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Saudi Journal of Kidney Diseases and Transplantation
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REVIEW ARTICLE Table of Contents   
Year : 1994  |  Volume : 5  |  Issue : 4  |  Page : 483-488
Immunological aspects of primary nephrotic syndrome in childhood

Department of Pediatric Nephrology, Maternity and Children's Hospital, Riyadh, Saudi Arabia

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Keywords: Primary nephrotic syndrome, Minimal change glomerulonephritis, Congenital nephritic syndrome, Immunological aspects.

How to cite this article:
Elzouki AY. Immunological aspects of primary nephrotic syndrome in childhood. Saudi J Kidney Dis Transpl 1994;5:483-8

How to cite this URL:
Elzouki AY. Immunological aspects of primary nephrotic syndrome in childhood. Saudi J Kidney Dis Transpl [serial online] 1994 [cited 2020 Mar 31];5:483-8. Available from: http://www.sjkdt.org/text.asp?1994/5/4/483/41137

   Introduction Top

The nephrotic syndrome (NS) can be broadly classified into primary and secondary. Among these, primary nephrotic syndrome (PNS) is the most prevalent glomerular injury in childhood (90% of the cases). The terminology applied to this syndrome reflects our poor understanding of its etiology and pathogenesis. The disease is a frequent cause of morbidity worldwide. The clinical definition entails the presence of heavy proteinuria (protein excretion of >40 mg/m2/hr or 3.5 g/1.73m2/day), hypoalbuminemia (serum albumin < 25 gm/L) and the absence of an evident cause.

Secondary nephrotic syndrome (10% of the cases) occurs as a consequence of; (a) systemic diseases like diabetes mellitus, Henoch Schonlein purpura, lymphoma and systemic lupus erythematosus, (b) various toxins such as heavy metal poisoning and (c) adverse effect of drugs.

The term congenital nephrotic syndrome is applied to NS occurring in the first three months of life [1] . There are three well recognized categories. They are:

(i) The recessively inherited NS of the Finnish type [2] ,

(ii) The acquired congenital NS which occurs secondary to intrauterine infections, and

(iii) The syndrome congenital NS, which includes rare disorders in which NS is associated with other conditions such as Drash syndrome [3] , Nail Patella syndrome [4] and Lowe syndrome [5] .

This review will focus on PNS occurring after the first 3 months of life and mainly on Minimal Change Nephrotic Syndrome (MCNS), which accounts for 85-90% of NS in childhood.

   Incidence, Age and Sex Distribution Top

The annual incidence of PNS in Europe and North America is 2-7 new cases per 100,000 children [6],[7] . There is male preponderance in the ratio of about 2:1 [8] . In the Arab countries, the reported incidence is 11 new cases per 100,000 children with a male to female ratio of 1.3:1 [9] . Predominantly, it is a disease of young children with a peak incidence between two and five years of age.

   Familial Incidence and Genetic Markers Top

Familial cases of PNS occur more frequently than can be explained by chance. In a survey of European centers, affected siblings have been found in 3.5% of nephrotic patients [10],[11] whereas among Arab children with PNS, three out of 111 (2.7%) had affected siblings [9] . An Arab family, in which four males had minimal change nephrosis which was thought to be apparently a hitherto unrecognized X-linked disorder [12] . It has been also noted that, there is an increased frequency of some major histocompatibility antigens in children with steroid responsive NS e.g., HLA DR7 in France, Spain and Australia [13] , HLA B12 in England [14] , HLA B8 in Ireland and Germany [15] . These findings raise the possibility that the disease may occur with different alleles in different populations [16] .

   Association with Atopy Top

Clinical features of allergy are more common in children with steroid-responsive NS than in normal children. It was reported that up to 11% of nephrotic children and/or their first degree relatives had clinical history of atopic disease [17] . IgE levels are elevated in a disproportionate number of patients with NS and such elevation may be a marker for frequent relapse or relative resistance to steroids [17],[18] . Human basophil degranula­tion test was reported to be positive in selected patients with idiopathic NS [19] . Attempts to treat MCNS with inhaled or orally administered analogue of disodium cromoglycate have been unsuccessful [20] . However, it is likely that selected patients may benefit from anti-allergic therapy [21],[22] .

   Immunity and Primary Nephrotic Syndrome Top

In recent years, different studies have been performed in relation to nephrotic syndrome and immunity. These studies can be included under two main categories, cellular immunity and humoral immunity. Shalhoub [23] was the first to postulate that MCNS could be produced by a systemic abnormality of T cell function. Glomeruli are innocent bystanders and their injury in MCNS is related to the presence of a soluble circulating factor, lymphokine, released because of a primary cellular immune abnormality. This factor could be responsible for the alteration of glomerular-electro-static barrier which leads to increased permeability of the glomeruli to negatively charged macromolecules such as plasma albumin. Shalhoub's hypothesis was based upon a selective interpretation of clinical observations related to MCNS which include:

a) remission induced by the measles virus, which modifies cell mediated immunity,

b) relapse of the disease after viral respiratory infections,

c)therapeutic benefits of steroids and cyclophosphamide, drugs that are known to depress cell mediated response,

d)the association between MCNS and Hodgkin's lymphoma,

e)the association between MCNS and atopy, and,

f)the susceptibility of patients with MCNS to pneumococcal infection.

Cellular Immunity and Nephrotic Syndrome

Number of T cells

A normal percentage and absolute number of E-rosettes was found in patients with nephrotic syndrome both in relapse and remission [22],[23],[24],[25],[26] . These reports differ from those reported by Tanphaichitr et al [27] and Matsumoto et al [28] who found a decreased percentage of E rosettes during active disease. This discrepancy could be due to the fact that in the study by Tanphaichitr et al [27] , the children investigated were those in relapse following prolonged treatment with steroids and cyclophosphamide, drugs known to decrease T cell number. Evaluation of lymphocyte subsets by antibodies against clonotypic differentiation antigens CD3 (T cell), CD4 (inducer T cell), and CD8 (suppressor cytotoxic T cell), have not identified significant differences between patients and control subjects [29],[30] .

Delayed Hypersensitivity Skin Reaction

Measurement of delayed skin reaction to purified protein derivative (PPD)*, streptoki­nase or streptodornase, showed no significant difference between nephrotic patients in relapse or remission, compared to a control group [25] . Sensitization after skin testing using a new antigen, dinitrochlorobenzene (DNCB) was significantly lower in nephrotic patients in relapse when compared either with patients in remission or with controls. This incapacity to become sensitized to new antigens could be explained by defective antigen presentation [25] . These results differ from those reported by Matsumoto et al [31] who evaluated cell-mediated immunity (CMI) in nephrotic patients by summation of delayed cutaneous hypersensitivity responses to four test antigens namely; PPD, Candida, mumps and key hole limpet hemocyanin (KLH).Nephrotic patients in relapse had less mean induration with the first three antigens when compared with normal controls or nephrotic patients in remission.

Lymphocyte Reactivity to Mitogens in MCNS

T-cell function as measured by lymphocyte transformation in response to phytohemag­glutinin A (PHA) using autologous plasma in cultures, was significantly decreased in patients with MCNS during relapse; such responses were significantly enhanced when autologous plasma was substituted by normal homologous plasma [32] .

Effects of MCNS Plasma on Normal Lymphocyte Reactivity

When normal lymphocytes were incubated with plasma obtained from MCNS patients, a reduction of lymphoproliferative capacity was observed [33] . This effect was greater if plasma was obtained from patients with active disease. The inhibitory effect of nephrotic plasma on lymphocyte proliferation has also been reported in MCNS of childhood by Fodor et al [25] , Minchin et al [34] , Inoue et al [35] and Martini et al [36] and in adults by Iitaka and West [37] , Sasdelli et al [32] and Taube et al [38] .

*in those who had been immunized with Bacilli Calmette-Guerin (BCG) and had a BCG scar

Hypoalbuminemia was one of the several factors that was thought to be responsible for the inhibitory effect of plasma of MCNS patients. However, plasma of patients in complete remission, in which the albumin deficit had been corrected, still showed an inhibitory effect [25],[37],[38] .

The increased serum concentration of very low density lipoprotein (VLDL) in MCNS was thought to be responsible for the inhibitory effect of the nephrotic plasma during active disease [39] . This has been suggested also by Menchach and Lefkowitz [40] . They observed a marked suppression of the blastogenic response to PHA when culturing lymphocytes from patients with MCNS in remission with normal pooled serum to which they added VLDL fraction to equal the usual nephrotic levels. However, a study by Inoue et al [41] showed that sera from patients with idiopathic MCNS inhibited concanavalin A (ConA) induced lymphocyte proliferative response as well as rosette formation of lymphocytes with sheep erythrocytes. The inhibitory effect on ConA response was observed not only in idiopathic MCNS serum but also in hyperlipidemic serum from patients with other glomerulonephritides as well as those having hyperlipoproteinemia and was related to the serum lipid level. However, the inhibitory effect on E-rosette formation was more specific for idiopathic MCNS and was not related to the serum lipid level. Low density lipoprotein (LDL) from idiopathic MCNS serum was more effective than that from normal serum in the inhibition of ConA response. On E-rosette formation, only LDL from idiopathic MCNS serum had inhibitory activity. Lipoprotein depleted serum did not inhibit either ConA response or E-rosette formation. Thus it was suggested that LDL of idiopathic MCNS serum contains some specific immunosuppressive factors different from those in normal LDL [41] .

Suppressor T cell Activity

It was suggested that suppressor T cell activity could give explanation for the alteration observed in idiopathic nephrotic syndrome. Osakabe and Matsumoto [42] reported increased T cell suppressor activity in patients with MCNS during relapse. An increase in a suppressor T cell subpopulation in acute phase MCNS has been demonstrated using monocolonal antibodies [43] . In a study regarding lymphocyte subpopulation in children with IgM mesangial nephropathy presenting as nephrotic syndrome, Lin and Chu [44] demonstrated that these patients had a significant increase of T8 cell and a decrease in the T4/T8 ratio during acute phase and relapse. Taube [45] reported that successful treatment of MCNS with cyclophosphamide was associated with long term impairment of suppressor cell function.

Identification of the Lymphokine Soluble Immune Response Suppressor in Urine of Nephrotic Children

In a study by Schnaper and Aune urine samples from MCNS patients were screened for activity of the lymphokine, soluble immune response suppressor (SIRS), a product of ConA or interferon activated suppressor T cells [46] . Urine from untreated MCNS patients suppressed polyclonal plaque forming cell responses of cultured sple­nocytes. This suppressive activity was identified as caused by human SIRS, and a possible role for SIRS in the suppressed immune responses, often found in nephrotic syndrome, was suggested [46] .

Some of the cellular immune defects mentioned previously which include delayed skin reactivity and impaired lymphocyte reactivity with decreased response to ConA and PHA were also present in types of nephrotic syndrome other than the idiopathic MCNS, such as, membranous nephropathy, membranoproliferative glomerulonephritis and lupus nephritis [47],[48] .

Humoral Immunity in Idiopathic Nephrotic Syndrome

In MCNS, serum IgG and IgA levels were found to be significantly reduced whereas serum IgM levels were elevated. It was postulated that the primary defect in idiopathic NS consists of deficiency in the T cell function that mediates the switch of IgM synthesis to IgG synthesis [49] . In a study of humoral immunity in idiopathic NS, Dechelette et al [50] demonstrated that patients with idiopathic MCNS are capable of producing, in vivo, active antibodies in response to viral or bacterial infections and to anti-poliomyelitis immunization. However, these patients presented with decreased IgG and increased IgM during exacerbation of the disease. On the other hand, the number of B lymphocytes and their distribution according to surface immunoglobulins were normal.

These reported studies indicate that there are evidences, to implicate immune mechanisms in the pathogenesis of idiopathic NS. However, a number of findings noted previously have been either inconsistent or have not been confirmed. Also, they could be a consequence of the NS itself. In these previous studies there was no attempt to study separately the cellular immunity in the different clinical categories of MCNS which include infrequent relapsers, frequent relap­sers, frequent relapsers who respond to long ­term small dose prednisolone therapy, steroid dependent NS and steroid non-responders [51] .

We can speculate that this clinical variability and heterogeneity seen in MCNS may reflect either different etiopathogenesis or different grades of severity. These phenomena were not addressed or looked at in the previous studies on cellular immunity and nephrotic syndrome. Another important aspect which has not been studied previously is the longitudinal profile of the cellular and humoral immunity in these patients; as new patients at initial presentation (before steroid treatment), during treatment with steroids, and during relapse of their disease. Studies are also needed to identify any markers that can predict whether a new patient will become infrequent relapser, frequent relapser or steroid dependent. Also, there have been no systematic studies to measure the immunological effects of the different cytotoxic drugs including cyclophosphamide, chlorambucil or cyclosporine in these patients and the mechanism involved in inducing remission by these drugs in such patients.

In conclusion, PNS which remains the most prevalent renal disease in childhood continues to be an enigma. The exact pathogenesis is unclear which, when unraveled will be of great interest. The exact definition of its pathogenesis would help the clinicians to decide on the optimal therapy for patients afflicted with this syndrome.

   References Top

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43.Lin CY. Lymphocyte subpopulations and lymphoproliferative studies in steroid responsive nephritic syndrome. Eur J Pediatr 1982; 140-158.  Back to cited text no. 43    
44.Lin CY, Chu CM. Studies of circulating immune complexes and lymphocyte subpopulations in childhood IgM mesangial nephropathy. Nephron 1986;44:198-203.  Back to cited text no. 44    
45.Taube D, Brown Z, Williams DG. Long­term impairment of suppressor-cell function by cyclo-phosphamide in minimal change nephropathy and its association with therapeutic response. Lancet 1981;l:235-8.  Back to cited text no. 45    
46.Schnaper HW, Aune TM. Identification of the lymphokine soluble immune response suppressor in urine of nephrotic children. J Clin Invest 1985;76:341-9.  Back to cited text no. 46    
47.Matsumoto K, Hatano M. Defective cellular immune responses in lupus nephritis. J Clin Lab Immunol 1984; 14:161-3.  Back to cited text no. 47    
48.Matsumoto K, Osakabe K, Katayama H, Yoshi- zawa N, Harada M, Hatano M. Cell mediated immunity in idiopathic membranous nephropathy. Int Arch Allergy Appl Immunol 1981;66:310-5.  Back to cited text no. 48    
49.Giangiacomo J, Cleary TG, Cole BR, Hoffsten P, Robson AM. Serum immunoglobulins in the nephrotic syndrome. A possible cause of minimal change nephrotic syndrome. N Engl J Med 1975;293:8-12.  Back to cited text no. 49    
50.Dechelette E, Batellier H, Seigneurin JM, Beau-doing A.{Humoral immunity in an idiopathic nephrotic Syndrome with minimal glomerular lesions and focal and segmental hyalinosis in children.} Etude del'immunite humorale des syndromes nephrotiques idiopathiques a lesions glomerulaites minimes et a hyalinose segmentaire et facale, Chez l'enfant Arch Fr Pediatr 1983;40:141-7.  Back to cited text no. 50    
51.Elzouki AY, Jaiswal OP. Long-term, small dose prednisone therapy in frequently relapsing nephrotic syndrome of childhood. Effect on remission, statural growth, obesity, and infection rate. Clin Pediatr 1988;27:387-92.  Back to cited text no. 51    

Correspondence Address:
AbdelAziz Yousef Elzouki
Department of Pediatric Nephrology, Maternity and Children's Hospital, P.O. Box 7855, Riyadh 11117
Saudi Arabia
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PMID: 18583776

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