Nephrotic syndrome

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 results 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.

The 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.[1] However, the role of immediate hypersensitivity in idiopathic GN has been seldom discussed.[2] In the past 20 years, elevated serum IgE levels have been noted in primary GN[3-5] and some reports have also described a few cases of lipoid nephrosis with atopic manifestations.[6,7] For many years observers have noted an association between allergic diseases and nephrotic syndrome (NS), both in affected individuals and in family members.[8-10] Indeed, several persons have had relapses of NS during asthma attacks or have undergone spontaneous remission of both renal and respiratory symptoms with hyposensitization therapy.[11,12]

With increasing knowledge of immunologic mechanisms, the pathogenesis of some forms of renal 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 antibodies to dust mite, egg white, and cow's milk.

MATERIALS AND METHODS

From January 1985 to December 1988, 206 children younger than 14 years old with NS who had been admitted in the Department of Pediatrics, Veterans General Hospital (Taipei, Taiwan, Republic of China) received questionnaires about allergic diseases and the returned questionnaires were studied. The definition of [NS.sup.13] is (1) proteinuria greater than 40 mg/sq m/h determined quantitatively on a 24-hour overnight urine collection, (2) puffy face or generalized edema, and (3) hypoalbuminemia less than 2.5 g/dl.

In these 206 patients, 100 children with NS received renal biopsies. The kidney biopsy specimen was immediately divided into three portions and processed for light, immunofluorescence, and electron microscopy as described elsewhere.[14] The pathologic diagnosis of minimal change nephrotic syndrome (MCNS), IgM mesangial nephropathy (IgMN), and focal segmental glomerular sclerosis (FSGS) are described elsewhere.[13-17] Briefly, the criteria of IgMN[14,15] include the following: (1) a diffuse increase of mesangial cellularity with greater than four mesangial cells in each cluster; (2) immunofluorescent studies that demonstrate that at least two different sources of FITC-labeled anti-IgM serum samples deposit in the mesangium, and (3) electron microscopic studies also showing electron-dense mesangial deposits corresponding to the immunofluorescent findings. The criteria for diagnosis of hepatitis B virus-associated membranous nephropathy (HBVMN)[14,17] are as follows: (1) renal biopsy specimen showing membranous glomerular thickening in light microscopy and immunofluorescent staining and demonstration of at least one of the diffuse granular capillary membranous deposits among hepatitis B surface antigen (HBsAg), hepatitis B core antigen (HBc), and hepatitis B e antigen (HBe) in immunohistology; (2) serum HBsAg positive; and (3) abnormal results of urinalysis.

None of the study subjects had either parasitic or connective tissue diseases according to usual clinical and biologic criteria, nor did any subjects have an atopic history using criteria that include asthma, atopic dermatitis, and allergic rhinitis.

Blood samples were taken during the acute nephrotic phase, before the start of steroid treatment, and during remissions and relapses.

Skin Tests

Skin tests were performed by the intradermal method, using extracts of egg white, cow's milk (Torri, Japan), Dermatophagoides pteronyssinus (Dp) and Dermatophagoides farinae (Df) (Allergon AB, Sweden), and phosphate-buffered solution as a negative control. Intradermal tests were performed on the external surface of the upper arm, using 0.02 ml of 1 x [10.sup.-5] extract and serial dilution to determine the threshold of the skin reactivity. No skin reaction at 1 x [10.sup.-5] dilution was considered negative; when the diameter of wheal was about 0.5 to 1.0 cm within 15 minutes, the reaction was read as positive.

Radioallergosorbent test (RAST)

Test kits for the RAST were obtained (Pharmacia Diagnostics, Sweden). In these tests, a paper disk coated with allergen including Dp, Df, egg white, and cow's milk is incubated with a small amount (50 [mu]l) of undiluted serum from a patient. After incubation and washing, radiolabeled anti-IgE antiserum is added. After further incubation and washing, the radiation count of the disk is determined. The specific IgE antibodies are graded from scores of 4 to 0, according to the reference serum diluted 1:1, 1:5, 1:25, and 1:50. It was assumed that score 0 represented a negative RAST response, score 2, 3, or 4 represented a positive response, and score 1 represented a borderline response.[18]

Total IgE Level

Serum IgE level was measured by the paper radioimmunosorbent test (PRIST). The test kits were obtained (Pharmacia Diagnostics, Sweden).[19]

Statistical Analysis

The statistical differences between the groups were assessed by the approximate t test or Student's t test, depending on the equality of the variances of the two groups being compared.

RESULTS

Correlation between Atopic Diseases and NS

A significantly higher incidence of atopic disease was noted in the 206 patients with NS than in the same age general population (Table 1). Boys with NS had three times more attacks of bronchial asthma than the general population. However, there was no difference in the girls with NS. Both boys and girls had rates of allergic rhinitis about three times higher than the general population. Both boys and girls had more than ten times higher rates of atopic dermatitis than the general population.

In the patients with positive allergic disease history, skin tests were done and allergen-specific IgE antibodies were measured by the RAST procedure. There were high Dp-specific IgE levels in these patients with either asthma (83.3 percent) or allergic rhinitis (76.9 percent). Both groups also had high intradermal Dp skin test positive rates: 91.6 percent of asthma patients and 84.6 percent of allergic rhinitis patients. In the Df antigen, Df-specific IgE RAST positive rate was 70.8 percent in asthma patients and 69.2 percent in allergic rhinitis patients. The Df intradermal skin test positive rate was 79.1 percent in asthma patients and 73.0 percent in allergic rhinitis patients. In the patients with a history of atopic dermatitis, egg white-specific IgE positive rate was 46.6 percent, skin test positive rate was 60 percent, cow's milk protein-specific IgE positive rate was 43.3 percent, and skin test positive rate was 50 percent.

Correlation between Serum IgE and NS

Of the 100 patients with NS who received renal biopsies, the correlation between serum IgE levels and the various pathologic groups of NS are shown in Figure 1 and Table 2. In the IgMN and MCNS groups, there was almost the same distribution with significantly higher mean serum IgE levels than controls (1,045 [+ or -] 1,189 IU/ml vs 268 [+ or -] 171 IU/ml, p<0.01; 1,223 [+ or -] 883 IU/ml vs 268 [+ or -] 171 IU/ml, p<0.01, respectively). However, high variance was also noted in these two groups. The FSGS group can be divided into two groups, one with high serum IgE level and good response to the steroid, cyclophosphamide, and anticoagulant triple therapy, the other with low serum IgE level and poor response to the triple therapy. Using HBVMN as an example of secondary nephritis, the mean serum IgE level was still significantly higher than the control (553 [+ or -] 107 IU/ml vs 268 [+ or -] 171 IU/ml, p<0.01).

During the remission stage, after stopping steroid therapy for one to three months, the IgE levels both in IgMN and MCNS groups were significantly lower (1,045 [+ or -] 1,189 IU/ml vs 742 [+ or -] 521 IU/ml, p<0.01; 1,223 [+ or -] 883 IU/ml vs 762 [+ or -] 514 IU/ml, p<0.01, respectively) than in those who were not treated. However, it was significantly higher than in the controls (742 [+ or -] 521 IU/ml vs 268 [+ or -] 171 IU/ml, p<0.01; 762 [+ or -] 514 IU/ml vs 268 [+ or -] 171 IU/ml, p<0.01, respectively).

[TABULAR DATA OMITTED]

Relationship between High Serum IgE Level in NS Patients and Incidence of Allergic Diseases

The relationship between serum IgE levels greater than 300 IU/ml in various pathologic types of NS in patients and allergic disease are shown in Table 3. Combining the before and within two years after onset of renal disease observation, only one third to one fourth of patients with either IgMN or MCNS with high serum IgE levels developed allergic diseases. In the patients with FSGS and HBVMN with high serum IgE levels, fewer (16.6 percent and 20.0 percent, respectively) developed allergic diseases.

DISCUSSION

In the present study, patients with NS had a higher incidence of allergic diseases. Many other observers have also noted an association between allergic diseases and NS.[6-10] Most of those allergic patients with NS also had higher allergen-specific IgE levels, including Dp, DF, egg white, and cow's milk. This was confirmed with positive intradermal skin tests. [TABULAR DATA OMITTED]

In MCNS, increased serum IgE values were observed in 17 (55 percent) of 31 patients and the geometric mean was significantly higher than controls. In IgMN, increased serum IgE values were observed in 18 (42 percent) of 43 patients. With regard to the serum IgE levels and atopic disease, a patient with an IgE level higher than 1,000 IU/ml can be without atopic disease, and a patient with a normal serum IgE level may have an atopic disease. We have observed four patients with normal total serum IgE levels and highly positive specific IgE antibodies and a positive response to an inhaled allergen by a challenge test.

In the study of the relationship between high serum IgE levels in patients with NS and incidence of allergic diseases, we found that only one third to one fourth of patients with either IgMN or MCNS with high serum IgE levels had developed an allergic disease. Therefore, increased serum IgE levels evidently do not automatically imply an atopic origin of the renal disease after excluding parasitic diseases, hematodermia, Hodgkin's disease, cirrhosis of the liver, and celiac disease. An increase in the IgE level may be a reflection of immune imbalance in the body that can further facilitate the occurrence of NS or glomerulonephritis[3,4] or it may be a disturbance of body immune regulation that plays a direct pathogenic role in the occurrence of NS and proteinuria. However, the time sequence of either increased serum IgE levels followed by NS development or NS development followed by increased serum IgE levels is still unknown. The same question also remains unanswered in the relationship between NS relapse and elevation of serum IgE level. Therefore, serial time course study and IgE-mediated immune studies should be done in children with NS to clarify this relationship.

REFERENCES

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[15] Churg J, Habib R, White RHR. Pathology of the nephrotic syndrome in children. Lancet 1970; 1:1299-1302

[16] Lin CY, Chen CM. Studies of circulating immune complexes and lymphocyte subpopulations in childhood IgM mesangial nephropathy. Nephron 1986; 44:198-203

[17] Lin CY. Hepatitis B virus associated membraneous nephropathy: clinical features, immunologic profiles and outcomes. Nephron (in press)

[18] Perera MG, Bernstein IL, Michael G, Johansson SGO. Predictability of the radioallergosorbent test (RAST) in ragweed pollenosis. Am Rev Respir Dis 1975; 111:605-10

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