Childhood Nephrosis Research Articles

Oxidant and Antioxidant Status in Childhood Nephrosis and its Relation to Hyperlipidemia

Background: Oxidative damage by free radicals has been implicated in a number of clinical disorders including renal injury. An abnormality in the oxidative system in patients with nephrotic syndrome (NS) has been reported.Objective: To assess the oxidant status (red cell MDA) and antioxidant status (red cell GSH, SOD' and plasma vitamin E, copper, zinc) in relation to hyperlipidemii in children with active nephrotic syndrome (NS) and during remission.Methods: This study was conducted on 65 children with NS; 35 with active NS (Group 1) & 30 with NS during remission (Group 2) and 20 healthy controls. Red cell glutathione (GSH), superoxide dismutase (SOD) and malonfiialdehyde (MDA) concentrations as well as plasma levels of vitamin E, copper, zinc and plasma lipids (total cholesterol ТС, triglycerides high density lipoprotein cholesterol and low density lipoprotein cholesterol LDL-C) were measured in children with NS and in controls.Results: SOD concentrations significantly increased in both group I & group 2 when compared to the controls. MDA concentrations significantly increased in both group 1 & group 2 compared to the controls. GSH concentrations along with plasma vitamin E concentrations significantly decreased in both group I & group 2 compared to controls. A significant decrease in plasma copper and zinc concentrations was observed in group 1 compared to controls. However, a non-significant decrease in plasma copper and zinc concentra-tions was observed in group 2 compared to controls. Plasma TC, TG, LDL-C concentrations significantly increased while plasma HDL-C significantly decreased in both group 1 & group 2 compared to controls. Significant +ve correlation was found between MDA and each of TC, TG, LDL-C, while significant -ve correlation existed between MDA and HDL-C. Significant -ve correlations existed between each of albumin, SOD, vitamin E, zinc, copper and each of TC, TG, LDL-C. Meanwhile, significant +ve correlations existed between HDL-C and each of albumin, SOD, vitamin E, zinc and copper.Conclusion: Increased pro-oxidant status with compensatory changes in antioxidant concentrations occur in children with NS. These changes are linked to lipid disorders in NS patients and may be related to the pathogenesis of NS.

Steroid-resistant idiopathic childhood nephrosis: overdiagnosed and undertreated

The rate of complete remission after induction therapy for steroid-resistant nephrotic syndrome (SRNS) due to either focal segmental glomerulosclerosis (FSGS) or minimal change nephrotic syndrome (MCNS) has been reported to be <50%. The present retrospective study investigated 86 children with SRNS due to FSGS and MCNS and found improved rates of complete remission in children with idiopathic FSGS and MCNS after combination therapies using ciclosporin A (CSA) and prednisolone (PRED). Eighty-six children with FSGS or MCNS and with SRNS receiving standard oral PRED therapy were analysed in a retrospective, non-randomized study. Fifty-two patients had idiopathic FSGS (group 1), 14 patients had MCNS (group 2), and 20 patients had genetic FSGS or syndrome-associated FSGS (group 3). In group 1A (n = 25), induction therapy consisted of CSA (initial dose 150 mg/day/m(2) divided into two doses) given in combination with intravenous methylprednisolone (IV-MPRED 300-1000 mg/day/m(2) for 3-8 days) and oral PRED. In group 1B (n = 27), CSA was combined with oral PRED (40 mg/m(2) on alternate days). In group 1, patients with idiopathic FSGS receiving IV-MPRED + oral PRED + CSA had a significantly better outcome than patients treated with oral PRED + CSA (84 vs 64% cumulative proportion of sustained complete remission, respectively; P = 0.02, log-rank test). Sixteen (40%) out of 40 children entering complete remission had a first relapse after a median interval of 1 year. All relapses were successfully treated with IV-MPRED + oral PRED + CSA or oral PRED + CSA. Three out of forty responding children developed stage 2 chronic kidney disease (CKD), and none advanced to stage 3-5; in contrast, 9 out of 12 children with persistent nephrotic syndrome (NS) developed CKD stage 2-5 (8 vs 75%, respectively; P < 0.001, Fisher's exact test). In group 2, all 14 children with steroid-resistant MCNS went into remission after receiving PRED + CSA (n = 11) or IV-MPRED + oral PRED + CSA (n = 3). No patient developed CKD. In group 3, NS persisted in all 20 children having a genetic or syndromic type of FSGS receiving either PRED + CSA (n = 9) or PRED alone (n = 11). Seventeen out of 20 patients entered stage 5 CKD and were successfully transplanted; one patient developed recurrent NS. Prolonged and intensified treatment of children with idiopathic non-genetic SRNS (FSGS or MCNS) with combined PRED + CSA therapy including IV-MPRED pulses resulted in a higher rate of remission when compared with previous reports on using CSA mono-therapy or other immunosuppressive combination therapies.

Cerebral thrombosis in childhood nephrosis

Sinovenous thrombosis is an uncommon but serious complication associated with nephrotic syndrome in children. We describe a 9-year-old Caucasian boy who presented with dehydration, vague neurological symptoms and seizures. A diagnosis of nephrotic syndrome was made during the course of hospitalization. The serum antithrombin III level was decreased and brain imaging showed cerebral sinovenous thrombosis. Anticoagulant therapy with heparin was commenced and the patient made a slow but gradual clinical, as well as radiological recovery. We describe this case and review available literature to highlight the importance of suspecting and recognizing this potentially life threatening complication and initiating early treatment.

Co-administration of cyclosporine and ketoconazole in idiopathic childhood nephrosis.

The concomitant use of cyclosporine (CsA) and ketoconazole (keto) in children with nephrotic syndrome (NS) has never been reported in the literature. This retrospective cohort study was conducted to investigate cost saving, safety, and efficacy of co-administration of keto and CsA in children with NS. The study included 186 nephrotic children receiving CsA therapy. Most were steroid dependent or resistant, and the most common pathology was focal segmental glomerulosclerosis (62%). Among our patients, 137 received daily keto therapy (keto group) 50 mg/day in addition to CsA, while 49 received CsA alone (non-keto group). The characteristics of both groups were comparable and the mean (+/-SD) duration of treatment was 22.9 +/- 8.1 months. Co-administration of keto significantly reduced the mean dose of CsA with an overall net cost saving of 37%. It also resulted in a significant improvement of CsA response, more successful steroid withdrawal, and decreased the frequency of renal impairment. Keto was generally well tolerated and safe. We conclude that co-administration of low-dose keto with CsA in children with idiopathic NS is safe, significantly reduces the cost of CsA therapy, and may improve the patient outcome.

Immunological, Biochemical and Clinical Aspects of Childhood Nephrosis before and after Different Immunomodulating therapies

Immunological, Biochemical and Clinical Aspects of Childhood Nephrosis before and after Different Immunomodulating therapies

Changing patterns in the histopathology of idiopathic nephrotic syndrome in children

It is widely accepted that minimal change nephrotic syndrome (MCNS) is the most common cause of nephrosis in children. Recent studies have demonstrated an increasing incidence of focal segmental glomerulosclerosis (FSGS) in adults. To determine possible changes in the etiology of childhood nephrosis, the clinical charts of 152 pediatric patients diagnosed with idiopathic nephrotic syndrome between 1978 and 1997 were reviewed. Histopathological diagnosis was available in 105 patients. MCNS was present in 35% of all biopsies, whereas FSGS was observed in 31%. Even if we assume that all patients without a histological diagnosis had MCNS (presumptive MCNS), the total incidence of MCNS (biopsy proven + presumptive) in our population was only 55%. We observed a dramatic increase in the incidence of FSGS during recent years. Before 1990, FSGS was diagnosed in 23% of all renal biopsies but increased to 47% afterward (P = 0.02). This pattern was observed in all ethnic groups. In African Americans, there was a trend for an increase in the incidence of FSGS from 38% before 1990 to 69% after 1990. A similar trend was observed in Caucasians (from 20 to 45%) and Hispanics (from 8 to 33%) Hispanics had the highest incidence of MCNS (biopsy proven + presumptive: 73%), followed by Caucasians (53%) and African Americans (37%). The mean age for presentation of nephrotic syndrome in African Americans (8.0 +/- 0.9 years) was higher than in Caucasians (4.1 +/- 0.05) and Hispanics (3.3 +/- 0.5). Our study showed that the incidence of FSGS in children with idiopathic nephrotic syndrome has increased recently. Furthermore, in African American children. FSGS is the most common cause of nephrotic syndrome. These findings may have significant implications in the management of childhood nephrotic syndrome.

Non-ketotic hyperosmolar coma complicating steroid treatment in childhood nephrosis

Two nephrotic children treated with prednisone developed steroid-induced diabetes and non-ketotic hyperosmolar coma (NKHC). Both patients presented with convulsions, coma and shock. The glucose concentration of the cerebrospinal fluid was 425 mg/dl and 622 mg/dl, respectively. Both patients had no diabetic family history, but had been treated with prednisone for 4 and 8 months, receiving total doses of 6.6 and 10.8 g, respectively. Despite conventional therapy, both patients deteriorated rapidly and died several hours later. Steroid-induced diabetes associated with NKHC is a rare but serious complication of steroid therapy.

Platelet Aggregometry - Dose-related Responses to Arachidonic Acid in Childhood Nephrotic Syndrome

A recent unexpected finding of inhibited platelet aggregation in response to a single (1.64 mmol/l) dose of arachidonic acid (AA), during the relapse of childhood nephrosis, prompted us to assess aggregation in response to multiple doses of AA: 1.64,0.82,0.41,0.20 mmol/l, in two groups of children, in the relapse (n = 34) or remission (n=41) phase of nephrotic syndrome. During relapse: the highest dose of AA (1.64 mmol/l) evoked reversible and inhibited aggregation in 91% of patients. However, at the lower doses there were enhanced responses as measured by both maximum aggregation (%) and slopes of the aggregation curves. In contrast, during remission, irreversible aggregation was obtained at the highest AA dose, while at the lowest two doses (0.41 and 0.20 mmol/l), no aggregation responses were obtained in 4 (9%) and 7 (17%) patients respectively; in those who responded there was a long lag phase. Healthy controls (n = 21) exhibited their highest responses to 1.64 and 0.82 mmol/l AA and at the lowest AA doses (0.41 and 0.20 mmol/l), a total absence of responses was noted in 40% and 71% of samples respectively. We conclude that during relapse platelet sensitivity, as shown by irreversible aggregation in response to multiple AA doses, shifts towards the lower doses, when compared with healthy controls; while during remission responses fall in-between the relapse and control groups, indicating the maintenance of platelet sensitivity during this phase of nephrosis.

Haemostatic measurements in childhood nephrotic syndrome

Blood coagulation and platelet aggregation were assessed in children with nephrotic syndrome who were divided into the following groups: (1) relapse without treatment: (2) relapse on steroids; (3) early remission; (4) late remission and (5) steroid resistant. The renal histological findings were also recorded. Plasma anti-thrombin III (ATIII) levels were markedly reduced in groups 1 and 2, below normal in group 3 and were normal in groups 4 and 5. There was significant urinary loss of ATIII in groups 1 and 2 as well as in group 5. Plasma fibrinogen fluctuations exhibited the expected negative correlations with plasma ATIII. Reptilase time showed significant prolongation in groups 1, 2 and 3, and was near normal in groups 4 and 5. Platelet aggregation in response to arachidonic acid exhibited aggregation followed by disaggregation in groups 1, 2, 4 and 5, and was normal in group 3. Hyperaggregation in response to decreasing doses of ADP was noted in all patient groups as well as controls with no relationship to serum albumin levels. Aggregation responses to collagen and ristocetin were normal. It is concluded that: 1. The fluctuations in ATIII levels in childhood nephrotic syndrome are determined by the response to steroids and not by the renal histology per se. 2. An acquired fibrin polymerization defect (dysfibrinogenaemia) and an abnormality of the prostaglandin pathway of platelet activation, both reversible, are yet other haemostatic abnormalities in childhood nephrosis. 3. The discrepancies in the literature on haemostatic parameters, specially ATIII in childhood nephrosis, would not have arisen if their fluctuation in relation to steroid therapy as well as the renal histological features of nephrotic syndrome had been documented simultaneously.

Childhood nephrotic syndrome in Northern Nigeria: management and follow-up of 40 patients.

While significant progress has been made in the search for suitable treatment of idiopathic minimum lesion nephrotic syndrome (IMLNS) which is by far the commonest form of childhood nephrosis encountered in temperate countries little progress has been made in the treatment of non-IMLNS groups of nephrosis which form the preponderance of cases in East and West Africa. A report of management a follow up of 40 children with nephrotic syndrome is presented here. The children received uniform conservative treatment consisting of salt restriction furosemide chloroquine proguanil and high protein diet in the absence of azotemia. No child was treated with corticosteroids. During the 1st admission 2 patients died and 4 had complete remission at discharge. 3 of those children in complete remission belonged to the membranoproliferative group and 1 belonged to the proliferative glomerulonephritis group. The latter remained in complete remission throughout the 12 months of follow-up. At 6 months 4 children were in complete remission but 2 of the 3 with membranoproliferative glomerulonephritis and previously in complete remission had relapsed. At 13 months 6 children were in complete remission while 4 had died. Lack of remission and relapses were common.

Serum 25 (OH) D and 24,25 (OH)2 levels in childhood nephrosis under different therapeutic regimens of steroid administration.

The effect of prednisone therapy on serum levels of 25-hydroxyvitamin D [25(OH)D] and 24,25-dihydroxyvitamin D [24,25(OH)2D] was investigated in 16 children with nephrotic syndrome. These serum levels were significantly lower in patients before prednisone therapy than in age- and season-matched normal subjects. Patients receiving daily prednisone therapy had lower serum levels than those receiving alternate-day prednisone therapy at the time when the total amounts of the steroid administered attained 1,500 or 2,000 mg/m2 of body surface area. Daily doses of 40 mg/m2 of prednisone for 3 days caused a significant decrease in serum 25(OH)D levels. Withdrawal of the steroid for 4 consecutive days was followed by a significant recovery of the serum levels. These results suggest that alternate-day prednisone therapy rather than daily treatment should be used in clinical practice to help maintain normal vitamin D metabolism.

Protein clearances and selectivity determinations in childhood nephrosis: a reappraisal.

To critically evaluate the clinical utility of determining specific proteins in patients with extensive proteinuria, we used immunonephelometric methods to measure albumin, transferrin, IgG, and alpha 2-macroglobulin in serum and in 24-h urine specimens from 37 children with idiopathic nephrotic syndrome. Renal biopsy demonstrated minimal change disease (I) in 15, focal glomerulosclerosis (II) in 15, and membranoproliferative glomerulonephritis (III) in seven patients. A three-group nonparametric rank test and three-group discriminant function analysis of the protein excretion and clearances of the four proteins we measured revealed significant differences in the excretion of IgG and the clearance of alpha 2-macroglobulin among the three groups of patients (p less than 0.05). Only patients with III had low serum complement C3 concentrations. Patients with I or II were best discriminated by differences in the excretion of transferrin and IgG, the clearance of alpha 2-macroglobulin, and the selectivity index (the clearance ratio of IgG/transferrin). These data indicate that measurement of specific urinary proteins and selectivity determinations may be helpful in predicting the type of histopathology and the prognosis of nephrotic children who have normal complement concentrations.

PREDNISOLONE PHARMACOKINETICS IN CHILDREN

Clinical observations suggest that some children with chronic diseases respond variably to corticosteroid treatment. 33 children have been studied for bio-availability and metabolism of orally administered prednisone. Physiological doses have been investigated in 5 children with congenital virilizing adrenal hyperplasia; pharmacological doses in 8 patients with dermatomyositis (DMS), 7 with systemic lupus erythematosus (SLE), 9 with childhood nephrosis (N), 2 with regional enteritis, 1 asthmatic and 1 renal transplant patient. Plasma prednisolone values have been determined by a specific radioimnunoassay developed in our lab. Bio-availability was calculated from peak plasma prednisolone levels attained; plasma½ -life values from % disappearance from peak values over hourly time intervals. Results indicate: (1) a regression line may be calculated for dose vs peak levels but there is wide variation among patients in bio-availability; (2) ½-life in children differs from adults (mean 125 minutes vs adult 205 minutes); (3) some children with N and DMS have impaired bio-availability but normal ½-life values; (4) a few children with severe disease (SLE, DMS) have markedly prolonged ½-life values. These studies support observations of clinical variability of drug effects when prednisone is utilized in pharmacolgical doses. Knowledge of bio-availability and metabolism may allow more precise and rational therapeutic programs.

MESANGIAL PROLIFERATE GLOMERULONE PHRITIS PRESENTING AS NEPHROTIC SYNDROMS IN CHILDHOOD

Despite two controlled investigations of childhood nephrosis totalling 373 patients, there remains a paucity of detailed clinical and pathologic information of mesangial proliferative glomerulonephritis with the nephrotic syndrome in childhood. We had the opportunity to study 8 patients with the nephrotic syndrome, the mean age of onset was 7.2 years with a range of 3.5 to 12.2 years; there were 5 males and 3 females. All patients had renal biopsies which were studied by light, electron and immuno-fluorescent microscopy. The pathologic findings with hematoxylin-eosin showed predominant mesangial proliferation in all patients. Immunofluorescences revealed positive mesangial fluorescence to immunoglobulin (Ig) M in 8 patients, 6 of 8 had C3 complement and fibrin/fibrinogen, 4 of 8 had IgG. Electron microscopy showed electron dense deposits in the mesangium. Seven of the 8 patients were steroid sensitive and frequent relapsing nephrotics. One is steroid resistant for 1.5 years but renal function remained normal. It has been assumed that children with steroid sensitive nephrotic syndrome with the onset before 5 years of age have idlopathic nephrotic syndrom: (I.N.S.), 2 of the present patients ware leas than 5 years at onset; therefore, this may no longer be an accurate assunption. Therefore previous studies of steroid sensitive nephrotic syndrome with onset less than 5 years without renal biopsies may not fulfill the pathologic criteria of I.N.S.

The significance of focal glomerular sclerosis in children who have nephrotic syndrome.

This study was undertaken to learn the significance of focal glomerular sclerosis in children who have nephrotic syndrome. Tissue obtained by percutaneous renal biopsy 10-15 years previously was re-examined. Initially, two of the 29 biopsy specimens contained focal segmental hyalinosis or sclerosis and five of the 29 had focal glomerular obsolescence. The paraffin blocks were serially sectioned and examined. Following this procedure, seven of the 29 biopsies had focal segmented hyalinosis and 16 of the 29 had focal glomerular obsolescence. The percentages of focal segmental hyalinosis and focal glomerular obsolescence were recorded. Only those patients whose focal segmental hyalinosis exceeded 2% progressed to renal failure. Age-matched autopsy material from patients dying without renal dysfunction was used as a control. Focal glomerular sclerosis was seen in 75.8% of the control specimens, although few glomeruli within each specimen were involved. Focal glomerular sclerosis may be found normally; it may be found in nephrotic children who do not develop renal failure. The quantification of sclerotic lesions may be of prognostic significance in childhood nephrosis.

Clinical and pathologic correlates in recurrently active childhood nephrosis.

On the basis of their response to corticosteroid therapy, 22 nephrotic children who have demonstrated continuous or recurrent disease activity for five or more years, and one other child who died in recent years of uremia after a protracted course, are divided into three clinical groups defined as follows: (1) corticosteroid sensitive, (2) corticosteroid dependent, (3) corticosteroid resistant. On light microscopy study, minimal or no pathological change was noted in all ten patients of group 1. Of six children in group 2, three had minimal disease or no pathologic findings; the others varied from mild to moderate and the disease was usually sclerotic in type. Significant pathologic conditions were noted in five of six patients in group 3, ranging from proliferation to glomerulosclerosis. Progression from minimal change to membranoproliferative disease to sclerotic disease was noted in one patient. Clinical response to corticosteroid therapy is a reliable indicator of current pathologic status.

Observations on infection of the urinary tract and childhood nephrosis.

"We would suspect a bacterial pyelonephritis in any nephrotic child who required an unusually large dose of steroids for improvement."

Do infective bacteria contribute to steroid resistance in childhood nephrosis?

Do infective bacteria contribute to steroid resistance in childhood nephrosis?

Effect of live measles virus vaccine on childhood nephrosis

Summary Evidence is presented which indicates that children with nephrosis may have transient improvement of renal status following inoculation with live measles virus vaccine. The difficulty of interpreting these results is briefly discussed.

A new look at steroid-resistant childhood nephrosis. The role of infection.

A new look at steroid-resistant childhood nephrosis. The role of infection.