allergic diseases. Chest. 1990 Jun;97(6):1408-11.
  • Lagrue G, Heslan JM, Belghiti D, Sainte-Laudy J, Laurent J. Basophil sensitization for food allergens in idiopathic nephrotic syndrome. Nephron. 1986;42(2):123-7.
  • Meadow SR, Sarsfield JK. Steroid-responsive and nephrotic syndrome and allergy: clinical studies. Arch Dis Child. 1981 Jul;56(7):509-16.
  • de Mouzon-Cambon A, Bouissou F, Dutau G, Barthe P, Parra MT, Sevin A, Ohayon E. HLA-DR7 in children with idiopathic nephrotic syndrome. Correlation with atopy. Tissue Antigens. 1981 May;17(5):518-24.

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