Relapse Of Proteinuria Research Articles

Expression of multidrug resistance P-glycoprotein on lymphocytes from nephrotic children treated with cyclosporine A and ACE-inhibitor

The aim of this work was to determine the expression of P-glycoprotein (P-gp) on peripheral lymphocytes (CD3) in children with steroid-dependent nephrotic syndrome (SDNS) during cyclosporine A (CyA) and ACE-inhibitor (ACE-I) treatment. The study group (I) consisted of 20 children with SDNS aged 5-18 years, with a subsequent proteinuria relapse at the time of prednisone dose reduction. All nephrotic syndrome (NS) children were examined three times: A--at proteinuria relapse, before CyA treatment; B--after 3 months; C--after 12 months of CyA administration. The control group (II) consisted of 20 healthy children. CD3/P-gp was measured using a flow cytometry assay. The serum CyA level was assessed by means of the immunofluorescence method. The expression of CD3/P-gp in NS relapse, prior to CyA+ACE-I administration, was much higher (median 9.15%, range 1.50-13.50%) when compared to healthy controls (median 1.20%, range 0.30-5.70%). The absolute number of CD3/P-gp in this examination was almost five times higher when compared to healthy controls (p<0.01). After 3 months of CyA+ACE-I therapy, the expression of CD3/P-gp decreased dramatically and was similar to the controls. Similar results were obtained after 12 months of treatment. A strong negative correlation was found between CD3/P-gp and serum CyA concentration in both examinations (r=-0.624, p<0.01; r=-0.464, p<0.01). We conclude that the results of our studies indicate that CyA+ACE-I in SDNS inhibits the expression of P-gp. CyA is an alternative therapy that may lead to the optimization of glucocorticoid (GC) doses, thus, reducing the risk that is associated with the treatment.

Vascular endothelial growth factor in children with nephrotic syndrome treated with cyclosporine A

To assess the effect of cyclosporine A (CyA) on the level of vascular endothelial growth factor (VEGF) in the plasma and urine of nephrotic syndrome children. The study material consisted of 15 children (F 6, M 9; group I) who were subjected to the following examinations: A) at the time of proteinuria relapse, before treatment with CyA, B) after 3 mo, C) after 6 mo, and D) after 12 mo of CyA administration with prednisone and convertase inhibitor. The control group (II) contained 20 healthy children. The immunoenzymatic ELISA method (R&D Quantikine) was used to determine plasma and urinary VEGF levels, while the immunofluorescence method was applied to assess CyA concentration in the plasma. The statistical program Statistica 6.0 was used for statistical analysis of the results. In the present study, plasma VEGF level in examination A was higher than in the control group (p<0.01). After proteinuria regression (B), it did not differ from the level observed in healthy children (p>0.05). After 6 and 12 mo of CyA administration, VEGF concentration increased and was higher than in the control group (p<0.05). In all the examinations, urinary excretion of VEGF was higher than in the control group, increasing proportionally with the duration of treatment and plasma CyA level. A positive correlation was observed between plasma and urinary VEGF levels and between VEGF and CyA concentrations in the plasma. Long-term CyA treatment of nephrotic syndrome children leads to an increase in plasma and urinary VEGF.

Vascular endothelial growth factor in children with nephrotic syndrome treated with cyclosporine A

Abstract Aim: To assess the effect of cyclosporine A (CyA) on the level of vascular endothelial growth factor (VEGF) in the plasma and urine of nephrotic syndrome children. Methods: The study material consisted of 15 children (F 6, M 9; group I) who were subjected to the following examinations: A) at the time of proteinuria relapse, before treatment with CyA, B) after 3 mo, C) after 6 mo, and D) after 12 mo of CyA administration with prednisone and convertase inhibitor. The control group (II) contained 20 healthy children. The immunoenzymatic ELISA method (R&amp;D Quantikine) was used to determine plasma and urinary VEGF levels, while the immunofluorescence method was applied to assess CyA concentration in the plasma. The statistical program Statistica 6.0 was used for statistical analysis of the results. Results: In the present study, plasma VEGF level in examination A was higher than in the control group (p&lt;0.01). After proteinuria regression (B), it did not differ from the level observed in healthy children (p&gt;0.05). After 6 and 12 mo of CyA administration, VEGF concentration increased and was higher than in the control group (p&lt;0.05). In all the examinations, urinary excretion of VEGF was higher than in the control group, increasing proportionally with the duration of treatment and plasma CyA level. A positive correlation was observed between plasma and urinary VEGF levels and between VEGF and CyA concentrations in the plasma. Conclusion: Long‐term CyA treatment of nephrotic syndrome children leads to an increase in plasma and urinary VEGF.

T-cell transcriptome analysis points up a thymic disorder in idiopathic nephrotic syndrome

Idiopathic nephrotic syndrome is a proteinuric disease secondary to the release of a nonidentified circulating glomerular permeability factor by T cells. Because specificities of T-cell activation in idiopathic nephrotic syndrome remain unknown, we evaluated transcriptional activation of T cells in nephrotic patients during proteinuria. Transcriptomes of CD2+ cells were analyzed by serial analysis of gene expression (SAGE) in a nephrotic child during proteinuria relapse and after remission, away from any immunosuppressive treatment. Expression of specific transcripts overexpressed during proteinuria relapse was compared by reverse transcription-polymerase chain reaction (RT-PCR) in CD2+ cells from 11 nephrotic patients during relapse and remission and 11 non nephrotic patients during infection and after recovery. Differential analysis of CD2+ cell transcriptome identified >200 mRNA tags overexpressed during proteinuria relapse, including many T-cell markers. RT-PCR analysis of expression of specific transcripts indicated that (1) under remission conditions, nephrotic children displayed induction of four transcripts, including IKBKB, and repression of NFKBIA as compared to non nephrotic children after recovery, and (2) proteinuria relapse was associated with induction of L-selectin and T-lymphocyte maturation-associated protein, two markers of T-cell differentiation and recent emigrant/naive T cells. Results indicate that circulating T cells from relapsing nephrotic patients include a significant population of low-mature cells while those from nephrotic patients in remission are characterized by constitutive activation of nuclear factor-kappaB (NF-kappaB), altogether suggesting a thymic dysregulation of apoptosis in nephrotic patients.

Transforming growth factor-?1 in nephrotic syndrome treated with cyclosporine and ACE inhibitors

The aim of the study was to assess urinary transforming growth factor (TGF)-beta1 in children with steroid-dependent nephrotic syndrome (SDNS) treated with cyclosporine A (CyA) and ACE inhibitors (ACEI). The study involved 24 children (14 boys and 10 girls) with SDNS and signs of focal segmental glomerulosclerosis. The children were treated with prednisone, CyA, and ACEI. All children were examined four times: A during relapse of proteinuria, before treatment with CyA and ACEI, and B after 3 months, C 6 months, and D 12 months of treatment. The control group consisted of 20 healthy children of the same age. The urinary TGF-beta1 level was determined by ELISA (R and D Quantikine). The serum CyA level was measured by monoclonal antibody fluorescence polarization immunoassay. Prior to CyA treatment, the urinary TGF-beta1 level was the highest (135.61+/-38.31 pg/mg creatinine). During CyA treatment, TGF-beta1 was reduced to 117.96+/-81.57 after 3 months, to 80.26+/-49.52 after 6 months, and to 44.00+/-31.83 pg/mg creatinine after 12 months, but it was still higher than in the control group. At 3 months there was a positive linear correlation between urinary TGF-beta1 and proteinuria (r=0.654, P<0.01). These results indicate that the urinary TGF-beta1 level increases in proportion to proteinuria during relapse of NS. Treatment with CyA and ACEI also influences urinary TGF-beta1, which is still higher after 12 months of treatment than in healthy children.

Glomerular hypertrophy in relapsing minimal change nephropathy.

Clincopathological and morphometric analysis of glomerular hypertrophy was conducted using biopsies from 89 patients with minimal change nephrotic syndrome (MCNS). Of the 80 patients, in 69 with complete remission and in 20 with one or more relapses, various clinical and morphometric parameters were compared to 15 normal controls. Proteinuria was more severe and serum creatinine (Cr) concentration significantly higher in patients with relapse of proteinuria. The morphometric analysis showed that the sizes of (1) glomerular tufts and (2) glomerular capillaries were significantly larger in patients in the relapse group than in the remission or control groups, but no difference in the size of Bowman's capsule was found between the two MCNS subgroups. The intertubular capillaries were narrower in patients who failed to reach prompt complete remission. A negative correlation between intra- and extraglomerular capillary size was evident (r = -0.83, p < 0.001). A definitive correlation was detected between the circumference of glomerular capillary loops and the degree of proteinuria (r = 0.89, p < 0.001). The mean tubulocapillary diffusion distance was significantly longer in biopsies of the patients in relapse and showed a close significant correlation with serum Cr level (r = -0.87, p < 0.001) and intertubular capillary size (r = -0.87, p < 0.001). These data suggest that extra- and intraglomerular hemodynamic alterations in MCNS lead to glomerular hypertrophy, and dilatation of the glomerular capillary loop plays a key role in the relapse of MCNS.

Relationship between interstitial infiltrates and steroid responsiveness of proteinuria in membranous nephropathy

Mononuclear inflammatory cells were retrospectively analysed using monoclonal antibodies in the interstitium and glomeruli of 16 renal biopsy specimens from patients with nephrotic syndrome due to idiopathic membranous nephropathy (IMN). The aim of the study was to determine the composition of the infiltrate and to assess the ability to predict the response of proteinuria to corticosteroids. All patients had received prednisolone as a sole treatment. Nine patients had shown a complete or partial remission of proteinuria (group A) and seven did not respond at all (group B). Both groups were matched for age and degree of proteinuria; also both groups had normal renal function at the time of biopsy. Very few intraglomerular leukocytes, mostly monocytes/macrophages (MM) were found. The majority of interstitial T cell population and B cells were a minor component. No significant differences were found between the two groups regarding the types of the intraglomerular cells. However, interstitial T-cells, CD4+ve T helper/inducer cells, CD8+ve T cytotoxic/suppressor cells and MM were significantly higher in group A than in group B. Also HLA-DR expressing interstitial cells were much in excess in group A. In addition patients with complete remission of proteinuria had higher numbers of interstitial cells compared to those with partial response. There was no correlation between the numbers of types of intraglomerular and interstitial cells and the degree of proteinuria at presentation. Also no association was found between intraglomerular or interstitial cell population and subsequent relapse of proteinuria. In conclusion, interstitial but not intraglomerular mononuclear cells seem to determine the initial response of proteinuria to corticosteroids in patients with IMN.

Cyclosporine in idiopathic nephrotic syndrome.

Idiopathic nephrotic syndrome encompasses two main forms of glomerular diseases, minimal change nephropathy and focal segmental glomerulosclerosis. Minimal change nephropathy is a disease of children which generally responds to corticosteroids. After remission, however, many patients show frequent relapses or steroid dependency. In these patients, cyclosporine may obtain remission of proteinuria in 80% of cases, although relapse usually occurs when the drug is stopped. Focal glomerulosclerosis is generally resistant to corticosteroids. Under cyclosporine some 40% of patients may attain complete or partial remission of the nephrotic syndrome particularly if low-dose prednisone is associated. Relapse of proteinuria usually occurs after stopping the drug. As cyclosporine may expose to chronic nephrotoxicity some guidelines should be followed to prevent this complication: - the doses should not exceed 5 mg/Kg/day - they should be adjusted whenever an increase in plasma creatinine of > or = 30% over the baseline values occurs - treatment should be stopped if there is no response within 3 months - a careful monitoring of patient under the supervision of a clinician trained with the use of cyclosporine is necessary. The term idiopathic nephrotic syndrome (INS) defines the association of a nephrotic syndrome with non specific glomerular lesions, in the absence of immune complex deposition (1). On the basis of renal histology two main types of INS are recognized: minimal change nephropathy (MCN) and focal and segmental glomerular sclerosis (FSGS).

Cyclosporin A in the treatment of childhood glomerulonephritis.

Seven children with steroid resistant nephrotic syndrome (focal segmental sclerosis in six, mesangial proliferation in one) were treated with Cyclosporin A for 12 weeks. Five of these children were also resistant to cyclophosphamide. All patients had normal renal function. Cyclosporin was started at 8 mg/kg/day then increased until a trough blood level of 100-300 ng/ml (HPLC) was achieved. Three of the seven patients achieved complete remission, and the other four had a significant reduction in their proteinuria (p less than 0.05). In the three patients who achieved complete remission, relapse of proteinuria occurred within six weeks of ceasing Cyclosporin. All patients experienced some impairment in renal function with mean creatinine clearance decreasing from 129 +/- 19 to 91 +/- 13 ml/min/1.73m2 (p less than 0.05). One child was subsequently treated with Cyclosporin for 12 months. He remains in remission with a repeat renal biopsy showing no evidence of nephrotoxicity. One other child with steroid sensitive minimal change nephrotic syndrome who had severe steroid toxicity was treated with a lower dose (5 mg/kg/day) for 12 months. She remained in remission off steroids, but relapsed 16 weeks after Cyclosporin was ceased. A renal biopsy after 12 months showed no nephrotoxicity. Cyclosporin should be considered in steroid resistant nephrotic syndrome, and in children with minimal change disease who show signs of steroid toxicity and short remission period after cyclophosphamide. Serial renal biopsies are recommended with prolonged therapy.

Long-term Outcome of Patients with Membranous Nephropathy After Complete Remission of Proteinuria

To assess the prognostic significance of complete remission in patients with idiopathic membranous nephropathy, 33 patients were followed for a median of 96 months after remission of proteinuria. All patients had had a histological diagnosis of membranous nephropathy and a nephrotic syndrome. Only patients with a complete remission lasting for at least six months and with a follow-up of at least four years after remission were considered. No relapse of proteinuria developed in 17 patients (51%), 7 patients had relapse of non-nephrotic proteinuria (21%) and 9 (27%) relapse of nephrotic proteinuria. However proteinuria disappeared again in some patients so that at follow-up 73% of patients are in complete remission, 21% have non-nephrotic proteinuria and only 6% have nephrotic syndrome. All patients maintained a normal plasma creatinine over the years. It is concluded that complete remission of proteinuria is a strong predictor of long-term favourable outcome in patients with idiopathic membranous nephropathy.