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ORIGINAL ARTICLE
Year : 2015  |  Volume : 28  |  Issue : 2  |  Page : 431-436

Serum immunoglobulin G, M, and IgG : IgM ratio as predictors for outcome of childhood nephrotic syndrome


Pediatric Department, Faculty of Medicine, Menoufia University, Menoufia, Egypt

Date of Submission08-Jul-2014
Date of Acceptance14-Oct-2014
Date of Web Publication31-Aug-2015

Correspondence Address:
Hassnaa Mahmoud Azab
Pediatric Department, Faculty of Medicine, Menoufia University, Al-Bajur, Al-Menoufia
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/1110-2098.163897

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  Abstract 

Objectives
The objectives of this study were to compare immunoglobulin (Ig) levels in children with nephrotic syndrome and healthy children to understand changes in diseased state and predict response to treatment.
Background
Nephrotic syndrome is an immune-mediated disorder of the kidney associated with T-cell dysfunction and secondary disturbance of B-cell with changes in levels of Ig and the IgG : IgM ratio. These changes in Ig levels can be used as a proxy marker to determine the clinical variety and prognosis of nephrotic syndrome.
Materials and methods
Twenty-five children with nephrotic syndrome attended the Nephrology Unit of Pediatric Department of Menoufia University Hospital from October 2011 to January 2013. Their ages ranged from 1 to 15 years (mean = 6.3 years); 12 (60%) were boys and eight (40%) were girls. All patients were in the active stage of the disease. Twenty-five apparently healthy children were enrolled as a control group.
Results
In the 25 children with nephrotic syndrome, 10 (40%) had steroid-sensitive nephrotic syndrome, five (20%) had steroid-resistant nephrotic syndrome, five (20%) developed frequent relapses, and five (20%) had infrequent relapse nephrotic syndrome. Compared with the healthy children, the IgG level was low, the IgM level was high, and the IgG : IgM ratio was low ( P ≤ 0.05). The serum IgG level and the IgG : IgM ratio were significantly lower in children with steroid-resistant nephrotic syndrome and in children with steroid-dependent nephrotic syndrome than in those with infrequent relapse nephrotic syndrome and in children with steroid-sensitive nephrotic syndrome ( P ≤ 0.05).
Conclusion
Management of different nephrotic syndromes is based on the levels of Ig along with clinical and biochemical parameters. The decrease in the IgG level as a predictive marker for an unfavorable prognosis of nephrotic syndrome in children needs further evaluation in larger scale studies.

Keywords: immunoglobulins, nephrotic syndrome, prognosis


How to cite this article:
Bahbah MN, El Mashad GM, Abdelnaby SA, Azab HM. Serum immunoglobulin G, M, and IgG : IgM ratio as predictors for outcome of childhood nephrotic syndrome. Menoufia Med J 2015;28:431-6

How to cite this URL:
Bahbah MN, El Mashad GM, Abdelnaby SA, Azab HM. Serum immunoglobulin G, M, and IgG : IgM ratio as predictors for outcome of childhood nephrotic syndrome. Menoufia Med J [serial online] 2015 [cited 2019 Jul 18];28:431-6. Available from: http://www.mmj.eg.net/text.asp?2015/28/2/431/163897


  Introduction Top


Nephrotic syndrome is characterized by massive proteinuria, hypoalbuminemia, and edema, although additional features such as hyperlipidemia are also usually present [1]

Nephrotic proteinuria involves a glomerular lesion as tubular lesions alone will not result in severe albuminuria. Increased glomerular permeability may occur when a lesion is present, either in the endothelium, podocytes basement membrane, or a combination of these elements, resulting in leakage of albumin from the vascular into the tubular compartment [2] .

Proteinuria might develop as a follows: an unknown trigger (s), such as infection or inhaled allergen, stimulates the immune cells such as T-cells and/or B-cells. Stimulated immune cells secrete cytokines that dysregulate the podocyte barrier function, and serum albumin leaks into the urinary space through damaged glomerular barrier [3] .

Nephrotic syndrome is considered either primary or secondary. Majority of children with nephrotic syndrome have the primary form of the disease, when it is not associated with a systemic disease, or occurs in association with any of a number of systemic conditions; thus, it is called secondary. Children with primary nephrotic syndrome are also classified according to their response to steroid therapy into steroid sensitive or steroid resistant [4] .

Nephrotic syndrome is an immune-mediated kidney disease associated with T-cell dysfunction and secondary disturbance of B-cell that leads to changes in the levels of immunoglobulins (Ig) [5] .

Dysgammaglobulinemia (low IgG, but high IgM and IgE levels) is a common feature in most nephrotic patients. There is a T-cell defect in the conversion from IgM-secreting T-cells into IgG-secreting T-cells (switching defect), leading to a high level of IgM and a low level of IgG [6] .

Children with nephrotic syndrome are at an increased risk of bacterial infection, most commonly with Streptococcus pneumonia. This increased susceptibility is because of urinary loss of Ig and complement components.

Treatment with corticosteroids and immunosuppressant therapy will also leave children susceptible to infection. Varicella zoster and measles infection may be life threatening in nonimmune children with nephrotic syndrome [7] .

The following are the terms commonly used for management

Complete remission

Urinary protein creatinine ratio (UPCR) less than 20 mg/mmol (<0.2 g/g) or less than 1+ of protein on urine dipstick for three consecutive days.

Partial remission

Proteinuria reduction of 50% or greater from the presenting value and absolute UPCR between 0.2 and 2 mg/mg (20-200 mg/mmol).

No remission: failure to reduce urine protein excretion by 50% from baseline or persistent excretion UPCR greater than 2 mg/mg (>200 mg/mmol).

Initial responder

Attainment of complete remission within the initial 4 weeks of corticosteroid therapy.

Initial nonresponder/steroid resistance

Failure to achieve remission after 8 weeks of corticosteroid therapy.

Relapse

UPCR of at least 200 mg/mmol (<2 g/g) or at least 3+ protein on urine dipstick for three consecutive days.

Infrequent relapse

One relapse within 6 months of initial response, or one to three relapses in any 12-month period.

Frequent relapse

Two or more relapses within 6 months of initial response, or four or more relapses in any 12-month period.

Steroid dependence

Two consecutive relapses during corticosteroid therapy, or within 14 days of ceasing therapy.

Late nonresponder

Persistent proteinuria during 4 or more weeks of corticosteroids following one or more remissions [8] .


  Materials and methods Top


The present study was carried out on 50 children: 25 apparently healthy children, who were enrolled as a control group, and 25 children with generalized edema diagnosed with primary nephrotic syndrome attending the Nephrology Unit of Pediatric Department of Menoufia University Hospital from October 2011 to January 2013. Their ages ranged from 1 to 15 years (mean = 6.3 years); 12 (60%) were boys and eight (40%) were girls. All patients were in the active stage of the disease (heavy proteinuria >40 mg/m 2 /h, hypoalbuminemia<2.5 g/dl, edema, and hyperlipidemia).

Children younger than 1 year or older than 15 years of age, children with nephrotic syndrome secondary to systemic disease such as (systemic lupus erythematosus, hepatitis B, Henoch-Schönlein purpura, lymphoma, or amyloidosis), and children with severe protein energy malnutrition were excluded from this study.


  Methods Top


After obtaining consent, all patients and controls were subjected to the following.

Complete assessment of history, with a focus on symptoms of nephrotic syndrome such as puffiness in the eye lid and lower limb swelling.

Thorough clinical examination focusing on signs of nephrotic syndrome such as lower limb edema, ascites, and scrotal edema, and blood pressure and any signs of infection.

Urine samples were collected on admission, and routine microscopic and physical examination. Spot UPCR or urinary total protein was measured using an autoanalyzer (RA50 chemistry analyzer). Venous blood sample of 5 ml was collected for the determination of serum albumin, total protein, cholesterol, creatinine, and blood urea. Serum Ig (IgG, IgM) levels were measured using a liquid-phase immunoprecipitation assay in all groups. Reference values of IgG and IgM were 7-16 and 0.4-1.5 g/l, respectively. The cut-off value for low IgG was less than 7 g/l, high IgM more than 1.5 g/l, and IgG : IgM more than 5.Chest radiography and ultrasonography of the kidneys, ureter, and bladder were performed for all the patients. Renal biopsy was performed for steroid-resistant nephrotic syndrome (SRNS) patients.

Statistical analysis

Qualitative data were expressed as mean ± SD.

Quantitative data were expressed as number and percentage.

For quantitative data, comparison between two groups was carried out using the Student t-test or the corresponding nonparametric one for variables that were not normally distributed.

Qualitative data were expressed as number and percentage and analyzed by χ2 -test.

The relation between different numerical variables was tested; P-value less than or equal to 0.05 was considered significant and less than 0.01 was considered highly significant.

Pearson's correlation coefficient r-test was used to detect the association between two quantitative variables. It indicates the type of relationship between these valuables (direct or indirect relationship) [9] .


  Results Top


Of the 50 children enrolled in the study, 29 were males and 21 were females. There was no significant difference in the sex distribution among the children in the nephrotic group and those in the control group (P > 0.50). The mean (±SD) age of the children in the control group was 6.9 ± 3.1 years and the mean (±SD) age of the children in the nephrotic group was 7.1 ± 3 (P > 0.50) [Table 1]. In the 25 children with nephrotic syndrome, 10 (40%) had steroid-sensitive nephrotic syndrome, five (20%) had SRNS, five (20%) developed frequent relapses, and five (20%) had infrequent relapse nephrotic syndrome (IFRNS) [Table 2].
Table 1 Clinical data of the groups studied

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Table 2 Clinical data of the patients according to response to steroid

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The IgG level was lower, the IgM level was higher, and the IgG : IgM ratio was lower in the patient groups than in the healthy controls (P ≤ 0.05) [Table 3].
Table 3 Serum IgG, IgM, and IgG : IgM ratio in the groups studied

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The mean (±SD) IgG level in the patient group was 759.8 ± 378.3 mg/dl. The mean (±SD) IgG level was normal, 1187 ± 303.3, in the healthy controls. The mean (±SD) IgM level in the patient group was 144.5 ± 96.5 mg/dl. The mean (±SD) IgM level was normal, 102.5 ± 24.6, in the healthy controls. The mean (±SD) IgG : IgM ratio in the patient group was 15.9 ± 19.5. The mean (±SD) IgG : IgM ratio, 20.1 ± 28.3, was normal in the healthy controls [Table 3]

The IgG level decreased in the frequent relapse nephrotic syndrome (FRNS) group and the IFRNS group, and was the lowest in the SRNS group. The IgM level increased in the FRNS group and the IFRNS group, and was the highest in the SRNS group. The IgG : IgM ratio decreased in the FRNS group and the IFRNS group, and was the lowest in the SRNS group [Table 4].
Table 4 Relation between IgG, IgM, IgG : IgM ratio, and clinical type of the nephrotic group

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There was a significant relationship (P 0≤ 0.05) between the degree of albuminuria (Upr : Ucr ratio) and the mean concentration of IgG in the sera of patients with nephrotic syndrome [Table 5]. An increase in albuminuria (Upr : Ucr ratio) is accompanied by a reduction in the mean concentration of serum IgG level [Figure 1].
Figure 1: Correlation between the Upr : Ucr ratio and the serum immunoglobulin G level. Ucr, urine creatinine ratio; Upr, urine protein ratio

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Table 5 Correlation of serum IgG, IgM, and IgG : IgM ratio with laboratory data of the patients

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There was a significant relationship (P ≤ 0.05) between the serum albumin and the mean concentration of IgG in the sera of patients with nephrotic syndrome [Table 3]. The decrease in serum albumin is associated with a decrease in the mean concentration of serum IgG level [Figure 2].
Figure 2: Relation between serum albumin and immunoglobulin G level

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There was a significant relationship (P 0≤ 0.05) between the serum albumin and the mean concentration of IgM in the sera of patients with nephrotic syndrome [Table 3]. A decrease in serum albumin is associated with an increase in the mean concentration of serum IgM level [Figure 3].
Figure 3: Relation between serum albumin and immunoglobulin M level

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There was a significant relationship (P ≤ 0.05) between the degree of hypercholesterolemia, and the mean concentration of IgG [Table 5]. An increase in serum cholesterol level is associated with a decrease in the mean concentration of serum IgG level [Figure 4].
Figure 4: Correlation between serum cholesterol and immunoglobulin G level of the patients

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  Discussion Top


Nephrotic syndrome is characterized by massive proteinuria, hypoalbuminemia, and edema. An additional feature such as hyperlipidemia is also usually present [1] .

Infection is the major complication of nephrotic syndrome. Children in relapse are an increased risk of developing bacterial infections because of urinary losses of Ig and properdin factor B, defective cell-mediated immunity, immunosuppressive therapy, malnutrition, and edema acting as a potential culture medium for organisms [6] .

Nephrotic syndrome is an immune-mediated kidney disease associated with T-cell dysfunction and secondary disturbance of B-cell that leads to changes in the levels of IgG and M [5] .

Therefore, the estimation of IgG and IgM levels and their ratio as well as the correlation of these values with clinical responsiveness to steroid therapy, relapse, and dependency is important to monitor management strategies and to determine the outcome [5] .

The aim of this study was to estimate serum IgG and IgM levels in children with nephrotic syndrome on presentation with patient follow-up for 1 year to evaluate response to therapy and the rate of relapse.

The results of this study showed that there were no statistically significant differences between the groups studied in demographic data and anthropometric measurements, and this result was in agreement with that reported by El-Shafie et al. [10] . Thus, the effect of age and sex can be excluded as a factor explaining the difference in their medical and biochemical characteristics.

Patients with nephrotic syndrome had unusual susceptibility to encapsulated bacterial infection. Studies showed that there are changes in the serum IgG, IgM levels associated with proteinuria in nephrotic patients. According to studies, changes in the serum Ig levels can be attributed to either T-cell dysfunction and/or increased urinary excretion of albumin [11] .

Chen et al. [12] and Sahali [13] reported changes in serum IgG and IgM in children with nephrotic syndrome; this is in agreement with our study. These results were not in agreement with those reported by Beale et al. [14] , who reported that in-vivo production of Ig, especially IgG, was either normal or increased. The difference in these results may be because of differences in age, number, and pathological types of nephrotic syndrome of the patients studied.

Chen et al. [12] reported that enhanced suppressor T-cell activity resulted in increased serum IgM and decreased serum IgG production in children with nephrotic syndrome.

However, Kaysen and Al-Bander [15] reported that in nephrotic syndrome, there is an increased urinary excretion of albumin and IgG accompanied by a decrease in their serum concentration. Our study showed that an increase in albuminuria is accompanied by a reduction in serum IgG level. These results were in agreement with those reported by Siberil et al. [16] .

High-molecular-weight IgM increases to defend serum protein concentration and oncotic pressure. Hypoalbuminemia associated with nephrotic syndrome is thus likely to affect the serum IgM level [15] . This explains the negative correlation between serum albumin level and serum IgM level.

Patients with nephrotic syndrome overproduce high-molecular-weight proteins, such as lipoproteins, which cause hyperlipidemia and are protected from urinary loss to maintain the oncotic pressure. Our study showed a significant correlation between serum cholesterol and serum IgG of the nephrotic group. These results were in agreement with those reported by Kemper et al. [17] and Sibιril et al. [16] .

After 1 year of follow-up, we found a significant correlation between IgG and IgM serum levels at initial presentation with response to therapy and rate of relapse. The higher the serum IgM and the lower the serum IgG levels at presentation, the higher the rate of relapse as reported by Roy et al. [18] .

Ahmed et al. [19] found that a low serum IgG level at the onset showed no significant relation with the rate of relapse.

In conclusion, IgG serum level is decreased and IgM serum level is increased in all patients with nephrotic syndrome compared with healthy children. Ig levels can be used as an important serological marker to predict responsiveness to treatment in different types of nephrotic syndrome. Serological markers for a rapid diagnosis are very important in the management of the disease.

The low level of IgG in nephrotic syndrome as reported in our study could be attributed to many factors such as their low molecular weight causing their excess loss in urine and isotype switching defect from IgM-secreting cells to IgG-secreting cells.

C-maf promotes T-helper (Th2) and attenuates Th1 differentiation. Downregulation of the interleukin (IL-12) receptor β2 subunit during relapse attenuates Th. Increased production of IL-13 induces Th2 cytokine during relapse.

Decrease in Th1 induces:

Decrease in IL-2, INF-g Decrease in IgG

Decrease in IL-5 Decrease in IgA



Increase in Th2 induces:

Increase in IL-4, IL-5 B-cell proliferation

Increase in IL-4, IL-5 Increase in IgM

Increase in IL-4 Increase in IgE

Increase in IL-13 Proteinuria




  Conclusion Top


Serum IgM and IgG levels have prognostic value in patients with nephrotic syndrome and can predict the outcome and the frequency of recurrence of disease. There is a close relation between the degree of albuminuria and the levels of serum IgG and M.


  Acknowledgements Top


Conflicts of interest

There are no conflicts of interest.



 
  References Top

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Gbadegesin R, Smoyer WE. In: Geary DF, Schaefer F, eds. Nephrotic syndrome. Comprehensive pediatric nephrology. 1st ed. 2008. Philadelphia: Elsevier; 206-218.  Back to cited text no. 1
    
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De Seigneux S, Martin PY. Management of patients with nephrotic syndrome. Swiss Med Wkly 2009; 139 :416-422.  Back to cited text no. 2
    
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Kaneko K. Pathogenesis in childhood idiopathic nephrotic syndrome: an update of patchwork. Curr Pediatr Rev 2009; 5 :56-64.  Back to cited text no. 3
    
4.
Nammalwar BR, Vijayakumar M. In: BR Nammalwar, M Vijayakumar, eds. Nephrotic syndrome in children. Principles and practice of pediatric nephrology New Delhi, India: Jaypee Brothers Medical Publishers (P) Ltd; 2007. 185-197.  Back to cited text no. 4
    
5.
Srivastava RN, Bagga A. In: Srivastava RN, Bagga A, eds. Nephrotic syndrome. Pediatric nephrology. 4th ed. New Delhi, India: Jaypee Brothers Medical Publishers (P) Ltd; 2005. 161-197.  Back to cited text no. 5
    
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Han JW, Lee KY, Hwang JY, Koh DK, Lee JS. Antibody status in children with steroid-sensitive nephrotic syndrome. Yonsei Med J 2010; 51 :239-243.  Back to cited text no. 6
    
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Dolan NM, Gill M. Management of nephrotic syndrome. Pediatr Child Health 2008; 18 :369-374.  Back to cited text no. 7
    
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KIDGO (Kidney disease Improving Global Outcomes). Kidney international supplements; 2012, pp: 259-274.  Back to cited text no. 8
    
9.
KirkwoodB R, HYPERLINK "http://eu.wiley.com/WileyCDA/Section/id-302479.html?query=Jonathan+Sterne" Sterne J A C (1990) :Essential Medical Statistics, 2nd Edition.Wiley-Blackwell, Chicago , 65-142.  Back to cited text no. 9
    
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El-Shafie AM, El-Nemr FM, Abdalla MH. Study of some haemostatic parameters in children with minimal change nephrotic syndrome [MSc thesis]. Pediatric Department, Menoufiya University, Menoufiya, Egypt; 2007  Back to cited text no. 10
    
11.
Nariman F, A.Azat. Evaluation of serum (immunoglobulin G, M) in children with nephrotic syndrome relapse. Fac Med Baghdad 2012; 54 :1.  Back to cited text no. 11
    
12.
Chen CH, Hsieh KH, Lee PP. Enhanced suppressor T cell activity resulting in increased IgM and decreased IgG productions in children with minimal change nephrotic syndrome. Int J Pediatr Nephrol 1987; 8 :75-80.  Back to cited text no. 12
    
13.
Sahali D, Lang P, Guellaen G, Bensman A. New insights about immunopathology of lipoid nephrosis. Bull Acad Natl Med 2002; 186 :683-690; discussion 690-693  Back to cited text no. 13
    
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Beale MG, Nash GS, Bertovich MJ, MacDermott RP. Immunoglobulin synthesis by peripheral blood mononuclear cells in minimal change nephrotic syndrome. Kidney Int 1983; 23 :380-386.  Back to cited text no. 14
[PUBMED]    
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Kaysen GA, Al Bander H. Metabolism of albumin and immunoglobulins in the nephrotic syndrome. Am J Nephrol 1990;Suppl 1 :36-42.  Back to cited text no. 15
    
16.
Sibéril S, Elluru S, Negi VS, Ephrem A, Misra N, Delignat S, et al. Intravenous immunoglobulin in autoimmune and inflammatory diseases: more than mere transfer of antibodies. Transfus Apher Sci 2007; 37 :103-107.  Back to cited text no. 16
    
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Kemper MJ, Altrogge H, Ganschow R, Müller-Wiefel DE. Serum levels of immunoglobulins and IgG subclasses in steroid sensitive nephrotic syndrome. Pediatr Nephrol 2002; 17 :413-417.  Back to cited text no. 17
    
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Roy RR, Roy E, Rahman MH, Hossain MM. Serum immunoglobulin G, M and IgG : IgM ratio as predictors for outcome of childhood nephrotic syndrome. World J Pediatr 2009; 5 :127-131.  Back to cited text no. 18
    
19.
Ahmed F, Prasad SK, Afroz S, Chowdhury K, Maruf-ul-Quader M A, Hanif M. Low serum IgG level during remission: a predictor of frequent relapse nephrotic syndrome. DS (Child) HJ 2011; 27 :64-67.  Back to cited text no. 19
    


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