Steroid-responsive Nephrotic Syndrome Research Articles

A highly cationic protein in plasma and urine of children with steroid-responsive nephrotic syndrome

We postulated that the reduction of surface negative charge on the glomerular capillary wall, which is believed to underlie the proteinuria of steroid-responsive nephrotic syndrome (SRNS), might be due to the presence of a cationic substance which binds to and neutralizes the negative charge on cells and membranes. Using a method to detect charge neutralizing substances based on inhibition of binding of the cationic dye Alcian blue 8GX to heparin, plasma and urine from children with SRNS were found to contain a protease-sensitive charge-neutralizing factor, which was not present in plasma or urine of healthy individuals. This factor has been partially purified from SRNS plasma and urine by ion exchange chromatography on QAE Sephadex, gel filtration on Sephadex G150, and FPLC on Mono-S. This cationic protein, which binds to and neutralizes the charge on heparin, may also neutralize the negative charge on the glomerular capillary wall and may thus be involved in the pathogenesis of SRNS.

Linear Growth of Children With Nephrotic Syndrome: Effect of Alkylating Agents

Growth velocity measurements were assessed in 12 children with steroid responsive but frequent relapsing or dependent nephrotic syndrome prior to and following treatment with either cyclophosphamide or chlorambucil and alternate day prednisone. Patients averaged 6 +/- 3 years (mean +/- SD) of age at the time of treatment. All of the patients underwent renal biopsy prior to treatment; 5 of the 12 showed mesangial proliferation; and in 10 of the 12, IgM deposits were seen within the mesangium of the glomerulus. Growth rates before treatment with the alkylating agent were 4.3 +/- 1.3 cm/y increasing to 8.7 +/- 2.5 cm/y (P less than .001) after therapy despite the relapses that occurred in 5 of the patients in the year following treatment. Short-term side effects of the treatment were minimal. The significant increase in growth associated with diminished use of steroids makes the use of alkylating agents reasonable for children with nephrosis who show signs of decreased growth velocity.

Major histocompatibility complex antigens in steroid-responsive nephrotic syndrome.

An increased frequency of specific major histocompatibility complex (MHC) class I, II and III antigens in children with steroid-responsive nephrotic syndrome (SRNS) has been reported. This frequency distortion, in some cases, is thought to affect the outcome of the disorder. We studied the phenotypic frequency of HLA antigens -A, -B, and -DR, as well as complement proteins Bf and C4 in an unrelated population of 25 SRNS children. Complete MHC haplotypes were also derived for four families in which 8 individuals developed SRNS. HLA-DR8, with a relative risk of 4.8, showed the strongest association with SRNS. Nonetheless, the 95% confidence intervals of this and the relative risks for all other antigens fell below 1.0. No common haplotype was found in SRNS patients in whom complete family studies were available, and disease and inheritance of the MHC were discordant in two of these families. In this study of well-characterized SRNS patients we were unable to discover a clear association between this disorder and the MHC.

Endogenous albumin as a marker of renal selectivity in steroid-unresponsive nephrotic syndrome.

Albumin electrical charge, conformation and hydrophobicity taken as indexes of renal selectivity were evaluated in 8 children affected by steroid-unresponsive nephrotic syndrome associated with glomerulosclerosis or mesangial hypercellularity. These characteristics related to urinary albumin have already been reported to vary markedly in steroid-responsive nephrotic syndrome of minimal-change nephropathy giving rise to new pathogenetic possibilities in this disease. In the steroid-unresponsive nephrotic children albumin was found to be more microheterogenous and cationic in urine than in serum and at the same time it was conformationally altered. Regarding these characteristics, the selectivity properties of the renal filter are similar in steroid-unresponsive nephrotic syndrome, suggesting a pathogenetic connection between these two renal disorders.

Acute Renal Failure in Minimal Change Nephrotic Syndrome

The appearance of unexplained acute renal failure during the course of idiopathic nephrotic syndrome is an uncommon but well-reported phenomenon in adults.1 Its occurrence in childhood has not been reported. We present an 8-year-old girl with minimal change nephrotic syndrome in whom inexplicable acute renal failure developed following exploratory laparotomy. CASE REPORT This 8-year-old girl had a 6-year history of frequently relapsing, steroid-responsive nephrotic syndrome clinically consistent with minimal change disease. While visiting the Buffalo area with her family, she suddenly had severe constant abdominal pain associated with nausea and emesis and was brought to the emergency room for evaluation. She was receiving alternate-day prednisone in an attempt to reduce the number of her relapses.

SHORT VERSUS STANDARD PREDNISONE THERAPY FOR INITIAL TREATMENT OF IDIOPATHIC NEPHROTIC SYNDROME IN CHILDREN

Two regimens of steroid treatment for the initial attack of idiopathic nephrotic syndrome in children were compared in a controlled multicentre study. Short-course prednisone therapy consisted of 60 mg/m 2 per 24 h until proteinuria had disappeared for 3 days, followed by 40 mg/m 2 per 48 h until complete remission had occurred. The standard prednisone therapy was 60 mg/m 2 per 24 h for 4 weeks, followed by 40 mg/m 2 per 48 h for 4 weeks. 61 children with a first attack of idiopathic nephrotic syndrome were allocated at random to these groups. Urinary remission in the short-course group was achieved after 14 days of daily prednisone, and complete remission after an additional 16 days of alternate day prednisone. The cumulative rate of patients with sustained remissions after two years was significantly lower after the short course than after standard treatment (19% versus 41%, p=0·001). The mean duration of remission in patients with a relapse was half as long after the short course (79 versus 169 days, p = 0·004). Complete initial remission of steroid responsive nephrotic syndrome can be obtained with half the standard prednisone dose, but the short course is followed by a higher rate of relapses, that require repeated prednisone administrations. In the long term, the standard regimen is preferable.

Cyclosporin in the Treatment of Steroid-responsive and Steroid-resistant Nephrotic Syndrome in Adults

The effect of cyclosporin on proteinuria was studied in 11 patients with steroid-responsive nephrotic syndrome (10 minimal change nephropathy, one IgM nephropathy) and in four patients with steroid-resistant nephrotic syndrome from focal segmental glomerulosclerosis. Cyclosporin (mean initial dose 7.7 mg/kg per day) produced a complete remission of proteinuria in 15 nephrotic episodes in the ten patients with minimal-change nephropathy after a mean 14.3 days (range 7-23 days) of therapy. All patients remained in remission while receiving cyclosporin (mean duration of follow-up 147 days; range 40-230 days). However, when cyclosporin was discontinued on nine occasions in five patients, all relapsed after a mean 47.8 days (range 7-180 days). Four of the five patients were subsequently rechallenged with cyclosporin and all responded. Maintenance cyclosporin therapy to prevent relapse was not associated with any adverse effects, and there was no significant difference between the creatinine clearance before and after 30 days of therapy (86.9 +/- 19.3 and 81.7 +/- 23.5 ml/min respectively, P greater than 0.1). The patient with steroid-responsive IgM nephrotic syndrome did not respond to cyclosporin, and there was no significant effect of cyclosporin on proteinuria in the four patients with FSGS. Cyclosporin is an effective agent for the treatment of patients with frequently relapsing minimal-change nephropathy who became steroid dependent when cyclophosphamide is contraindicated. However, unlike cyclophosphamide, long-term remissions which persist after treatment is withdrawn are not obtained, and patients may be said to be cyclosporin dependent.

Lymphocyte subpopulations in children with steroid responsive nephrotic syndrome

Lymphocyte subpopulations in children with steroid responsive nephrotic syndrome

Steroid-responsive nephrotic syndrome with glomerular IgA deposits: clinicopathological evaluation.

Steroid-responsive nephrotic syndrome with glomerular IgA deposits: clinicopathological evaluation.

Intermittent versus long-term tapering prednisolone for initial therapy in children with idiopathic nephrotic syndrome

Forty-six children with steroid-responsive nephrotic syndrome were randomly allocated to receive two different prednisolone regimens for initial therapy. Twenty-nine children (group 1) received an intermittent regimen (60 mg/m2/day for 4 weeks, followed by 40/mg/m2/day on 3 days a week for 4 weeks); 17 children (group 2) had a long-term regimen (60 mg/m2/day for 4 weeks, followed by the same dose on alternate days for 4 weeks and the doses tapered by 10 mg/m2, given on alternate days every 4 weeks for 5 months). There was no difference between the two groups in the regimen used to treat relapses, steroid responsiveness, number of patients with relapses, and frequency of toxic reactions to steroids. However, the number of patients with a relapse within 6 months after initial therapy and the number of those with frequent relapses or steroid dependence were significantly higher in group 1 than in group 2 (P less than 0.05 for both). The data indicate that the long-term tapering regimen appears to be both safe and preferable to the intermittent regimen for initial therapy in children with idiopathic nephrotic syndrome.

Inhibition of lipoprotein lipase by plasma from children with the steroid responsive nephrotic syndrome.

The study was designed to investigate the hyperlipidaemia associated with the steroid responsive nephrotic syndrome in children and in particular to examine the mechanism for the delayed clearance of the circulating triglyceride-rich lipoproteins. The possibility that plasma from patients with steroid responsive nephrotic syndrome may contain an inhibitor of lipoprotein lipase activity was studied by examining the effect of the addition of plasma from patients, on normal postheparin lipoprotein lipase activity. Plasma from children with steroid responsive nephrotic syndrome significantly inhibited lipoprotein lipase activity (p less than 0.001), whereas that from patients with familial hypercholesterolaemia and normal children had no significant effect. The inhibition of lipoprotein lipase activity by plasma from patients with steroid responsive nephrotic syndrome correlated significantly with their increased plasma cholesterol and reduced plasma albumin concentrations (p less than 0.001 and less than 0.02, respectively), but there was no significant correlation with plasma triglyceride concentrations. Thus, the degree of inhibition probably reflected the severity of the condition at the time of study. Neither the cholesterol, albumin nor triglyceride concentrations appeared to directly influence the lipoprotein lipase activity of postheparin plasma.

Decreased sensitivity to heparin in vitro in steroid–responsive nephrotic syndrome

The in vitro heparin sensitivity of 18 nephrotic children was compared with that of 10 normal children and 13 children with other renal diseases. The influence of age on the heparin sensitivity of 52 normal subjects (aged 12 to 85 years) was also studied. The heparin sensitivity was calculated from the dose-response curve obtained when increasing amounts of heparin were added to plasma and the kaolin partial thromboplastin time (KPTT) was measured. There was a significantly-reduced heparin sensitivity in nephrotic children compared to the control children and a progressive decline in heparin sensitivity with age. In the nephrotic syndrome heparin-sensitivity correlated with albumin and triglyceride concentrations but not with antithrombin III, platelet factor 4, cholesterol, fibrinogen, heparin cofactor II or histidine-rich glycoprotein. Addition of exogenous albumin did not restore the heparin sensitivity of nephrotic plasma. Four patients with Type II hyperlipidemia had a normal sensitivity to heparin. The decreased sensitivity to heparin thus does not appear to be a consequence of the nephrotic state, and may be a reflection of an underlying disturbance of charged macromolecules in steroid-responsive nephrotic syndrome.

Steroid-responsive nephrotic syndrome of childhood: a long-term study of clinical course, histopathology, efficacy of cyclophosphamide therapy, and effects on growth.

The long-term clinical course of 60 children with steroid-responsive nephrotic syndrome, observed for a minimum of 10 years from onset, was studied (mean 14.5 +/- 0.5 years). Four children had only a single episode, seven children experienced only one to three relapses early in their course, and the remaining 49 patients (82%) experienced frequently relapsing steroid-dependent disease. Nearly half of these (47%) continued to relapse into their late teens and early twenties. All 20 children treated with cyclophosphamide because of steroid-induced side effects developed complete remissions of the nephrotic syndrome. These were sustained in 70% for 9.1 +/- 0.6 years, with a reduction of disease severity in the remaining 30%. In contrast, only 48% of patients treated with prednisone alone were in remission at last follow-up (P = .06). Ten of the children treated with cyclophosphamide had the minimal change lesion prior to therapy; 90% of these had permanent remissions. Only 50% of the six children with focal glomerulosclerosis and four children with mesangial proliferation have had permanent remissions. None of the patients developed renal insufficiency. Children treated with prednisone alone were -0.93 +/- 0.3 SD below the mean for height at last follow-up. Cyclophosphamide treatment was associated with an increase in height SD scores from -0.84 +/- 0.4 to -0.28 +/- 0.3. Children with severe growth impairment demonstrated dramatic catch-up growth when treated with cyclophosphamide with SD scores increasing from -2.29 +/- 0.8 to -0.43 +/- 0.6 (P less than .05).(ABSTRACT TRUNCATED AT 250 WORDS)

Steroid-sensitive mechanism of soluble immune response suppressor production in steroid-responsive nephrotic syndrome.

Soluble immune response suppressor (SIRS), a lymphokine that suppresses antibody production and delayed type hypersensitivity in vivo, has been detected in urine and serum from certain patients with nephrotic syndrome. In the present paper, the relationship between SIRS production and nephrotic syndrome is further characterized. A striking correlation was found between detection of SIRS and the presence of steroid-responsive nephrotic syndrome (SRNS). A potential mechanism of SIRS production in SRNS patients was identified, in that lymphocytes from patients produced SIRS without requiring activation by exogenous agents, and incubation of normal lymphocytes with serum from patients activated the cells to secrete SIRS in culture. Although SIRS disappears rapidly from urine or serum after initiation of corticosteroid therapy, hydrocortisone (10(-6)-10(-7) M) did not block secretion of SIRS by activated suppressor cells. It did, however, inhibit in vitro activation of lymphocytes to produce SIRS by concanavalin A, interferon, or SRNS patient serum. The association of suppressor cell activation with SRNS and the sensitivity of both to steroids suggest that the pathogeneses of albuminuria and SIRS production are related.

Paucity of minimal-change lesion in children with early frequently relapsing steroid-responsive nephrotic syndrome.

It is widely believed that the most common morphological lesion in children with the idiopathic nephrotic syndrome who manifest a frequently relapsing steroid-responsive course is the minimal-change lesion. However, there are no prospective renal biopsy studies in such patients to substantiate this assertion. We performed a renal biopsy in all children with early frequently relapsing steroid-responsive nephrotic syndrome during the years 1980-1984. In 16 affected children, only 4 (25%) had minimal-change lesion, 7 had IgM nephropathy, 3 had diffuse mesangial hypercellularity, and 2 had focal segmental glomerulosclerosis. Fourteen of these patients have required immunosuppressive therapy with cyclophosphamide. Long-term follow-up revealed that 10 patients have remained protein free, 4 have persistent proteinuria despite cyclophosphamide therapy, 1 had progressed to end-stage renal disease, and 1 is lost to follow-up. On the basis of these findings, we recommend that all children with nephrotic syndrome and an early frequently relapsing steroid-responsive course undergo a prompt renal biopsy. Such patients constitute a high-risk group with a spectrum of renal histopathological lesions characterized by an unpredictable response to therapy and an unfavorable prognosis.

Thromboembolic Complications in Children with Nephrotic Syndrome

Coagulation studies were performed in 16 children with steroid responsive minimal change nephrotic syndrome in order to elucidate the incidence of thromboembolic complications. Fibrinogen and alpha 2-macroglobulin concentrations were inversely correlated with serum albumin concentrations, antithrombin III correlated positively (p less than 0.001). Factor VIII:R:AG concentration was elevated. Coagulation disturbances in children are not less severe than in adults with nephrotic syndrome. Combined scintigraphic pulmonary ventilation and perfusion studies were employed in 26 children to detect noninvasively events of pulmonary embolism, respectively their residual changes. The lung scintigraphic investigation demonstrated a pattern consistent with pulmonary embolism in 7 patients (27.9%), residual changes in 10 (38.5%) and normal findings in 9 (34.9%). The incidence of thromboembolic complications in children with severe nephrotic syndrome is as high as reported for adults. Pulmonary symptoms may well be due to pulmonary embolism.

Pharmacodynamic determinants of furosemide diuretic effect in children.

The pharmacodynamics of 1 or 2 mg/kg of furosemide administered as a single dose orally or intravenously were studied in 34 hospitalized children (ranging in age from 9 days to 16.5 years) with normal renal function. These patients were divided into 3 groups: infants (furosemide 1 mg/kg, intravenously); children with steroid-responsive nephrotic syndrome (furosemide 2 mg/kg, orally and intravenously); patients with urinary tract infections and mild hypertension (furosemide 2 mg/kg, orally). A statistically significant positive linear relationship was found in these groups between the furosemide urinary excretion rate and urine flow rate, but log dose-response curves to furosemide were found to vary between the groups of patients studied. This variability reflects differences in the relationship between the amounts of furosemide reaching active sites and the pharmacodynamic effect of the drug. No sigmoid-shaped log dose-response curve (i.e., one approaching a zero response at very low furosemide urinary excretion rates, and a maximum response at very high excretion rates) was attained in this study. This suggests that the capacity of the kidney tubules to respond diuretically to the administered doses of furosemide was not exceeded in the studied patients. However, in the infants, a very steep log dose-response curve to a 1 mg/kg intravenous dose of furosemide suggests that higher doses may not result in a significant increase in diuretic response in infants with reasonably normal renal function. The lowest mean furosemide urinary excretion rate associated with significant diuresis was 0.58 +/- 0.33 micrograms/kg/min. Also, a significant correlation was found between the amount (in milligrams), of furosemide excreted in the urine during the first 6 h after administration and the urine volume collected during that time (r = 0.71; p less than 0.001; number of measurements = 43).

HEIGHT ATTAINMENT IN CHILDREN WITH STEROID-RESPONSIVE NEPHROTIC SYNDROME

The heights of 80 patients with steroid-responsive nephrotic syndrome (SRNS) were measured 5-24 years after diagnosis. During childhood most patients had received repeated courses of high-dose corticosteroids and prolonged maintenance therapy. Although at the time of taking corticosteroids growth was suppressed, those who had completed growth had a mean height standard deviation score (SDS) of - 0·22, equivalent to a height on the 40th centile. Total corticosteroid dose prescribed was correlated only weakly with height SDS; there was no correlation between total dose and height when the post-pubertal patients were studied separately, indicating that their ultimate height attainment was not affected significantly.

STEROID-RESPONSIVE NEPHROTIC SYNDROME: A GENERALISED DISORDER OF MEMBRANE NEGATIVE CHARGE

A simple chemical test, based on the binding of the cationic dye alcian-blue 8GX (AB), has been devised to measure negative charge on cell membranes. The test has demonstrated that AB binding to red blood cells and platelets is significantly less in children with steroid-responsive nephrotic syndrome (SRNS) or nephrotic syndrome associated with focal segmental glomerulosclerosis than in normal controls. However, the sialic acid content of the nephrotic cell membrane is normal. This suggests that a generalised loss of membrane negative charge occurs in SRNS and that this is due to neutralisation rather than absence of anionic groups.

1575 IDIOPATHIC NEPHROTIC SYNDROME: LONG-TERM PROGNOSIS

The clinical course of idiopathic nephrotic syndrome (NS) was studied in 65 children (mean age 3.3 yrs, range 1-14 yrs) who were either steroid responsive (61 pts) or had steroid-resistant minimal change disease (4 pts) at onset. All pts were followed for a minimum of 10 yrs (range 10-25 yrs) and follow-up was 15 yrs in 29 pts (45%).Of the 61 steroid responsive pts, 53 had a frequently relapsing-steroid dependent course. Of these pts, 20 were treated with cytoxan which induced a permanent remission in 13 (mean duration 8.7 yrs, range 6-12 yrs) and significantly reduced the rate of relapses in 4 others. Of the 33 pts not given cytoxan, 35% continue to experience relapses 10-18 yrs after onset while the others have been in remission for the past 2-16 yrs (mean 7.6 yrs).Of the 4 pts with steroid resistant minimal change disease, 3 were treated with cytoxan and all achieved a remission. Two of these pts have had no relapses 10 and 12 yrs after onset and 1 pt had a single relapse.At the completion of follow-up (mean 14.4 yrs), all pts have normal renal function (Scr < 1.5 mg/dl), 17% have BP ≥ 140/80 and 76% have a height which is < 50%tile (adjusted for sex and age) while 33% are < 25%tile for height. These findings suggest that in children with steroid responsive NS or steroid resistant minimal change disease there is: a) a favorable long-term outcome; b) the duration of relapsing disease is reduced by treatment with cytoxan and c) short stature is a significant consequence of therapy.