Resistant Idiopathic Nephrotic Syndrome Research Articles

First clinical application of cord blood mesenchymal stromal cells in children with multi-drug resistant nephrotic syndrome

Background and objectivesChildren with multi-drug resistant idiopathic nephrotic syndrome (MDR-INS) usually progress to end-stage kidney disease with a consistent risk of disease recurrence after transplantation. New therapeutic options are needed for these patients. Mesenchymal stromal cells (MSCs) are multipotential non-hematopoietic cells with several immunomodulatory properties and growing clinical applications. Cord blood-derived MSC have peculiar anti-inflammatory and immunosuppressive properties. We aimed at assessing safety and efficacy of cord-blood-derived MSCs (CB-MSCs) in children with MDR-INS.Design, setting, participantsProspective, open-label, single arm phase I–II pilot study. Pediatric patients with MDR-INS, resistant to at least two lines of therapy, were enrolled. Allogenic CB-MSCs were administered intravenously on days 0, 14, and 21 at a dose of 1.5 × 106 cells/kg. Patients were followed for at least 12 months. The primary outcomes were safety and toxicity. The secondary outcome was remission at 12 months evaluated by urinary protein/urinary creatinine ratio (uPr/uCr). Circulating regulatory T cells (Tregs) were monitored.ResultsEleven pediatric patients with MDR-INS (10 females, median age 13 years) resistant to a median of 3 previous lines of therapy were enrolled. All patients completed the CB-MSC infusion schedule. No patient experienced any infusion-related adverse event or toxicity. Nine patients were assessable for efficacy. At the 12 months follow-up after the treatment, the median uPr/uCr did not change significantly from baseline (8.13 vs. 9.07; p = 0.98), while 3 patients were in partial or complete remission. A lower baseline uPr/uCr was a predictor of remission (2.55 vs. 8.74; p = 0.0238). Tregs count was not associated with CB-MSCs therapy.ConclusionsCB-MSCs are safe and may have a role in the immunosuppressive therapy of pediatric patients with MDR-INS. This preliminary experience paves the way toward further phase II studies addressing MSC efficacy in immune-mediated kidney diseases.

Predictive Value of Platelet Aggregation Responses and Coagulation Parameters for Thromboembolic Risk in Children with Idiopathic Nephrotic Syndrome.

Introduction: Idiopathicnephrotic syndrome (INS) is the most common renal disease among children. INS present with proteinuria, hyperlipidemia, edema, hypoalbuminemia, and hypercoagulability. A serious consequence of INS is arterial and/or venous thromboembolism e.g., deep vein thrombosis (DVT), pulmonary emboli and renal vein thrombosis. This hypercoagulability may be due to urinary loss of small proteins, specifically antithrombin (AT) III, protein C and S. INS children have been observed to develop thrombocytosis and platelet hyper aggregation leading to increased thromboembolic risk. Aim of the Study: To evaluate the coagulation profile and results of platelet functions during active nephrosis in children with steroid sensitive and steroid resistant INS. Methods: Thirty-six children with INS were studied.Twenty-four steroid sensitive and 12 steroid resistant patients were evaluated for platelet function and coagulation parameters during active nephrosis (either at presentation or relapse). The study also included 15 healthy age and sex matched children as control.Doppler imaging was done to confirm thromboembolic events. Results: Thrombo-embolic complications were observed in 14/36 patients, diagnosed both clinically and/or by doppler.Prolonged PTT was observed during active nephrosis, compared to control. Hypoalbuminemia and hyperlipidemia contributed to hypercoagulability. Mean platelet aggregation to ADP and Ristocetin were significantly elevated among both groups (108.3±10.8% and 104.8±13.2% respectively). Levels of ATIII were significantly reduced, further adds to thrombotic risk. Conclusion: Thromboembolic complications are not uncommon in nephrotic children. Platelet hyperaggregability positively correlated with VTE in INS children and can be a beneficial predictor of thrombosis during active nephrosis especially those past history of VTE.

Quality of life of children with idiopathic nephrotic syndrome according to clinical types

Idiopathic nephrotic syndrome (INS) is a major manifestation of chronic idiopathic glomerulonephritis and a common disease in children. The cause and pathogenesis of the disease have not been clarified so far. The treatment is usually a long-term process, from a few months to several years, even decades, including the period of hospitalisation, outpatient treatment period and follow-up period after treatment. The INS patients are negatively affected by the disease and its treatment process. The aim of this study is to assess the health-related quality of life (QOL) of children with INS according to clinical types in Haiphong Children's Hospital. Object: Describe some factors related to the QOL of children with INS. Subjects: 71 patients diagnosed with INS, who are being monitored and treated at Haiphong Children's Hospital from 10/2015 to 05/2016. Methods: Prospective studies, descriptive cross-sectional. QOL of the patients is assessed by the PedsQL 4.0 scale; the higher score shows that the lower QOL. Results: The general QOL score of children with INS (21.24±13.91) was higher than normal children (16.98±10.20). Children with steroid-resistant INS have a higher score (31.62±14.32) than children with steroid-dependent (20.57±9.08) and responsive INS (14.58±6.83). The QOL score of children with one of the symptoms Cushing's face, hirsutism or acne are significantly higher than children without the corresponding symptoms. Children who finished their treatment had a lower score (15.47±7.42) than children being treated (21.33±10.23). The average QOL score has a linear correlation with the duration of INS. Conclusion: The general QOL of children with INS substantially declined compared with that of healthy children. The QOL of children with steroid-dependent and resistant INS is lower than that of the children with steroid-responsive type. The QOL of children with one of the symptoms Cushing's face, hirsutism or acne is significantly lower than that of children without the corresponding symptoms. The QOL of children who completed treatment is higher than the group being treated. The longer the duration of treatment, the more the children's QOL declined.

Steroid-resistant idiopathic nephrotic syndrome in children: long-term follow-up and risk factors for end-stage renal disease

Steroid resistant idiopathic nephrotic syndrome (SRINS) in children is one of the leading causes of progression to chronic kidney disease stage V (CKD V)/end stage renal disease (ESRD). The aim of this retrospective study is to evaluate the efficacy of immunosuppressive drugs (IS) and to identify risk factors for progression to ESRD in this population. Clinical and biochemical variables at presentation, early or late steroid resistance, histological pattern and response to cyclosporine A (CsA) and cyclophosfamide (CP) were reviewed in 136 children with SRINS. The analyzed outcome was the progression to ESRD. Univariate as well as multivariate Cox-regression analysis were performed. Median age at onset was 5.54 years (0.67-17.22) and median follow up time was 6.1 years (0.25-30.83). Early steroid-resistance was observed in 114 patients and late resistance in 22. Resistance to CP and CsA was 62.9% and 35% respectively. At last follow-up 57 patients reached ESRD. The renal survival rate was 71.5%, 58.4%, 55.3%, 35.6% and 28.5% at 5, 10, 15, 20 and 25 years respectively. Univariate analysis demonstrated that older age at onset, early steroid-resistance, hematuria, hypertension, focal segmental glomerulosclerosis (FSGS), and resistance to IS were risk factors for ESRD. The Cox proportional-hazards regression identified CsAresistance and FSGS as the only predictors for ESRD. Our findings showed that CsA-resistance and FSGS were risk factors for ESRD.

Nuclear HSP90 regulates the glucocorticoid responsiveness of PBMCs in patients with idiopathic nephrotic syndrome

Resistance to glucocorticoid (GC) is a challenge for the treatment of patients with idiopathic nephrotic syndrome (INS). Most of the effects of GC are mediated by the GC receptor (GR). Heat shock protein 90 (HSP90) is an important molecular chaperone for the GR and is supposed to be the key factor in regulating GC effects. In a previous study, we found that both the expression and nuclear distribution of HSP90 were increased in GC resistant INS patients. The aim of this study is to explore how these phenomena contribute to GC resistance in INS patients.Healthy subjects and INS patients with different GC responses were recruited. The total HSP90 expression was determined by reverse transcription-PCR and flow cytometric analysis. Western blot analysis was used to evaluate the expression of nuclear HSP90. Co-immunoprecipitation and electrophoretic mobility gel shift assays were performed to explore the interaction between HSP90 and the GR in the nucleus as well as the DNA-binding activity of GR.We induced the upregulation of the expression of total HSP90 in PBMCs by treatment with interleukin-6 in vitro and found that the nuclear HSP90 level, the DNA-binding activity of the GR and the cell apoptotic responsiveness to GC remained unchanged. Furthermore, an increased nuclear HSP90 was demonstrated mainly by binding to GR in the nucleus, while the DNA-binding activity of the GR dramatically decreased in GC resistant INS patients. The present results suggest that the accumulation of HSP90 in the nucleus potentially hinders DNA-binding activity and transactivation, which may contribute to GC resistance in patients with INS.

Rituximab in Children with Resistant Idiopathic Nephrotic Syndrome

Idiopathic nephrotic syndrome resistant to standard treatments remains a therapeutic dilemma in pediatric nephrology. To test whether the anti-CD20 monoclonal antibody rituximab may benefit these patients, we conducted an open-label, randomized, controlled trial in 31 children with idiopathic nephrotic syndrome unresponsive to the combination of calcineurin inhibitors and prednisone. All children continued prednisone and calcineurin inhibitors at the doses prescribed before enrollment, and one treatment group received two doses of rituximab (375 mg/m(2) intravenously) as add-on therapy. The mean age was 8 years (range, 2-16 years). Rituximab did not reduce proteinuria at 3 months (change, -12% [95% confidence interval, -73% to 110%]; P=0.77 in analysis of covariance model adjusted for baseline proteinuria). Additional adjustment for previous remission and interaction terms (treatment by baseline proteinuria and treatment by previous remission) did not change the results. In conclusion, these data do not support the addition of rituximab to prednisone and calcineurin inhibitors in children with resistant idiopathic nephrotic syndrome.

No Benefit from Adjunct Rituximab in Children with Resistant Idiopathic Nephrotic Syndrome

Prednisone-resistant idiopathic nephrotic syndrome (INS) is one of the most frustrating chronic kidney diseases in children. Because of promising preliminary reports, the monoclonal anti-CD20 antibody rituximab has become a popular adjunctive therapy for resistant INS. In a multicenter, open-label, randomized trial, researchers examined the effectiveness of rituximab …

The accumulated experience with the use of mycophenolate mofetil in primary glomerulonephritis

Importance of the field: The use of mycophenolate mofetil (MMF) has been extended from renal transplantation to the treatment of glomerulonephritis. MMF has been used in patients with steroid- and ciclosporin A (CsA)-dependent or -resistant idiopathic nephrotic syndrome and in patients with deteriorating renal function or adverse reactions to other drugs. MMF has been also used in patients with membranous and IgA nephropathy after failure of other regimens as well as initial treatment.Areas covered in this review: The rationale of MMF treatment in primary glomerulonephritis is based in its antifibrotic and antiproteinuric effects. The mechanism of action is described; the results of cohort and randomized trials in minimal change disease, focal segmental glomerulosclerosis, idiopathic membranous nephropathy and IgA nephropathy are presented along with the adverse reactions profile and the expert opinion.What the reader will gain: This is an up-to-date review providing insight on this novel agent that is increasingly used in the therapeutics of primary glomerulonephritis.Take home message: Although the results are conflicting, MMF seems to be effective at least in some patients, who do not respond to corticosteroids, ciclosporin or cytotoxic drugs. However, the experience with MMF in primary glomerulonephritis is limited and further research is required in order to establish MMF in the treatment of patients with glomerular disease.

Blood T-Cell Repertoire in Idiopathic Nephrotic Syndrome Recurrence Following Kidney Transplantation

Corticosteroid resistant idiopathic nephrotic syndrome (CR-INS) is a glomerulopathy that recurs after kidney transplantation in 30-50% of patients, suggesting the involvement of systemic albuminuric factors, probably produced by activated T cells. We investigated peripheral T-cell selection and expansion before and after transplantation to identify and characterize T-lymphocyte patterns potentially associated with INS recurrence. We used a combined qualitative and quantitative assessment of Vbeta mRNA alterations at the level of the complementary determining region 3-length distribution (CDR3-LD) of the T-cell receptor (TCR). Peripheral blood mononuclear cells (PBMC) were collected from 18 CR-INS patients (8 with recurrence and 10 without recurrence) on the day of transplantation as well as at 1 month, 1 year and 5 years after transplantation, and Vbeta transcriptomes were analyzed. Our data show that blood T cells from patients with INS recurrence display a TCR repertoire that is stable in time and has a similar level of CDR3-LD alterations as the T-cell repertoire of control patients, both before and after transplantation. These results suggest that the process of INS recurrence does not involve TCR activation or specific clonal expansion of T cells. However, these results do not exclude a role for T cells in the production of an albuminuric factor.

Mapping a gene (SRN1) to chromosome 1q25-q31 in idiopathic nephrotic syndrome confirms a distinct entity of autosomal recessive nephrosis.

Idiopathic nephrotic syndrome (INS) in childhood is characterized by massive proteinuria and minimal glomerular changes. Most patients with INS respond to steroid therapy. INS is generally regarded as a sporadic disease with favorable outcome. We investigated a distinct subgroup of nephrosis--the familial form of steroid resistant INS (SRN). These patients always progress to end-stage renal failure within a few years and show absence of recurrence of the disease after renal transplantation. The occurrence of the disorder in siblings and the high incidence of inbreeding in these families made an autosomal recessive mode of inheritance very likely. We performed whole genome linkage analysis in nine multiplex families of European or Northern African origin. Our results allowed us to assign a disease locus (SRN1) to a defined chromosomal region on 1q25-1q31, thus confirming the existence of a distinct entity of autosomal recessive nephrosis. Exclusion of linkage to the entire region in one family proves genetic heterogeneity.

Long-term renal tolerance of cyclosporin A treatment in adult idiopathic nephrotic syndrome

Repeat renal biopsies and serial serum creatinine measurements were done in 36 adults who were treated for steroid-dependent or -resistant idiopathic nephrotic syndrome with 5.54 +/- 0.81 mg/kg/day of cyclosporin A (CsA). Pre-CsA renal biopsy (RB1) had been carried out 11.6 +/- 12.2 months prior to CsA treatment. It showed minimal glomerular changes (MCD) in 22, and 1 to 16 glomeruli with lesions of focal segmental glomerulosclerosis (FSGS) per biopsy in 14. Pretreatment serum creatinine levels were (mumol/liter) 97.6 +/- 39.4 and were higher in FSGS (117.1 +/- 48.3) than in MCD (85.2 +/- 26.9; P < 0.04). Repeat biopsy (RB2) was done after 19.6 +/- 15.2 months (6 to 78) of CsA treatment. At this time, in 15 patients the minimal glomerular lesions observed on RB1 were unchanged, whereas in 7 patients lesions of FSGS were now visible. In patients with FSGS on RB1 and RB2, serum creatinine at the end of CsA treatment was 130.6 +/- 60.1 mumol/liter, significantly greater (P = 0.022) than the corresponding levels in the subset with MCD (87.3 +/- 24.8). The contrast between the remarkable stability of renal function in the patients with MCD and the worsening of renal function in the subgroup with FSGS was explained in the latter by an aggravation of renal histologic lesions, with a greater number of glomeruli with FSGS, of obsolescent glomeruli, and of interstitial fibrosis/infiltrates. This aggravation of the primary renal disease was observed in some cases where CsA had obtained partial or even complete remission. Few of the tubular lesions and of vascular changes were typical of CsA toxicity but rather suggested development of the primary renal disease. In contrast, although some increase in the degree of tubulointerstitial lesions was observed on RB2, the rating of such lesions was much less severe in patients whose renal biopsy showed persistently normal glomeruli after exposure to CsA. Overall, the most severe interstitial/vascular lesions were observed in patients treated with the highest CsA dosages, and the "cut-off" of dosage safety appeared to be 5.5 mg/kg/day. Two patients died during the study period. Long-term surveillance of the extant 34 patients showed that 8, all of whom had FSGS, evolved to end-stage renal failure due to progression of their primary renal disease after ending CsA treatment. Four patients were failures of CsA and returned to conventional therapy. CsA treatment was continued for 12 to 60 months in fourteen patients who achieved remission.(ABSTRACT TRUNCATED AT 400 WORDS)