Clinical trial of focal segmental glomerulosclerosis in children and young adults

This NIH-funded multicenter randomized study of focal segmental glomerulosclerosis (FSGS) treatment compared the efficacy of a 12-month course of cyclosporine to a combination of oral pulse dexamethasone and mycophenolate mofetil in children and adults with steroid-resistant primary FSGS. Of the 192 patients enrolled, 138 were randomized to cyclosporine (72) or to mycophenolate/dexamethasone (66). The primary analysis compared the levels of an ordinal variable measuring remission during the first year. The odds ratio (0.59) for achieving at least a partial remission with mycophenolate/dexamethasone compared to cyclosporine was not significant. Partial or complete remission was achieved in 22 mycophenolate/dexamethasone- and 33 cyclosporine-treated patients at 12 months. The main secondary outcome, preservation of remission for 26 weeks following cessation of treatment, was not significantly different between these two therapies. During the entire 78 weeks of study, 8 patients treated with cyclosporine and 7 with mycophenolate/dexamethasone died or developed kidney failure. Thus, our study did not find a difference in rates of proteinuria remission following 12 months of cyclosporine compared to mycophenolate/dexamethasone in patients with steroid-resistant FSGS. However, the small sample size might have prevented detection of a moderate treatment effect

Clinical trials treating focal segmental glomerulosclerosis should measure patient quality of life

Optimal therapy of patients with steroid-resistant primary focal segmental glomerulosclerosis (FSGS) remains controversial. This report describes the initial study design, baseline characteristics, and quality of life of patients enrolled in the FSGS Clinical Trial, a large multicenter randomized study of this glomerulopathy comparing a 12-month regimen of cyclosporine to the combination of mycophenolate mofetil and oral dexamethasone. Patients with age ranging 2–40 years, with an estimated glomerular filtration rate >40 ml/min per 1.73 m2, a first morning urine protein-to-creatinine ratio over one, and resistant to corticosteroids were eligible. The primary outcome was complete or partial remission of proteinuria over 52 weeks after randomization. In all, 192 patients were screened, of whom 138 were randomized for treatment. Ethnic distributions were 53 black, 78 white, and 7 other. By self- or parent-proxy reporting, 26 of the 138 patients were identified as Hispanic. The baseline glomerular filtration rate was 112.4 (76.5, 180.0) ml/min per 1.73 m2, and urine protein was 4.0 (2.1, 5.3) g/g. Overall, the quality of life of the patients with FSGS was lower than healthy controls and similar to that of patients with end-stage renal disease. Thus, the impact of FSGS on quality of life is significant and this measurement should be included in all trials

Gender, Philanthropy, and the Great War in the Works of Wharton and Hemingway

Comparison study drawing on Derrida\u27s theories of the gift to examine the complicated attitudes of both authors regarding the authenticity of philanthropy within the context of war relief. Argues that while genuine philanthropy appears elusive in Wharton\u27s treatment, public volunteer service does offer women characters opportunities for liberation and self-fulfillment. Hemingway\u27s war fiction, on the other hand, focuses on the ultimate gift of death as an opportunity for sympathetic identification with the other (e.g., the mentally ill, the enemy, the civilian). Compares Wharton\u27s The Marne (1918), The Refugees, and Summer (1916), with Hemingway\u27s A Farewell to Arms and A Way You\u27ll Never Be

Complement Activation in Patients with Focal Segmental Glomerulosclerosis.

Recent pre-clinical studies have shown that complement activation contributes to glomerular and tubular injury in experimental FSGS. Although complement proteins are detected in the glomeruli of some patients with FSGS, it is not known whether this is due to complement activation or whether the proteins are simply trapped in sclerotic glomeruli. We measured complement activation fragments in the plasma and urine of patients with primary FSGS to determine whether complement activation is part of the disease process.Plasma and urine samples from patients with biopsy-proven FSGS who participated in the FSGS Clinical Trial were analyzed.We identified 19 patients for whom samples were available from weeks 0, 26, 52 and 78. The results for these FSGS patients were compared to results in samples from 10 healthy controls, 10 patients with chronic kidney disease (CKD), 20 patients with vasculitis, and 23 patients with lupus nephritis.Longitudinal control of proteinuria and estimated glomerular filtration rate (eGFR).Levels of the complement fragments Ba, Bb, C4a, and sC5b-9 in plasma and urine.Plasma and urine Ba, C4a, sC5b-9 were significantly higher in FSGS patients at the time of diagnosis than in the control groups. Plasma Ba levels inversely correlated with the eGFR at the time of diagnosis and at the end of the study. Plasma and urine Ba levels at the end of the study positively correlated with the level of proteinuria, the primary outcome of the study.Limited number of patients with samples from all time-points.The complement system is activated in patients with primary FSGS, and elevated levels of plasma Ba correlate with more severe disease. Measurement of complement fragments may identify a subset of patients in whom the complement system is activated. Further investigations are needed to confirm our findings and to determine the prognostic significance of complement activation in patients with FSGS

Plasma and urine Ba levels at the end of the study were correlated with clinical outcomes.

<p>Ba, Bb, and sC5b-9 levels were measured in samples obtained at the end of the FSGS CT (week 78). The plasma Ba level was significantly correlated with the (A) primary outcome and (B) eGFR at the end of the study. (C) The urine Ba level was significantly correlated with primary outcome for the study. No significant correlations between Bb levels or sC5b-9 levels and clinical outcomes were seen.</p

Levels of plasma Ba correlate with proteinuria and a reduced glomerular filtration rate.

<p>The levels of Ba, Bb, C4a, and sC5b-9 for individual patients were correlated with the degree of proteinuria (urine protein/creatinine ratio; Up/c) and the estimated glomerular filtration rate (eGFR). (A) None of the fragments measured in plasma were significantly correlated with the Up/c. (B) Plasma Ba was inversely correlated with the eGFR. (C) Urine Ba was significantly correlated with the Up/c. (D) None of the fragments measured in the urine were significantly correlated with the eGFR.</p

Circulating Supar In Two Cohorts Of Primary Fsgs

Overexpression of soluble urokinase receptor (suPAR) causes pathology in animal models similar to primary FSGS, and one recent study demonstrated elevated levels of serum suPAR in patients with the disease. Here, we analyzed circulating suPAR levels in two cohorts of children and adults with biopsyproven primary FSGS: 70 patients from the North America based FSGS clinical trial (CT) and 94 patients from Podo Net, the Europe-based consortium studying steroid-resistant nephrotic syndrome. Circulating suPAR levels were elevated in 84.3% and 55.3% of patients with FSGS patients in the CT and PodoNet cohorts, respectively, compared with 6% of controls (P<0.0001); inflammation did not account for this difference. Multiple regression analysis suggested that lower suPAR levels associated with higher estimated GFR, male sex, and treatment with mycophenolate mofetil. In the CT cohort, there was a positive association between the relative reduction of suPAR after 26 weeks of treatment and reduction of proteinuria, with higher odds for complete remission (P=0.04). In the PodoNet cohort, patients with an NPHS2 mutation had higher suPAR levels than those without a mutation. In conclusion, suPAR levels are elevated in geographically and ethnically diverse patients with FSGS and do not reflect a nonspecific proinflammatory milieu. The associations between a change in circulating suPAR with different therapeutic regimens and with remission support the role of suPAR in the pathogenesis of FSGS.WoSScopu