Levamisole treatment in steroid-sensitive and steroid-resistant nephrotic syndrome

Since 1992 we have treated 11 children with frequently relapsing steroid-sensitive (n=6) or steroid-resistant (n=5) nephrotic syndrome with levamisole. All had been non-responsive to other immunosuppressive medication before levamisole treatment. All steroid-sensitive patients had signs of steroid toxicity. At least 1 kidney biopsy had been performed prior to study in each patient. Five children had minimal glomerular changes and the other 6 focal segmental glomerular sclerosis. The patients were treated with levamisole (2.5 mg/kg per 48 h) for at least 2 months (up to 18 months, median 10 months). Two patients had additional immunosuppression (cyclosporine A) during levamisole treatment. All patients with steroid-sensitive nephrotic syndrome became free of proteinuria within 2 months and have remained in remission after discontinuation of levamisole (follow-up time 8–50 months, median 24 months). None of the children with steroid-resistant nephrotic syndrome experienced a remission. Side effects were observed in 2 patients and included a granulocytopenia and a severe psoriasis-like cutaneous reaction; both were reversible after discontinuation of levamisole. We conclude that levamisole is of benefit in steroid-sensitive nephrotic syndrome but not in steroid-resistant nephrotic syndrome. Received August 10, 1997; received in revised form February 11, 1998; accepted February 12, 1998     

Steroid-responsive nephrotic syndrome in a patient with nail-patella syndrome

Nail-patella syndrome (NPS) is a rare disorder with autosomal dominant mode of inheritance. We report a child with NPS and steroid-responsive, frequently relapsing nephrotic syndrome. The child had dystrophic nails, flexion contractures of both elbows and normal renal functions. X-rays of the knees and pelvis showed hypoplastic patellae and iliac horns. Renal histology was unremarkable with mild focal increase in mesangial cellularity compatible with minimal change disease. Ultrastructural features of NPS including thickening of the glomerular basement membrane with electron-lucent areas were not found.     

Steroid-sensitive nephrotic syndrome in two families

Few reports of familial cases of steroid-sensitive nephrotic syndrome (SSNS) are available. Of 123 children with SSNS, four cases in two families are presented. Two sisters and a father and his daughter developed SSNS. The incidence of SSNS siblings in Japan seems to be similar to the incidence reported in other countries. SSNS in two generations is rare. To our knowledge, cases of SSNS in a parent and a child in Japan have not been reported.     

Serum selenium level and glutathione peroxidase activity in steroid-sensitive nephrotic syndrome

In our previous study the pattern of glutathione peroxidase (GPX) activity in the course of steroid–sensitive nephrotic syndrome (SSNS) in children suggested a defect in antioxidant defense. In the present report the serum selenium (Se) level, an essential component of GPX activity, was measured in a comparable group of children with SSNS at the same clinical stages at which GPX activity was determined in the previous study. Nephrotic children had normal serum Se levels during the edematous stage, at the end of prednisone treatment, and in remission. At the end of high-dose prednisone treatment, the serum Se level increased (P<0.01) simultaneously with enhanced activity of GPX. These results suggest that children with SSNS have a persistent defect in the antioxidant defense at the important stage of hydrogen peroxide and fatty acid hydroperoxide decomposition. This defect is transiently alleviated by high-dose prednisone treatment.     

HLA-DR7 predicts the response to alkylating agents in steroid-sensitive nephrotic syndrome

There is a lack of reliable predictors of the response to alkylating agents in children with idiopathic nephrotic syndrome (NS). HLA-DR7 is strongly associated with the frequency of relapses in steroid-sensitive NS before cytostatic therapy. We therefore examined retrospectively the time to the first relapse and the incidence of subsequent relapses in 54 HLA-typed children with frequently relapsing NS, after treatment with cyclophosphamide (n = 49) or chlorambucil (n = 5) for 8 or 12 weeks; 38 patients were HLA-DR7 positive and 16 negative with 80% in both groups being steroid dependent. HLA typing was performed using serological or DNA typing methods. Renal biopsy showed minimal glomerular changes. A lower proportion of HLA-DR7 positive than negative patients remained in remission after 3 years (36% vs. 81%, P<0.02) and 5 years (36% vs. 72%, P<0.03). In the first 3 years after cytostatic therapy the mean number of prednisone-treated relapses was 1.3/patient per year in HLA-DR7-positive patients compared with 0.4 in negative patients (P<0.025). There was no statistically significant difference in the proportion of relapse-free patients with and without steroid dependency. The HLA status predicts the response of NS patients to alkylating agents better than the rate of previous relapses. Received September 19, 1995; received in revised form and accepted April 16, 1996     

Circannual variation in the onset and relapse of steroid-sensitive nephrotic syndrome

Idiopathic nephrotic syndrome is the most common form of nephrotic syndrome in children, but little is known about the etiology of the disease. To obtain new insights into the etiology of the disease, we studied circannual patterns of initial episodes and relapses of steroid-sensitive nephrotic syndrome (SSNS). From 1986 to 2003, there were 45 children with SSNS in our hospital, and they experienced 43 relapses during that period. Initial episodes of SSNS were found to show significant circannual variation with an autumn peak both by Rogers test and Freedmans test, and the circannual pattern was more obvious in patients with high serum IgE levels. Chronological evaluation by means of Fourier analysis showed a clear circannual pattern. In contrast, relapses of SSNS showed circannual variation with a spring peak, which was a result of a high frequency of relapses after upper respiratory infections in January. These results suggest that circannual variation in initial episodes of SSNS might be associated with allergic predisposition, whereas circannual variation in relapses might be associated with preceding upper respiratory infections.     

ACE I/D gene polymorphism in primary FSGS and steroid-sensitive nephrotic syndrome

The role of angiotensin-converting enzyme (ACE) insertion/deletion (I/D) gene polymorphism in various renal disorders has been investigated. We evaluated the association between the clinical characteristics and ACE genotypes of Turkish children with primary focal segmental glomerulosclerosis (FSGS) and steroid-sensitive nephrotic syndrome (SSNS). Patients with FSGS (n=30) were classified into two groups: one with remission together with stable renal function (n=22) and the other without remission and with impaired renal function (n=8). We classified children with SSNS (n=43) that were followed for at least 4 years into two subgroups as having more frequent (n=19) and less frequent relapses (n=11). The DD genotype was more frequent in the SSNS group than that in controls (37% vs. 17%, ²=4.98, P=0.025). However, among SSNS subgroups, the frequency of the DD genotype was not different. The distribution of ACE genotype was similar among patients with FSGS and SSNS. There was no difference in the ACE I/D distribution between children with FSGS and normal controls (II 10%, ID 60%, DD 30% vs. II 13%, ID 70%, DD 17%). The frequency of the DD genotype was higher in FSGS patients with declining renal function (63%) than in those with stable renal function (18%) (P=0.031). Progressive renal impairment was significantly more frequent in patients with FSGS with the homozygous D allele compared with FSGS patients with ID and II genotypes. Our results indicate that the DD genotype may be a risk factor for the development of progressive renal impairment in children with FSGS; however, larger studies are required to confirm this.The abstract of this study was accepted as a poster for the 36th meeting of the European Society of Paediatric Nephrology, Bilbao, September 2002. This study was supported in part by a grant from the Istanbul University Research Fund (no T-849/17072000)     

HLA-DQB1 and DRB1 alleles in Egyptian children with steroid-sensitive nephrotic syndrome

Steroid-sensitive nephrotic syndrome (SSNS) of children has been associated with several HLA-DR and DQ alleles. To investigate this association in Egyptian children, 27 patients with SSNS were typed for HLA-DRB1 and DQB1 alleles using DNA polymerase chain-reverse hybridization technique. The results were compared with 121 healthy subjects for HLA-DRB1 and 59 subjects for DQB1 alleles. We found that: (1) patients have higher frequencies of both DQB1 ^* 0601 (81.5% vs. 10.2% in controls, Pc = 0.0001) and DRB1 ^* 01 (44.4% vs. 3.3% in controls, Pc = 0.00003). Their relative risks are significantly high [38.9, confidence interval (CI) = 10.7–140.7, and 23.4, CI=6.7–81.9, respectively]; (2) the frequency of DRB1 ^* 11 alleles was low in SSNS patients (3.75% vs. 32.2% in controls), but was not significant when P was corrected (P = 0.005, Pc = NS). These findings suggest that DQB1 ^* 0601 and DRB1 ^* 01 or closely associated unknown genes confer susceptibility to SSNS. However, further studies with larger numbers of patients are needed. Received June 27, 1997; received in revised form October 23, 1997; accepted October 26, 1997     

Family structure and the course of steroid-sensitive nephrotic syndrome

The number of children in nontraditional families is growing. The objective of this study was to determine the effects of family structure on the course of childhood steroid-sensitive idiopathic nephrotic syndrome (SSNS). Sixteen children, 2–15 years of age, with SSNS were enrolled in the study. The effects of family structure (traditional versus nontraditional) on the number of hospitalizations and outpatient visits for the previous 2 years and disease relapses for the preceding year were evaluated. Behavior differences were assessed using the Child Behavior Checklist (CBCL). Of the 16 families, 9 were traditional and 7 nontraditional. Hospitalizations, outpatient visits, and behavior were not different between family groups. However, children from nontraditional homes relapsed 3 times more than children from traditional homes (P=0.003). We conclude that children with SSNS from nontraditional homes may be at risk for more relapses compared with children from traditional families. Heightened support and monitoring is necessary for these children. Received: 23 January 2001 / Revised: 20 June 2001 / Accepted: 10 July 2001     

Increased nitric oxide production by T- and B-cells in idiopathic nephrotic syndrome

The pathogenesis of idiopathic nephrotic syndrome (INS) remains unclear. To study the role of nitric oxide (NO) in INS, we measured intracellular NO produced by T- and B-cells using a novel fluorescent indicator. Twelve children with INS (mean age 7.3 years; group A-1: in relapse, group A-2: in remission) were enrolled in the study together with 16 children with other renal diseases (9.5 years; group B) and 42 healthy control children (7.7 years; group C). The amount of NO produced by CD3+ cells (T-cells) and CD19+ cells (B-cells) and of plasma NO_x was measured by flow cytometry and colorimetry, respectively. The average amount of NO produced by CD3+ and CD19+ cells in group A-1 subjects was significantly higher than that produced by these cells in group A-2 and B patients and the healthy controls (group C), respectively (P < 0.01), and it decreased after the patients achieved remission (P < 0.01). Plasma NO_x levels in group A-1 patients was also highest among the different groups (P < 0.01). There were no significant differences in intracellular NO and plasma NO_x among group A-2, B, and C subjects (P > 0.05). A significant correlation between plasma NO_x and urinary protein excretion was found only in group A patients and not in group B patients. We conclude that an aberrant immune system may exist not only in T-cells but also in B-cells, and NO may play some role in INS.     

Treatment of steroid-resistant post-transplant nephrotic syndrome with cyclophosphamide in a child with congenital nephrotic syndrome

A child with congenital nephrotic syndrome underwent renal transplantation, was treated for acute rejection, and then developed nephrotic syndrome and renal failure. He was felt to have minimal change disease on allograft biopsy, but failed to respond to therapy with corticosteroids. Cyclophosphamide was substituted for cyclosporine and rapidly induced a complete remission of his nephrotic syndrome. We feel that this case not only represents an important example of a useful therapeutic approach to the child with congenital nephrotic syndrome who develops nephrotic syndrome post transplantation, and also raises questions concerning the pathogenesis of congenital nephrotic syndrome.     

Atherosclerosis risk factors in young patients formerly treated for idiopathic nephrotic syndrome

A total of 30 patients (ten female/20 male), 9 years to 22 years old (mean age 17.3 years) and 30 healthy teenage controls (mean age 16.4 years) were included in our study. The patients had steroid-sensitive idiopathic nephrotic syndrome (INS) and had completed steroid therapy 4 years to 15 years ago. Height and weight, body mass index (BMI), body composition, and intima-media thickness (IMT) were determined, as were levels of total cholesterol (TCh), low-density lipoprotein cholesterol (LDL-Ch), high-density lipoprotein cholesterol (HDL-Ch), triacylglycerols (TAGs), homocysteine (HCY), and high-sensitivity C-reactive protein (hsCRP). We did not observe any differences between the study and control groups in IMT (0.47 ± 0.1 vs 0.46 ± 0.1 mm) and body composition (fat tissue and water content). Differences in HDL-Ch and hsCRP levels between groups were not significant. In the study group we found significantly higher TCh levels (187.6 ± 57.2 mg/dl vs 158.8 ± 25.7 mg/dl; P = 0.012), LDL-Ch (115.9 ± 63.7 mg/dl vs 79.4 ± 25.4 mg/dl; P = 0.005), HCY (12.3 ± 7.7 μmol/l vs 7.6 ± 1.6 μmol/dl; P < 0.001), apolipoprotein B (ApoB) (113.6 ± 30.0 mg/dl vs 78.7 ± 13.6 mg/dl; P < 0.001) and ApoA1 (203.5 ± 50.8 mg/dl vs 156.5 ± 12.4 mg/dl; P < 0.001) levels. Multi-factor analysis of the influence of independent factors (number of recurrences, duration of remission, age, gender, and BMI) on the parameters under investigation indicated a positive correlation between IMT and the number of recurrences. Conclusions: 1. Patients treated for idiopathic nephrotic syndrome in the past should undergo regular laboratory tests of atherosclerosis risk factors, including not only cholesterol and its fractions, but also ApoA1, ApoB and HCY. 2. It is necessary to continue systematic check-ups of the intima-media thickness of the carotid arteries among young patients with anamnesis of INS, especially among patients who suffered from numerous relapses of this disease.     

Expression of nephrin in acquired forms of nephrotic syndrome in childhood

Nephrin is a podocyte adhesion molecule located at the slit diaphragm between adjacent glomerular epithelial cells. Mutations in the gene encoding nephrin result in the absence of nephrin or alterations in nephrin causing massive proteinuria in patients with congenital nephrotic syndrome. Given the importance of nephrin to the structural integrity of the glomerular filtration barrier, we postulated that it might also be altered in acquired forms of nephrotic syndrome (NS). To test this hypothesis, frozen kidney biopsy sections from 29 pediatric patients with acquired NS and 5 controls were examined for expression of nephrin. The pathological diagnoses were minimal change disease (MCNS) (19) and focal segmental glomerulosclerosis (FSGS) (10). To determine if nephrin expression differed between children and adults with NS, 10 adult patients and 3 controls were also examined. Nephrin expression was evaluated by immunoperoxidase staining with a monoclonal antibody against the extracellular FnIII portion of human nephrin. In all cases, nephrin expression was seen along the glomerular basement membrane in a finely granular/linear pattern. Expression of nephrin was similar to controls in all 19 patients with MCNS and all 10 patients with FSGS. Areas of sclerosis in patients with FSGS did not demonstrate nephrin expression. A distinctly granular pattern to nephrin expression was seen in adult patients with NS as well as controls. These findings suggest that an alteration in nephrin expression is not a feature of acquired forms of NS in childhood.     

Glucocorticoid receptors expression and histopathological types in children with nephrotic syndrome

Background: Some children with idiopathic nephrotic syndrome (NS) patients fail to respond even when given high dose of steroid. The aim of this study was to assess the GCR expression on the T lymphocytes of children with NS and its relation to the response to steroid and to histopathological type. Methods: Forty-six pediatric patients with idiopathic NS and 20 age and sex matched apparently healthy children as controls were included. Flow cytometry was employed to determine the percentage of CD3+/GCR+ cells which then correlated with pattern of steroid response. Renal biopsy was done for steroid-dependent and steroid-resistant cases for determination of the underlying histopathological type. Results: The mean percentage of T lymphocyte expression of GCRs (CD3+/GCR) was significantly higher in early steroid responders than in late responders and was slightly lower than the controls. There was a significantly lower GCRs expression in steroid-resistant patients in comparison to early responders, late responders and controls. Renal biopsy showed that most cases of late responders were of the focal segmental glomerulosclerosis (FSGS) type. The mean percentage of lymphocyte expression of GCRs was significantly higher in patients with minimal change disease (MCD) compared to patients with FSGS. Conclusion: Evaluation of the expression of intracellular GCRs in T lymphocytes at time of diagnosis of NS can predict the response to steroid therapy and can help in determination of the outcome of NS patients regarding future relapses.     

Cerebral oedema in congenital nephrotic syndrome

We report an infant with congenital nephrotic syndrome who showed clinical and radiological evidence of cerebral oedema, which resolved during prolonged intravenous albumin therapy. The cerebral oedema in this case can possibly be attributed to the relative immaturity of the blood-brain barrier in early infancy.     

Prediction of subsequent relapse in children with steroid-sensitive nephrotic syndrome

Among nephrotic children with frequent relapses at risk for cumulative steroid toxicity, identification of children who may be at high risk for subsequent relapse is very important in making the decision to introduce cytotoxic drugs. We examined the clinical course of 467 relapses in 121 steroid-sensitive nephrotic children to elucidate the risk factors for subsequent relapse, using the Cox proportional-hazards regression model. Gender, age at onset, duration of illness from onset, prednisolone dosage at the most-recent relapse, and regimens of initial steroid therapy at onset were not associated with risk. Relapse within the 1st year was a powerful independent predictor of subsequent relapse irrespective of the duration of illness. The hazard ratio of patients with more than one relapse within the 1st year increased to 1.72–2.12 compared with those without a relapse within the 1st year. The remission period just before the most-recent relapse was also a significant predictor. The risk for patients with a 1-year or longer remission period decreased to 0.57. Patients treated with cyclophosphamide for 12 weeks had a significantly longer remission than those treated with prednisolone alone. Our results suggest that early relapse after onset and/or a short remission period just before recent relapse are independent risk factors for subsequent relapse. Cytotoxic therapy has serious adverse effects and its effect may be limited. Our results may be helpful in deciding on the suitability of cytotoxic drugs. Received: 21 September 2000 / Revised: 12 June 2001 / Accepted: 14 June 2001     

Mizoribine in steroid-dependent nephrotic syndrome of childhood

We evaluated a 1-year course of a newly developed immunosuppressant, mizoribine (at a dosage of 3 mg/kg body weight per day), in nine children with steroid-dependent nephrotic syndrome. Steroid treatment could be discontinued in two patients and the maintenance dosage of steroid could be reduced to less than half of that given before mizoribine therapy in a third. There were no beneficial effects in the remaining six patients. No adverse effects of mizoribine were observed during the course of therapy. Received September 20, 1996; received in revised form and accepted April 24, 1997     

Atorvastatin in dyslipidaemia of the nephrotic syndrome

SUMMARY:   The combined dyslipidaemia that accompanies the nephrotic syndrome increases the cardiovascular risk and appears to worsen long-term renal function. Our aim was to determine the efficacy and safety of 10 mg atorvastatin in the control of dyslipidaemia in these patients. We carried out a prospective, open, 6 month study of 10 patients with primary or secondary nephrotic syndrome (proteinuria >3.5 g/day, hypoalbuminaemia, oedema and hyperlipidaemia). The changes in lipids and plasma lipoproteins were measured, as well as the safety profile (transaminases, creatine phosphokinase, fibrinogen and antithrombin III activity) and parameters of renal function. The addition of 10 mg atorvastatin daily for 6 months resulted in a 41% reduction in low density lipoprotein (LDL) cholesterol and 31% in triglycerides (both P  < 0.05), and a 15% increase in high density lipoprotein (HDL) cholesterol (NS). The drug was well tolerated and there was no change in the safety profile or deterioration in renal function. In fact, the levels of proteinuria fell in all but one patient (6.2 ± 2.6 vs 4.8 ± 2.5 g/24 h; P  < 0.05). Atorvastatin, at the above dose, and for the time used proved to be a safe drug that effectively reduced dyslipidaemia in patients with nephrotic syndrome.