Apoptosis and antioxidant defense in the nephrotic syndrome

Nephrotic syndrome (NS) is accompanied, and probably caused by, abnormalities in T lymphocyte function. The aim of this study was to investigate the antioxidant status of children with NS and its influence on the apoptosis of T cells. Fifty-seven children with NS were studied, aged 4–16 years (mean 7.4 years), 34 with a first episode (group I) and 23 in remission (>6 months) of NS (group II). The control group comprised 26 healthy children matched for age. Annexin V-FITC was used as a sensitive probe for identifying cells undergoing apoptosis. We found that apoptotic T lymphocytes occurred more frequently in patients with a first episode of NS than in children in remission and in the controls. In group I, total antioxidant status (TAS, plasma) was significantly reduced compared with controls (0.77±0.14 vs. 1.18±0.42 mmol/l, P<0.001). In group I children, glutathione reductase (GR, red blood cells) and glutathione peroxidase (GPX, red blood cells) activity was lower than in controls (GR 8.10±2.40 vs.10.55±3.81 U/g Hb, P<0.001) (GPX 28.65±6.99 vs. 33.84±13.11 U/g Hb, P=0.010). TAS levels and GR activity in group II were also lower than in the controls. A negative correlation between GR activity and the apoptosis rate of T lymphocytes was found. We conclude that in patients with NS, reduced antioxidant defense may contribute to an increase in the apoptosis rate of circulating lymphocytes.     

Antioxidant status of children with acute renal failure

The production of free radicals can cause renal injury and play a role in the pathogenesis of acute renal failure (ARF). The indirect markers of reactive oxygen species (ROS) were evaluated in children with ARF and controls. Forty patients with ARF aged 0–10 years were selected. Twenty age- and gender-matched healthy children were included as controls. Plasma malondialdehyde, protein carbonyl, nitrite, copper, ascorbic acid, zinc, and ceruloplasmin levels were estimated in patients with ARF and controls. The plasma malondialdehyde (p < 0.01), copper (p < 0.001), ascorbic acid (p < 0.05), and ceruloplasmin (p < 0.001) levels were significantly raised in ARF patients in comparison with controls. Significantly higher levels of plasma malondialdehyde (p < 0.01), nitrite (p < 0.001), copper (p < 0.001), and ceruloplasmin (p < 0.001) and lower plasma zinc (p < 0.01) were found in ARF nonsurvivors in comparison with survivors. The cutoff levels of plasma nitrite and ceruloplasmin were found to be most accurate in predicting mortality in ARF patients and had maximum sensitivity (100%) and specificity (60.7%) among the parameters studied. In conclusion, the increased levels of oxidants and antioxidants suggest the production of ROS and their possible role in ARF pathogenesis. Plasma nitrite and ceruloplasmin concentrations demonstrated predictive ability in relation to mortality. Financial Support: The study was supported by Departmental Research Grant of Pediatrics, Institute of Medical Sciences, Banaras Hindu University, Varanasi-221005, India.     

Varicella vaccination in children with steroid-sensitive nephrotic syndrome

We have studied serological and clinical response to live, attenuated varicella zoster virus (VZV) vaccine (Varilrix, SmithKline Beecham) in 20 patients with steroid-sensitive nephrotic syndrome (SSNS) in remission and 22 normal controls who had no history of varicella and no detectable antibody to VZV. Nephrotic patients included 15 boys and 5 girls, with a mean age of 4.7 years (range 2–11.4 years). The controls were healthy age-matched children (13 girls and 9 boys). Seventeen patients with SSNS (85%) and 19 healthy controls (86%) seroconverted 8 weeks after vaccination. One patient with SSNS had a relapse 20 days after vaccination, and 1 child in the control group had a rash. Two years after vaccination, antibodies to VZV were detected in 12 of 17 responders, 2 of 3 non-responders, and 13 of 22 controls. Within 2 years of vaccination, 3 of the vaccine responder children with SSNS had a mild varicella infection. Two responder and 1 non-responder nephrotic children and 9 controls were lost to long-term follow-up. Our results show that immunization with a single dose of VZV vaccine is safe and effective in children with SSNS in remission. Received: 9 May 2001 / Revised: 15 November 2001 / Accepted: 18 November 2001     

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     

Risk factors for glucocorticoid-induced obesity in children with steroid-sensitive nephrotic syndrome

The objective of this work was to determine the prevalence of obesity, defined as BMI >95th percentile, in children treated with glucocorticoids for steroid-sensitive nephrotic syndrome (SSNS), and to identify risk factors for the development for glucocorticoid-induced obesity. The experimental design involved a cross-sectional study of 96 individuals (4 to 21 yrs) treated with glucocorticoids for SSNS and 186 healthy reference subjects. Logistic regression was used to generate odds ratios for obesity. Glucocorticoid exposure was classified as recent in the 54 subjects treated with glucocorticoids in the prior six months, and remote in the remaining 42 subjects. Recent exposure was associated with significantly increased odds of obesity [odds ratio (95% CI): 26.14 (7.54, 90.66)] in non-blacks only. Each one-unit increase in maternal BMI was associated with a 35% increase in the odds of obesity in recent SSNS subjects (p=0.003). The effect of maternal BMI on the odds of obesity was significantly greater in recent SSNS subjects than in reference subjects (test for interaction p=0.038). The odds of obesity were also significantly increased [odds ratio 5.22 (1.77, 15.41), p=0.003] in all subjects with remote glucocorticoid exposure (black and non-black). These results indicate that non-black race and increased maternal BMI are risk factors for glucocorticoid-induced obesity in subjects with recent exposure.Dr. Foster was supported by a National Research Service Award F32DK62637–01 and by a Duncan L. Gordon Fellowship from the Hospital for Sick Children Foundation, Toronto, Canada. The protocol was supported by NIH grants K08-DK02523 (MBL) and the General Clinical Research Center (M01RR00240) at the Children’s Hospital of Philadelphia, University of Pennsylvania School of Medicine.     

Management of steroid-sensitive nephrotic syndrome in children with type 1 diabetes

Four children with steroid-sensitive nephrotic syndrome (SSNS) coexisting with type 1 diabetes are presented. This number is higher than expected according to the estimated prevalence rates for each disease separately. In three, diabetes preceded nephrotic syndrome (NS), and in one it developed almost simultaneously. None of the patients had hypertension or retinopathy. Two had a renal biopsy: in one it was compatible with minimal change histology (MCH), and the other had MCH and early diabetic nephropathy changes. In addition to the two presented here, in 11 of 12 previously reported cases with biopsy proven SSNS coexisting with type 1 diabetes, the biopsy showed MCH. In none was treatment influenced by biopsy results. However, our experience suggests that daily steroid taper allows easier glycaemic control than alternate day steroids. We conclude that the indications for a renal biopsy in nephrotic children with and without insulin-dependent diabetes mellitus (IDDM) should be similar. Received: 27 July 2001 / Revised: 15 January 2002 / Accepted: 15 January 2002     

儿童激素敏感性肾病综合征复发的原因和相关因素分析

目的分析儿童激素敏感性肾病综合征复发的原因,为合理治疗肾病综合征复发提供依据。方法对激素敏感性肾病综合征患儿进行定期随访检查,复发时进行详细病史询问、体检和血尿常规、血生化、血皮质醇测定,分析肾病复发的原因。结果纳入儿童激素敏感性肾病综合征93例,未复发28例（未复发组）;复发65例,共计116例次复发,其中频复发31例（频复发组）,非频复发34例（非频复发组）。复发原因最多为激素依赖和（或）免疫抑制剂依赖（占49．1％）,之后依次为感染（占36．2％）,激素停用（占1．7％）,过敏和接种（占1．7％）,外伤（占1．7％）,10．3％原因不明。血清皮质醇水平减低在频复发组中的比例显著高于非频复发组和未复发组（P〈0．05和P〈0．01）,而严重低血清白蛋白血症和低IgG血症在各组中无显著差别。结论糖皮质激素依赖和感染是儿童激素敏感性肾病综合征复发的主要原因,而血皮质醇水平低下可能是儿童激素敏感性肾病综合征出现频繁复发和激素依赖的重要机制。     

Major histocompatibility complex class II antigens in steroid-sensitive nephrotic syndrome in Chinese children

Steroid-sensitive nephrotic syndrome (SSNS) has been postulated to have an immunopathogenic basis. To determine whether SSNS is associated with specific class II antigens of the major histocompatibility complex, we studied HLA-DR and DQ in 40 children with SSNS. HLA-DR7 was found in 40% of SSNS patients compared with only 11.23% of controls (P=0.00025). HLA-DR9 occurred in 71.40% of patients with frequent relapses, compared with 27.37% of controls (P=0.016). It seems likely that SSNS has an immunogenetic basis.     

Pulmonary thrombosis in steroid-sensitive nephrotic syndrome

Thrombo-embolic episodes are an uncommon but known complication of nephrotic syndrome. However, pulmonary thrombosis/thromboembolism is rare, especially in children. We describe the cases of two girls, aged 12 years, who presented with severe oedema in relapse. They had intermittent tachypnoea, and CT pulmonary angiography (CTPA) provided a less invasive and more definitive way of confirming pulmonary thrombosis/thromboembolism. They received heparin with resolution of the tachypnoea. Anticoagulation was continued for 6 months after the episode in one patient. They have been in remission for more than 1 year, and a thrombophilia screen does not indicate a predisposing tendency to the formation of clots. Pulmonary thrombosis/thromboembolism could present with subtle symptoms and needs prompt diagnosis and treatment to prevent a fatal outcome.     

Vitamin D insufficiency in steroid-sensitive nephrotic syndrome in remission

Serum 25-hydroxyvitamin D [25(OH)D] concentrations are the best indicator of vitamin D nutritional status. We measured serum 25(OH)D concentrations in 94 healthy controls and in 41 subjects (aged 4–22 years) with steroid-sensitive nephrotic syndrome (SSNS) in remission. Children with remitted SSNS had significantly lower 25(OH)D concentrations than healthy controls (median 16.4 ng/ml versus 23.9 ng/ml, P <0.001). In a multivariable logistic regression model, the odds ratios (OR) of vitamin D insufficiency [25(OH)D <20 ng/ml] were independently increased in SSNS subjects [OR 11.2 (95% confidence interval 3.5–36.2)], non-whites [OR 12.9 (4.6–36.2)], older children [OR 1.20 per year (1.06–1.36)], and winter months [OR 6.7 (2.5–18.4)]. Within the SSNS subjects, multiple linear regression determined that serum 25(OH)D concentrations were not associated with SSNS disease characteristics measured in this study, such as duration of disease, number of relapses, cumulative glucocorticoids, and interval since last relapse. In conclusion, children with remitted SSNS have lower serum 25(OH)D concentrations than healthy controls. This difference persisted after adjusting for the potential confounding effects of age, race, season, and milk intake. Children with remitted SSNS may benefit from routine measurement of 25(OH)D, but the clinical significance of low 25(OH)D in this population remains unclear.     

Paraoxonase, total antioxidant response, and peroxide levels in children with steroid-sensitive nephrotic syndrome

Reactive oxygen species (ROS) are reported to play a role in inducing the proteinuria of nephrotic syndrome (NS). This study investigated paraoxonase (PON), total antioxidant response (TAR), and oxidant total peroxide together with serum proteins and lipoproteins in children with steroid-sensitive NS. The study included 40 children with steroid-sensitive NS (21 with acute-period NS in group I, 19 nonproteinuric while receiving steroids in group II) and 22 sex- and age-matched formerly nephrotic children in remission weaned from steroids (group III). The following parameters were determined: total peroxide, oxidative stress index (OSI), PON and TAR. Serum proteins and lipoproteins were also determined. Patients in the active phase of NS had significantly lower PON and TAR levels and higher OSI and total peroxide values than those in full remission; no differences were found in PON, TAR, or OSI values of groups I and II. Significant correlations were found between PON, TAR, and total peroxide. Serum total protein had a significantly positive correlation with PON and negative correlation with total peroxide in acute-period NS patients. Our results demonstrate greater oxidative stress and decreased antioxidants in the active phase of steroid-sensitive NS and while patients receive steroids than during full remission. Low-dose alternate-day steroids do not seem to decrease oxidative stress even while proteinuria ceases. Despite some conflicting data increased oxidation and/or decreased antioxidant response may be related to the pathogenesis of steroid-sensitive NS.     

Influence of age at onset on the outcome of steroid-sensitive nephrotic syndrome

To investigate whether age at onset of steroid-sensitive nephrotic syndrome (SSNS) is predictive of subsequent relapses, or influences outcome, we retrospectively studied 60 patients who were under 10 years of age at onset and were followed for over 10 years. They were divided into three groups according to age at diagnosis: group 1–3 (1.0–3.9 years at onset, n=24), group 4–6 (4.0–6.9 years at onset, n=22), and group 7–9 (7.0–9.9 years at onset, n=14). In the 51 patients with long-term remission, defined as remaining relapse-free over 3 years, the total number of relapses was significantly more in group 1–3 (n=18) than in group 4–6 (n=19), and the interval between onset and long-term remission was significantly longer. Group 4–6 and group 7–9 had fewer patients with active disease at 10 years, follow-up than group 1–3, as assessed by the Kaplan-Meier method. These data suggest that the age at onset of SSNS influences the clinical course (i.e., frequency of relapses) and the time to reach long-term remission. An age of less than 4 years at onset of SSNS is associated with greater likelihood for frequent relapses and a greater time interval to attain long-term remission. Received September 12, 1997; received in revised form February 17, 1998; accepted February 19, 1998     

Asymptomatic intracardiac thrombus in steroid-sensitive nephrotic syndrome

Arterial and venous thrombotic events can lead to severe complications in the nephrotic syndrome, but may remain clinically silent in a substantial proportion of patients. Intracardiac thrombi associated with multiorgan thrombosis have been described in autopsy cases of the earlier literature, but have never been documented in vivo. We here report an asymptomatic intracardiac thrombus in a child with frequently relapsing steroid-sensitive nephrotic syndrome and a ventricular septal defect. Received: 7 May 2001 / Revised: 19 November 2001 / Accepted: 24 November 2001     

Spectrum of infections in Indian children with nephrotic syndrome

We conducted a retrospective analysis of infections in 154 children (114 boys, 40 girls) with nephrotic syndrome who satisfied the International Study of Kidney Disease in Children criteria. Their mean age at onset of symptoms was 6.2 years (range 6 months to 16 years) and the mean duration of follow-up was 32 months (range 6–55 months). One or more infectious complications were observed in 59 of the 154 children (38%), with urinary tract infection being the commonest (13.7%), followed by pulmonary tuberculosis (10.4%), peritonitis (9.1%), skin infections (5.2%), upper respiratory infections (5.2%), lower respiratory tract infections (3.9%) and pyomeningitis (0.6%). There were 3 deaths, the mortality in 2 patients being attributable to infections. There was no significant difference between children who developed infection and those who didn't in terms of age of onset, sex, duration of disease, serum creatinine, blood urea nitrogen and 24-h proteinuria. However, the children who developed infectious complications had significantly higher serum cholesterol levels (P<0.01) and lower serum albumin levels (P<0.02). The frequency of infections was higher inchildren who were frequent relapsers, steroid dependent and subsequent non-responders (28/60) compared with infrequent relapsers and initial non-responders (29/94).     

Reduced response to hepatitis B virus vaccination in boys with steroid-sensitive nephrotic syndrome

Vaccination against hepatitis B virus (HBV) was performed in 18 boys (aged 5.7±2.4 years) suffering from steroid-sensitive nephrotic syndrome (SSNS) and in a control group of 21 healthy boys (aged 5.6±3.8 years). The percentage of patients who responded to vaccination was significantly lower than the control group 1, 6, 8, 12, 18 and 24 months after the start of vaccination. The titre of antibodies to HBV surface antigen produced by responders at 6 and 24 months was significantly lower in patients than in the control group. Boys with SSNS have an impaired response to HBV vaccination.     

Efficacy of zinc supplements in reducing relapses in steroid-sensitive nephrotic syndrome

Relapses in steroid-sensitive nephrotic syndrome (SSNS) often follow infections of the respiratory or gastrointestinal tract. Based on data that zinc supplements reduce the risk of infections, we examined the efficacy of such supplements in reducing relapse rates in these patients. Eighty-one patients with SSNS (1–16 years old) were stratified into frequent (n = 52) and infrequent (n = 29) relapsers and randomized to receive 12-months of therapy with the recommended dietary allowance of zinc (10 mg/day) (n = 40) or placebo (n = 41). Patients with frequent relapses also received long-term, alternate-day prednisolone. Subjects receiving zinc showed a 20% lower frequency of relapses, with 44.7% of the patients having sustained remission compared to 27.5% in the placebo group (P > 0.05). Patients with frequent relapses receiving zinc showed a 28% reduction in relapse rates and a significantly higher likelihood of sustained remission (P = 0.02). Findings from this double blind, randomized study suggest that zinc supplementation results in trends towards remission and reduced relapses, especially in patients with frequent relapses. Prospective, adequately powered studies are required for confirmation of these findings. Cochrane Renal Group Registry (CRG030600044)     

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.     

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     

HLA antigens in Arab children with steroid-responsive nephrotic syndrome

Forty-eight Arab patients with steroid-responsive childhood nephrotic syndrome were studied for the frequency of HLA-A,-B,-C and-DR antigens. HLA-DR7 was significantly increased in the patient group (63% vs. 28%,P=0.0002) confirming reports of a DR7 association in other ethnic groups and indicating a universal association with this antigen. HLA-CW6 was also significantly increased (44% vs. 21%,P corr.=0.042). HLA-DQW1 was significantly reduced in the patients (29% vs. 57%,P corr.=0.012) as was HLA-CW4 (6% vs. 24%,P corr.=0.042).     

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