Suzanne Vento

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.

Phase 1 Trial of Adalimumab in Focal Segmental Glomerulosclerosis (FSGS): II. Report of the FONT (Novel Therapies for Resistant FSGS) Study Group

BACKGROUND Patients with primary focal segmental glomerulosclerosis (FSGS) resistant to current treatment regimens are at high risk of progression to end-stage kidney disease. Antifibrotic agents, such as tumor necrosis factor alpha antagonists, are a promising strategy to slow or halt the decline in renal function, based on preclinical and clinical data. STUDY DESIGN Phase 1 clinical trial to assess the pharmacokinetics, tolerability, and safety of adalimumab, a human monoclonal antibody to tumor necrosis factor alpha. SETTING & PARTICIPANTS 10 patients (4 male and 6 female) aged 16.8 +/- 9.0 years with an estimated glomerular filtration rate of 105 +/- 50 mL/min/1.73 m(2) were studied. INTERVENTION Adalimumab, 24 mg/m(2), every 14 days for 16 weeks (total, 9 doses). OUTCOMES Pharmacokinetic assessment, tolerability, and safety. MEASUREMENTS Estimated glomerular filtration rate, proteinuria, and pharmacokinetic assessment after initial dosing and steady state. RESULTS Pharmacokinetic evaluation indicated that the area under the curve was decreased by 54% (P < 0.001) and clearance was increased by 160% (P < 0.01) in patients with resistant FSGS compared with healthy controls and patients with rheumatoid arthritis. Adalimumab was well tolerated with no serious adverse events or infectious complications attributable to the drug. Proteinuria decreased by > or = 50% in 4 of 10 treated patients. LIMITATIONS Insufficient power to assess the safety or efficacy of adalimumab therapy for patients with resistant FSGS. CONCLUSIONS Pharmacokinetic assessment showed increased clearance of adalimumab in patients with resistant primary FSGS and validated the need to evaluate the disposition of novel therapies for this disease to define appropriate dosing regimens. The study provides a rationale to evaluate the efficacy of adalimumab as an antifibrotic agent for resistant FSGS in phase 2/3 clinical trials.

Novel therapies for resistant focal segmental glomerulosclerosis (FONT) phase II clinical trial: study design

BackgroundThe lack of adequate randomized clinical trials (RCT) has hindered identification of new therapies that are safe and effective for patients with primary focal segmental glomerulosclerosis (FSGS), especially in patients who fail to respond to corticosteroids and immunosuppressive therapies. Recent basic science advances have led to development of alternative treatments that specifically target aberrant pathways of fibrosis which are relevant to disease progression in FSGS. There is a need for a flexible Phase II study design which will test such novel antifibrotic strategies in order to identify agents suitable for phase III testing.Methods/DesignThe Novel Therapies for Resistant Focal Segmental Glomerulosclerosis (FONT) project is a multicenter Phase I/II RCT designed to investigate the potential efficacy of novel therapies for resistant FSGS. Adalimumab and galactose will be evaluated against conservative therapy consisting of the combination of lisinopril, losartan and atorvastatin. The sample size is defined to assure that if one of the treatments has a superior response rate compared to that of the other treatments, it will be selected with high probability for further evaluation. Comparison of primary and secondary endpoints in each study arm will enable a choice to be made of which treatments are worthy of further study in future Phase III RCT.DiscussionThis report highlights the key features of the FONT II RCT including the two-step outcome analysis that will expedite achievement of the study objectives. The proposed phase II study design will help to identify promising agents for further testing while excluding ineffective agents. This staged approach can help to prevent large expenditures on unworthy therapeutic agents in the management of serious but rare kidney diseasesTrial RegistrationClinicalTrials.gov, NCT00814255

Idiopathic membranous nephropathy in pediatric patients: presentation, response to therapy, and long-term outcome.

BackgroundIdiopathic membranous nephropathy (IMN) is one of the most common causes of primary nephrotic syndrome in adults. However, it is a relatively rare entity in the pediatric population and there is a paucity of data about the incidence, prognosis, and optimal treatment of IMN in children and adolescents. We conducted this study to evaluate pediatric patients with IMN in order to clarify the presentation, response to therapy, and clinical outcome.MethodsA retrospective chart review was performed on patients identified with biopsy-proven IMN between 1988–2005. Patients with systemic lupus erythematosus or hepatitis-related lesions were excluded. The following data were tabulated: age, gender, ethnicity, presenting clinical and laboratory findings, proteinuria in a first morning urine specimen, estimated glomerular filtration rate (GFRe), histopathology, type and duration of treatment, and clinical status at final evaluation.Results13 cases of IMN were identified out of 460 renal biopsies performed for evaluation of primary kidney disease during the study interval. Mean age was 9.6 ± 4.6, gender 6 M:7 F, ethnicity 8 W:2 B:3 H. At the initial visit hematuria was present in 9 patients, edema in 5, nephrotic-range proteinuria in 5, and hypertension in 3. Mean urinary protein:creatinine ratio 3.3 ± 2.5 and all patients had a normal GFRe. Classic glomerular findings of IMN were seen in all renal specimens, with concomitant interstitial changes in 2 cases. Treatment included an angiotensin converting enzyme inhibitor or angiotensin receptor blocker in 11 cases. Most patients were also given immunosuppressive medications – prednisone in 10, a calcineurin inhibitor in 5, and mycophenolate mofetil or azathioprine in 3 patients. At the last follow-up, 42 ± 35 months after the diagnostic biopsy, 7 children were hypertensive and the urine protein:creatinine ratio was 2.3 ± 3.1. The mean GFRe was 127 ± 57 mL/min/m2. Three patients had Chronic Kidney Disease Stage 3, all of whom were also hypertensive.ConclusionIMN is a rare but serious glomerulopathy in pediatrics. We estimate that it accounts for approximately 3% of renal biopsies. Long-term prognosis is guarded because approximately 50% of patients may have evidence of progressive kidney disease.

Follow-up of phase I trial of adalimumab and rosiglitazone in FSGS: III. Report of the FONT study group

BackgroundPatients with resistant primary focal segmental glomerulosclerosis (FSGS) are at high risk of progression to chronic kidney disease stage V. Antifibrotic agents may slow or halt this process. We present outcomes of follow-up after a Phase I trial of adalimumab and rosiglitazone, antifibrotic drugs tested in the Novel Therapies in Resistant FSGS (FONT) study.Methods21 patients -- 12 males and 9 females, age 16.0 ± 7.5 yr, and estimated GFR (GFRe) 121 ± 56 mL/min/1.73 m2 -- received adalimumab (n = 10), 24 mg/m2 every 14 days or rosiglitazone (n = 11), 3 mg/m2 per day for 16 weeks. The change in GFRe per month prior to entry and after completion of the Phase I trial was compared.Results19 patients completed the 16-week FONT treatment phase. The observation period pre-FONT was 18.3 ± 10.2 months and 16.1 ± 5.7 months after the study. A similar percentage of patients, 71% and 56%, in the rosiglitazone and adalimumab cohorts, respectively, had stabilization in GFRe, defined as a reduced negative slope of the line plotting GFRe versus time without requiring renal replacement therapy after completion of the FONT treatment period (P = 0.63).ConclusionNearly 50% of patients with resistant FSGS who receive novel antifibrotic agents may have a legacy effect with delayed deterioration in kidney function after completion of therapy. Based on this proof-of-concept preliminary study, we recommend long-term follow-up of patients enrolled in clinical trials to ascertain a more comprehensive assessment of the efficacy of experimental treatments.

Treatment of Recurrent Focal Segmental Glomerulosclerosisin Pediatric Kidney Transplant Recipients: Effect of Rituximab

Recurrence of focal segmental glomerulosclerosis (FSGS) after renal transplantation is a complication that often leads to graft loss. There is no consensus on the optimal treatment of recurrent FSGS. Rituximab, a monoclonal antibody to CD20, may be a useful treatment of this complication. Methods. We report four pediatric cases of recurrent FSGS treated with rituximab and plasmapheresis. Results. Four children (2M/2F), age 15.3 ± 2.6, with recurrent FSGS posttransplant were identified. Four doses of rituximab were administered 171 ± 180 days posttransplant and 114 ± 169 days after the start of plasmapheresis. Three children responded with complete remission, one of whom relapsed after four months. One child had a partial response with a decrease in proteinuria that was not sustained. No adverse side effects were reported during treatment or followup (mean 22.5 months). Conclusions. Rituximab is a safe and well-tolerated ancillary treatment for recurrent FSGS in pediatric patients in conjunction with plasmapheresis.

Diagnostic yield of renal biopsies: a retrospective single center review

BackgroundPrevious studies have examined the spectrum of diseases identified with a kidney biopsy and the complications of the procedure. However, few studies have examined the utility of the test to clarify the diagnosis and guide treatment of pediatric patients. This retrospective, single-center chart review was performed to test the hypothesis that at least 80% of native kidney biopsies provide clinically valuable information that rationally guides diagnosis and patient management.Methods200 biopsies performed between January 1, 2000 and June 30, 2008 were reviewed. A scheme composed of six categories was devised to classify the utility of each kidney biopsy.Results196 complete case files were available for review. Twenty-four (12.2%) biopsies did not shed light on the diagnosis and were unhelpful in patient management – 21 biopsies (10.7%) were non-diagnostic and 3 (1.5%) failed to yield enough tissue for examination. The number of unhelpful biopsies did not cluster in any specific disease entity.ConclusionOur findings provide guidance to nephrologists about the total risk of a kidney biopsy, including uninformative results, when seeking informed consent for the procedure. The results suggest an appropriate balance has been reached which maximizes the use of kidney biopsies while minimizing the risk of this invasive procedure (word count: 202).

Is antibiotic prophylaxis indicated for a voiding cystourethrogram

Sirs, Most published data about the association of urinary catheterization and urinary tract infection (UTI) relate to long-term catheterization. In contrast, the risk of UTI from the one-time insertion of a catheter that is subsequently promptly removed appears to be low [1, 2], although at least one sepsis-related fatality is known to have occurred in a 6-week-old male following a voiding cystourethrogram (VCUG) (O. Mehls, personal communication). More recently, in a study of 123 adults who had undergone pressure flow studies, Logadottir et al. [3] reported that 4.1% had a positive urine culture and symptoms of infection 1 week after the procedure, and required antibiotic treatment. The authors concluded that routine antibiotic prophylaxis was not indicated after a study involving a brief catheterization of the bladder. This conclusion was supported by another study of 94 women who had undergone urodynamic testing involving two catheterizations. Those patients were randomly assigned to receive trimethoprim-sulfamethoxazole prophylaxis or a placebo. One week after the urodynamic testing, cleancatch urine samples showed UTI in 5.4% of the treated patients and 6.1% of the placebo patients (P=0.6) [4]. We were able to find only one study of the risk of UTI associated with VCUGs in children. In that retrospective study of 932 children who had undergone VCUGs, 18 patients (1.9%) developed a febrile UTI within 7 days of undergoing a VCUG. The risk was higher in boys, infants, patients with vesicoureteral reflux, and patients with other urinary tract abnormalities, but was not significantly lowered by antibiotic prophylaxis [5]. A few months ago, the occurrence of a UTI a few days after a VCUG in one of our patients prompted us to try to determine whether or not pediatric nephrologists routinely provide antibiotic prophylaxis to their patients who are scheduled to undergo a VCUG. To achieve this, we sent the following email to the subscribers of the PEDNEPH Internet Pediatric Nephrology List: UTI occurs in a small proportion of patients who undergo a VCUG. Do you prescribe prophylactic antibiotic treatment against that risk? Fifty-three responses were received. We included our own answers to the question for a total of 56 responses. Two respondents gave equivocal answers that were not included in the final count. One of those prescribed an antibiotic, after the procedure, only when the catheterization was difficult. The other prescribed prophylaxis for infants but not for older children. Of the remaining 54, 25 (46%) reported that they did not routinely provide prophylaxis and 29 (54%) reported that they did. There was a disparity in the practice of pediatric nephrologists working in the United States and those working in other countries. Of the 35 American respondents, 20 (57%) did not recommend prophylaxis and 15 (43%) did. Of the 19 non-American respondents, only 5 (26%) did not recommend prophylaxis, while 14 (74%) did. The difference between American and non-American nephrologists was statistically significant (chi-squared 4.71, P 0.05). In view of the absence of a clear-cut association between VCUG and post-VCUG UTI, after many years of performing the procedure, we suggest that UTI is an infrequent complication and that antibiotic prophylaxis cannot be considered the “standard of care.” This conclusion is supported by the fact that only slightly more than half of pediatric nephrologists who responded to our question recommended prophylaxis. What little evidence is available does not support antibiotic prophylaxis for VCUGs. B. Gauthier · M. Vergara · R. Frank · S. Vento · H. Trachtman Division of Nephrology, Schneider Children’s Hospital of the North Shore-Long Island Jewish Health System, Long Island Campus for the Albert Einstein College of Medicine, New Hyde Park, New York, USA

Exposure to bisphenols and phthalates and association with oxidant stress, insulin resistance, and endothelial dysfunction in children

Background:The health effects of bisphenol A (BPA) and di-(2-ethylhexyl) phthalate (DEHP) have been studied extensively in children. The impact of other chemicals in these two classes has not been investigated as fully.Methods:We conducted a cross-sectional pilot study of 10–13 y old healthy children. We assessed descriptive, univariable, and multivariable associations of urinary metabolites of bisphenols and phthalates with oxidant stress, insulin resistance, body mass, and endothelial dysfunction. Possible associations with brachial artery distensibility, pulse wave velocity (markers of vascular stiffness), and serum endothelial cell-derived microparticle levels were also assessed.Results:We enrolled 41 participants, 12.1 ± 1.0 y, most of whom were Mexican Americans (42%) or other Hispanics (34%). Increased BPA levels were associated with increased levels of F2-isoprostane (ng/ml) (P = 0.02), with a similar trend for DEHP metabolites. Each log unit increase of high molecular weight (HMW) phthalate metabolites was associated with a 0.550 increase in Homeostatic Model Assessment of insulin resistance (HOMA-IR) units (P = 0.019) and altered circulating levels of activated endothelial cell-derived microparticles (% per ml) (P = 0.026). Bisphenol S (BPS), a replacement for BPA, was associated with increased albumin (mg):creatinine (g) ratio (P = 0.04). Metabolites of HMW phthalates were also associated with decreased brachial artery distensibility (P = 0.047).Conclusion:Exposure to bisphenols and phthalates, including a BPA replacement, is associated with increased oxidant stress, insulin resistance, albuminuria, as well as disturbances in vascular function in healthy children.

Proteinuria and renal disease: prognostic value of urine dipstick testing for leukocytes

Proteinuria is utilized to screen for underlying kidney disease and serves as a marker of disease progression. The aim of this study was to test the hypothesis that patients with proteinuria will have a higher frequency of urine dipstick positive for leukocytes as an index of noninfectious renal inflammation. In this retrospective analysis, 1,099 urine specimens were evaluated from 676 patients. Proteinuria was present in 39% of the samples and leukocyturia in 5.1%. The percentage of urines that were dipstick positive for leukocytes was similar in those specimens with or without proteinuria. However, in patients with proteinuria and concomitant leukocyturia, the mean serum creatinine concentration was higher (P=0.003) and the calculated GFR was lower (P=0.01) compared to those without this additional abnormality. These differences were noted despite similar age, gender distribution, and array of underlying diseases in these two groups. Based on these findings, urine dipstick testing for leukocytes as a primary means of screening otherwise healthy children for serious renal disease is of little value. However, in patients with established proteinuria, a positive dipstick result for leukocytes is a simple means of identifying those with more prominent noninfectious renal inflammation, a process which may promote kidney disease progression. This finding may serve as an early marker of the severity of renal injury, regardless of whether the primary process is glomerular or tubular.