Acute myocardial infarction in a young boy with nephrotic syndrome: a case report and review of the literature

A 7-year-old boy with a 5-year history of steroidunresponsive nephrotic syndrome due to minimal change disease presented with acute myocardial infarction. Angiography was suggestive of a dissected atherosclerotic plaque at the initial and mid portions of the right coronary artery, as well as a lesion in the mid portion of the circumflex artery. The child had a long history of extreme hypercholesterolemia and hypertriglyceridemia, along with apolipoprotein-E 4/3 phenotype. The mother, who also has apolipoprotein-E 4/3 phenotype, has mild hypercholesterolemia. The case suggests that children with long-lasting nephrotic syndrome and even mild familial propensity for hyperlipidemia may be at increased risk for ischemic cardiovascular events. The literature is reviewed regarding the relationship between nephrotic syndrome and the incidence of ischemic heart disease.     

Probucol for treatment of hyperlipidemia in persistent childhood nephrotic syndrome

 In a prospective, uncontrolled multicenter study, we have evaluated the effects of probucol on hyperlipidemia, proteinuria, and glomerular filtration rate (GFR) in hyperlipidemic children with persistent nephrotic syndrome. Probucol was started for a total of 12 weeks in 8 children and for 24 weeks in 14 children. Lipoprotein profiles, serum malondialdehyde (MDA) levels, proteinuria, renal function, and electrocardiogram were monitored every 4 weeks. Side effects were recorded by questionnaire. Treatment was completed by 7 of 8 patients for 12 weeks and by 7 of 14 children for 24 weeks. After 12 weeks, the mean serum concentrations of triglycerides (−15%), total cholesterol (−25%), very low-density lipoprotein-cholesterol (−27%), low-density lipoprotein-cholesterol (−23%), and high-density lipoprotein-cholesterol (−24%), as well as apolipoprotein (apo) A-I (−19%), apo B (−21%), and MDA (−32%) were reduced. The positive effects of probucol on the lipoprotein profile persisted over 24 weeks; however, there was no significant effect on either proteinuria or GFR. In conclusion, probucol had beneficial effects on lipoproteins and lipid peroxidation, but improved neither proteinuria nor GFR. The drug was generally tolerated well, but had to be discontinued because of a prolonged QT interval in 4 of 22 patients. Received: 17 November 1997 / Revised: 12 June 1998 / Accepted: 18 June 1998     

Budd-Chiari syndrome and inferior vena cava thrombosis in a nephrotic child

We observed Budd-Chiari syndrome in a boy aged 2 years 6 months with nephrotic syndrome due to hepatic vein and inferior vena cava thrombosis, confirmed by Doppler imaging. Normal values of the routine hemostatic parameters proved that they are of little predictive value for the thrombotic state. Immediate heparin infusion was initiated. High doses of heparin up to 59 IU/kg per hour were required for efficient anticoagulation. A remission of the nephrotic syndrome was achieved with vincristine. Oral anticoagulation with a vitamin K antagonist was continued for 6 months. Doppler imaging then indicated full re-establishment of the blood flow through the affected vessels. The clinical and Doppler data in this case are compatible with acute Budd-Chiari syndrome due to incomplete outflow obstruction of the hepatic veins and inferior vena cava. The favorable outcome was due to the immediate heparin infusion and prompt remission of the nephrotic syndrome. Doppler imaging was an important tool for non-invasive diagnosis and follow-up. Received: 31 May 1999 / Revised: 30 August 1999 / Accepted: 3 September 1999     

Apolipoprotein E polymorphism in childhood nephrotic syndrome

Recent clinical reports have demonstrated that the progression and prognosis of renal diseases are possibly influenced by apolipoprotein E (apoE) genotypes and alleles. In this study we investigated whether apoE genotypes and alleles can be a prognostic criterion for the steroid responsiveness in childhood nephrotic syndrome. One hundred and seven pediatric patients with primary idiopathic nephrotic syndrome and 83 healthy volunteers were enrolled in the study. Eighty-seven of the patients had steroid-sensitive nephrotic syndrome (SSNS) and 20 had steroid-resistant nephrotic syndrome (SRNS). The ɛ2 allele frequency and ɛ2/3 genotype frequency of the SNRS group were statistically higher when compared with SSNS and control groups (P<0.05). The higher frequency of the ɛ2 allele in steroid resistant nephrotic patients suggests that the ɛ2 allele gives a possible genetic predisposition to steroid resistance in our population, but further studies are needed to clarify this subject. Received: 15 November 2000 / Revised: 15 November 2001 / Accepted: 18 November 2001     

Hemostatic problems and thromboembolic complications in nephrotic children

A hypercoagulable state and the risk of thromboembolism in both arterial and venous circulation is a relatively frequent and serious feature of nephrotic syndrome (NS) in children and adults. The aim of this study was to evaluate the coagulation states of children with NS before and after corticosteroid (CS) therapy and to compare the results with a healthy control group. The first group consisted of 49 nephrotic children (30 boys and 19 girls) with a mean age of 6.5±4.9 years (range 1–16 years). The control group included 17 healthy children (9 boys and 8 girls). At the time of admission, all patients were evaluated for the presence of clinical thromboembolism, hematological and biochemical indicators of a hypercoagulative state, and renal disease. This was repeated after CS treatment. Deep vein thrombosis was observed in 2 nephrotic patients who had very low plasma antithrombin III (AT III) levels and fibrinogen levels above 750 mg/dl. Thus, the prevalence of thromboembolism was 4% in our pediatric nephrotic population. The mean AT III level of the study group was 68.2±23.4% at the onset of the disease, which was significantly lower than the level of the control group (84.0±7.6%). Plasma AT III levels increased to 74.4±15.3% after CS treatment, which correlated with the serum albumin levels. However, there was no correlation with urinary protein excretion. Protein C levels were higher than controls during all stages of the disease in both steroid-responsive and -unresponsive patients. The mean protein S level was similar in both groups. Plasma fibrinogen and cholesterol levels were significantly higher in the study group but decreased to within normal limits with remission. Our study suggests that thromboembolic complications are not infrequent in children with NS, and may be related to low plasma AT III and albumin and high fibrinogen and cholesterol levels. Received: 3 August 1998 / Revised: 27 May 1999 / Accepted: 1 June 1999     

Lithium-induced nephrotic syndrome in a young pediatric patient

Lithium-induced nephrotic syndrome is a rare complication of lithium therapy and is even rarer in children. Most reported cases have been secondary to minimal change disease, which reverses within 1–4 weeks on discontinuation of lithium therapy. However, focal glomerulosclerosis (FSGS) has occasionally been reported and is not always reversible with discontinuation of lithium. We report an 11-year-old child with lithium-induced FSGS nephrotic syndrome who went into full remission after lithium was discontinued. Received: 11 June 2001 / Revised: 9 October 2001 / Accepted: 9 October 2001     

Glucocorticoid receptors in idiopathic nephrotic syndrome

The variable response of patients with idiopathic nephrotic syndrome (NS) to glucocorticoid (GC) treatment has not been explained. Earlier studies indicated that the response is limited by cellular GC receptors. We investigated these receptors in mononuclear leukocytes of 28 pediatric patients with NS divided into three groups: steroid-sensitive in relapse, steroid-sensitive in remission, and steroid-resistant. Density and binding affinity of GC receptors were determined by a dexamethasone binding assay; no significant differences were found between the three patient groups and between these and healthy controls, although a few patient values fell outside the range of controls. Total and free plasma concentrations of cortisol were low in all three patient groups. A weak positive correlation was found between the number of GC receptors and total plasma cortisol (r=0.36, P=0.03). The results suggest that factors other than GC receptors that mediate the cellular effects of GC are involved in the variable response of NS patients to GC. Received: 29 December 1998 / Revised: 12 April 1999 / Accepted: 19 April 1999     

Development of hyperthyroidism in a patient with idiopathic nephrotic syndrome

We present a 13-year-old boy who developed hyperthyroidism during the clinical course of idiopathic nephrotic syndrome treated with glucocorticoid. He had a second relapse of minimal change nephrotic syndrome, and complete remission of nephrotic syndrome was achieved immediately with oral glucocorticoid. However, when the steroid dosage was reduced, signs of hyperthyroidism such as systolic hypertension and tachycardia were observed. Laboratory findings revealed thyroid-stimulating hormone (TSH) below 0.05 μU/ml, free tri-iodothyronine of 16.1 pg/ml, free thyroxine of 5.6 ng/dl, and anti-TSH receptor antibody of 90%. Thus, a diagnosis of hyperthyroidism was made and treatment with thiamazol was started. Massive proteinuria may decrease the activity of hyperthyroidism due to urinary loss of thyroid hormones. A decrease in glucocorticoid dosage may also be involved in the development of hyperthyroidism due to a reduced immunosuppressive effect. Received: 11 July 2001 / Revised: 22 October 2001 / Accepted: 27 November 2001     

Fibronectin glomerulopathy with nephrotic syndrome in a 3-year-old male

Familial non-immune-mediated glomerulopathy has recently been recognized as a distinct clinical entity. The presentation includes proteinuria, often in the nephrotic range, microscopic hematuria, and hypertension. Renal function may remain intact long term, or may progress slowly to renal failure. A 3-year-old boy was referred with proteinuria (>8 g/day), microscopic hematuria, and hypertension (184/150 mmHg). Renal function was intact. Diagnostic evaluation uncovered no evidence of systemic disease. A renal biopsy specimen showed no immune deposits in the glomeruli, but fibronectin deposits were detected in the peripheral loop and mesangium by immunofluorescence. The basement membrane was intact. Twelve other family members subsequently were found to have some renal pathology. Renal function was preserved during 7 years of follow-up. The pathogenesis of fibronectin glomerulopathy is discussed. Received: 06 April 2001 / Revised: 13 December 2001 / Accepted: 13 December 2001     

Increased apoptosis of peripheral blood lymphocytes in children with nephrotic syndrome

Nephrotic syndrome is accompanied by and probably related to abnormal T-lymphocyte function. Decreased stimulation of survival factors and increased levels of ”dead signals” may lead to the malfunction of many cells, including lymphocytes. In our study, we investigated the process of apoptosis within T cells in children with a first attack of nephrotic syndrome (NS). We found that the number of apoptotic T cells is greater in these patients than in both children in remission from NS and in controls. The percentage of annexin-V-fluorescein isothiocyanate (FITC)-positive CD3+ cells was 27.30± 12.13% in children with a first attack of NS, 19.22± 15.16% (P=0.006) in children in remission and 16.20± 6.13% (P=0.004) in controls. The percentage of annexin-V-FITC-positive CD3+CD4+ cells was 7.35±7.72% in children with a first attack of NS, 3.80±3.75% (P=0.0001) in children in remission and 3.82±2.01% (P=0.0002) in controls. We conclude that abnormal number and function of T lymphocytes found in NS patients may be related to an increased apoptotic rate of circulating lymphocytes. Received: 30 May 2001 / Revised: 11 October 2001 / Accepted: 13 October 2001     

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     

A pharmacokinetic study of Neoral in childhood steroid-dependent nephrotic syndrome

Seven children with steroid-dependent nephrotic syndrome who were on stable remission under Sandimmun therapy were switched to Neoral at the same dosage. During the 4-month follow-up period, two patients relapsed, due to poor compliance in one of them. Serum creatinine remained stable in all patients. Pharmacokinetic profiles were performed at day 0 while on Sandimmun and 4 weeks after conversion to Neoral. Following conversion to Neoral, the peak concentration occurred earlier (2±1.4 h vs 3.9±2.4 h), and the maximum concentration (677±386 ng/ml vs 488±265 ng/ml) and the area under the curve (3082±1536 ng/ml/h vs 2201± 889 ng/ml/h) were higher. We conclude that Neoral results in an increased bioavailability of cyclosporine (CsA) as compared to Sandimmun in patients with steroid-dependent nephrotic syndrome in remission. Received: 28 April 2000 / Revised: 5 October 2000 / Accepted: 5 October 2000     

Peritonitis as a risk factor of acute renal failure in nephrotic children

Idiopathic acute renal failure (IARF) is an uncommon but severe complication in children with relapsing nephrotic syndrome and may require long-term dialytic support until recovery of renal function takes place. Due to limited understanding of the pathophysiology of IARF, specific guidelines for its prevention and therapy have not been developed. Among triggering factors, peritonitis was present in half of all pediatric patients with this complication described in the English literature over the past 15 years. We report an additional nephrotic child who developed IARF following spontaneous bacterial peritonitis. The renal biopsy showed tubular epithelial changes consistent with acute tubular necrosis. A discussion of related literature and possible pathogenesis of this association is presented. Received: 13 September 1999 / Revised: 18 April 2000 / Accepted: 23 April 2000     

Disseminated autoimmune disease during levamisole treatment of nephrotic syndrome

Side effects such as cutaneous vasculitis, which occur during prolonged levamisole treatment, may discourage the utilization of the drug in relapsing nephrotic syndrome. We describe a child who developed disseminated vasculitis during prolonged treatment with levamisole. The acute phase was characterized by hepatosplenomegaly, hemolytic anemia, IgM anticardiolipin and p-antineutrophil cytoplasmic antibodies. One month after withdrawal of therapy all symptoms had disappeared and tests normalized. This case report, together with other reports on cutaneous vasculitis, suggest caution and close monitoring during prolonged levamisole therapy. Received: 24 June 1998 / Revised: 17 November 1998 / Accepted: 20 November 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     

Purtscher-like retinopathy in nephrotic syndrome associated with mild chronic renal failure

A sudden loss of vision attributable to Purtscher-like retinopathy occurred in a 4-year-old boy with focal segmental glomerulosclerosis and nephrotic syndrome as well as mild chronic renal failure. This retinopathy was bilateral. After treatment with intravenous methylprednisolone, infusion of 20% albumin, and low molecular weight heparin (nadroparin calcium), his visual acuity improved within 3 days. Ischemic retinal blanching and hemorrhages gradually disappeared. The pathogenesis of this disorder is unknown. Received: 23 November 1999 / Revised: 26 April 2000 / Accepted: 27 April 2000     

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     

Oxidative damage of erythrocyte membrane in nephrotic syndrome

 Erythrocytes are target cells for peroxidative damage. Abnormal susceptibility of erythrocyte lipids to peroxidation is believed to reflect a similar abnormality in other organs and tissues. The changes in erythrocyte lipid peroxidation [measured by malonyldialdehyde (MDA) concentration] and erythrocyte membrane cholesterol (EMC) and their correlation with plasma lipid changes were studied in 36 children with steroid-responsive minimal change nephrotic syndrome (MCNS) (16 in relapse, 20 in remission) and 30 matched healthy controls. Erythrocyte MDA levels were significantly higher in relapse [126.3±40.6 nmol/g hemoglobin (Hb)] compared with remission (101.2±21.3 nmol/g Hb, P<0.02) and in controls (95.4±20.4 nmol/g Hb, P<0.001). Plasma MDA levels in relapse were also higher than in remission (4.26±1.19 nmol/ml vs. 3.16±1.18 nmol/ml, P<0.01), and in controls (2.49±0.86 nmol/ml, P<0.001). The EMC content changed significantly during remission (1.22±0.15 mg/10¹⁰ cells in relapse, 1.09±0.19 mg/10¹⁰ cells in remission, P<0.04). These results show an increased sensitivity of red cells to lipid peroxidation in patients with steroid-sensitive nephrotic syndrome without the development of renal failure and anemia. Lipid peroxidation of plasma lipids and erythrocyte membrane may be a primary phenomenon, but this should be confirmed by investigation of peroxidation of renal lipids. Received: 7 January 1998 / Revised: 4 May 1998 / Accepted: 13 August 1998     

Low protein Z levels in children with nephrotic syndrome

Acquired deficiency of anticoagulant proteins, due to loss in the urine, has been proposed as one of the major thrombogenic alterations in nephrotic syndrome (NS). Protein Z (PZ) is a single-chain vitamin K-dependent glycoprotein. Low PZ levels are reported to be a risk factor for thrombosis. The aim of this study was to investigate protein Z and other natural anticoagulant levels in children with NS. Thirty children aged between 1.5 and 12 years with NS (Groups I and II) and 19 age-and-sex-matched healthy controls (Group III) were enrolled into the study. Patients were divided into two groups: Group I (proteinuria >40 mg/m²/hr) and Group II (patients in remission). Plasma PZ levels in Group I were significantly lower than Group II (p=0.009) and group III (p=0.018). Plasma levels of AT III for Group I were significantly lower than for Groups II and III (p=0.009, p=0.005, respectively). Protein C levels in Group I were higher than in Group II and Group III (p=0.002, p=0.000, respectively). Protein Z levels positively correlated with serum total protein and albumin levels (p=0.003, p=0.003, respectively) and negatively with the degree of proteinuria (p=0.000). Protein Z levels were positively correlated with AT III (r=0.037, p=0.04). Along with the other coagulation abnormalities, decreased protein Z may contribute to increased risk of thromboembolic complications in children with NS. The negative correlation between proteinuria and PZ level suggests the possibility of renal PZ loss. Further studies are needed to investigate the mechanism and role of decreased PZ in NS.