Cynthia G. Pan

Mesangial cell immune injury. Synthesis, origin, and role of eicosanoids.

The synthesis, cell origin, and physiologic role of eicosanoids were investigated in a model of mesangial cell immune injury induced by a monoclonal antibody against the rat thymocyte antigen Thy 1.1 also expressed in rat mesangial cells. A single intravenous injection of the antibody resulted in enhanced glomerular synthesis of thromboxane (Tx)B2, leukotriene (LT)B4, and 12-hydroxyeicosatetraenoic acid (HETE), whereas that of PGE2 and PGF2 alpha was either unaltered or impaired. The enhanced eicosanoid synthesis was associated with decrements in glomerular filtration rate (GFR) and renal blood flow (RBF). Complement activation mediated both the increments in TxB2, LTB4, and 12-HETE and the decrements in GFR and RBF. The decrements in GFR were abolished by the TxA2 receptor antagonist SQ-29,548. Although both neutrophiles and Ia (+) leukocytes infiltrated glomeruli, glomerular LTB4 originated mainly from the latter. Platelets entirely accounted for the enhanced 12-HETE synthesis in isolated glomeruli and to a lesser extent for that of LTB4 and TxB2. Glomerular PGE2 and PGF2 alpha originated from mesangial cells as their impaired synthesis coincided with extensive mesangial cell lysis. The observations indicate that in mesangial cell immune injury vasoactive and proinflammatory eicosanoids originate from recruited or activated Ia (+) leukocytes and platelets and may exert paracrine effects on mesangial cells.

Vitamin D3 Decreases Parathyroid Hormone in HIV-Infected Youth Being Treated With Tenofovir: A Randomized, Placebo-Controlled Trial

BACKGROUND The study goal was to determine the effect of vitamin D (VITD) supplementation on tubular reabsorption of phosphate (TRP), parathyroid hormone (PTH), bone alkaline phosphatase (BAP), and C-telopeptide (CTX) in youth infected with human immunodeficiency virus (HIV) receiving and not receiving combination antiretroviral therapy (cART) containing tenofovir disoproxil fumarate (TDF). METHODS This randomized, double-blind, placebo-controlled multicenter trial enrolled HIV-infected youth 18-25 years based on stable treatment with cART containing TDF (n = 118) or no TDF (noTDF; n = 85), and randomized within those groups to vitamin D3, 50 000 IU (n = 102) or placebo (n = 101), administered at 0, 4, and 8 weeks. Outcomes included change in TRP, PTH, BAP, and CTX from baseline to week 12 by TDF/noTDF; and VITD/placebo. RESULTS At baseline, VITD and placebo groups were similar except those on TDF had lower TRP and higher PTH and CTX. At week 12, 95% in the VITD group had sufficient serum 25-hydroxy vitamin D (25-OHD; ≥20 ng/mL), increased from 48% at baseline, without change in placebo (P < .001). PTH decreased in the TDF group receiving VITD (P = .031) but not in the noTDF group receiving VITD, or either placebo group. The decrease in PTH with VITD in those on TDF occurred with insufficient and sufficient baseline 25-OHD (mean PTH change, -7.9 and -6.2 pg/mL; P = .031 and .053, respectively). CONCLUSIONS In youth on TDF, vitamin D3 supplementation decreased PTH, regardless of baseline 25-OHD concentration. CLINICAL TRIALS REGISTRATION NCT00490412.

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.

Secondary hypertension in overweight and stage 1 hypertensive children: a Midwest Pediatric Nephrology Consortium report.

J Clin Hypertens (Greenwich). 2010;12:34–39. ©2009 Wiley Periodicals, Inc.

Association of Higher Plasma Vitamin D Binding Protein and Lower Free Calcitriol Levels with Tenofovir Disoproxil Fumarate Use and Plasma and Intracellular Tenofovir Pharmacokinetics: Cause of a Functional Vitamin D Deficiency?

ABSTRACT Tenofovir disoproxil fumarate (TDF) causes bone, endocrine, and renal changes by an unknown mechanism(s). Data are limited on tenofovir pharmacokinetics and these effects. Using baseline data from a multicenter study of HIV-infected youth on stable treatment with regimens containing TDF (n = 118) or lacking TDF (n = 85), we measured cross-sectional associations of TDF use with markers of renal function, vitamin D-calcium-parathyroid hormone balance, phosphate metabolism (tubular reabsorption of phosphate and fibroblast growth factor 23 [FGF23]), and bone turnover. Pharmacokinetic-pharmacodynamic associations with plasma tenofovir and intracellular tenofovir diphosphate concentrations were explored among those receiving TDF. The mean age was 20.9 (standard deviation [SD], 2.0) years; 63% were male; and 52% were African American. Compared to the no-TDF group, the TDF group showed lower mean estimated glomerular filtration rates and tubular reabsorption of phosphate, as well as higher parathyroid hormone and 1,25-dihydroxy vitamin D [1,25-OH(2)D] levels. The highest quintile of plasma tenofovir concentrations was associated with higher vitamin D binding protein, lower free 1,25-OH(2)D, higher 25-OH vitamin D, and higher serum calcium. The highest quintile of intracellular tenofovir diphosphate concentration was associated with lower FGF23. Higher plasma tenofovir concentrations were associated with higher vitamin D binding protein and lower free 1,25-OH(2)D, suggesting a functional vitamin D deficiency explaining TDF-associated increased parathyroid hormone. The finding of lower FGF23 accompanying higher intracellular tenofovir diphosphate suggests that different mechanisms mediate TDF-associated changes in phosphate handling. Separate pharmacokinetic properties may be associated with distinct TDF toxicities: tenofovir with parathyroid hormone and altered calcium balance and tenofovir diphosphate with hypophosphatemia and FGF23 regulation. IMPORTANCE (The clinical trial registration number for this study is NCT00490412 and is available online at http://clinicaltrials.gov/ct2/show/NCT00490412.)

Blood pressure control in pediatric hemodialysis: the Midwest Pediatric Nephrology Consortium Study

Hypertension is frequent in pediatric patients receiving dialysis, with an especially high rate reported in children on hemodialysis (HD). We performed the present study to assess blood pressure (BP) status and identify risk factors for poor BP control in children on maintenance HD. One month’s dialysis records were collected from 71 subjects receiving HD in ten dialysis units participating in the Midwest Pediatric Nephrology Consortium (MWPNC). For each HD session, data on pre- and posttreatment weights and BPs were recorded. Hypertension, defined as mean BP ≥ 95th percentile, was found in 42 (59%) subjects. Eleven subjects (15.5%) had prehypertension, defined as mean BP between the 90th and 95th percentiles, while 18 subjects (25.3%) had normal BP (<90th percentile). BP significantly decreased at the end of a dialysis session; however, only 15 of 42 hypertensive subjects (35%) normalized their BP. Hypertensive subjects were younger (p = 0.03), had higher serum phosphorus (p = 0.01), and had more elevated posttreatment weight above estimated dry weight (p = 0.02). Logistic regression showed that younger age (p = 0.02) and higher serum phosphorus (p = 0.02) independently predicted hypertensive status. In conclusion, this study emphasizes the difficulty of BP control in pediatric HD patients. Especially poor BP control was found in younger children; those patients who do not reach their posttreatment weight goals, perhaps reflecting their hypervolemic state; and those who have higher serum phosphorus levels.

Hepatocellular injury inStreptococcus pnumoniae-associated hemolytic uremic syndrome in children

Streptococcus pneumoniae is a uncommon etiological organism in hemolytic uremic syndrome (HUS). Production of neuraminidase byS. pneumoniae results in exposure of red blood cell T-antigen, resulting in hemolysis, thrombocytopenia, and acute renal failure. Hepatic involvement in this form of HUS has not been described in the literature. We report in three children withS. pneumoniae-associated HUS the presence of severely elevated transaminases and conjugated hyperbilirubinemia. Increases in asparagine transaminase ranged from 11 to 46 times normal values and an increase in alanine transaminase ranged from 1.6 to 8 times normal. In all patients the rise in total bilirubin was 7–15 times normal. Biliary tree obstruction and viral causes for liver dysfunction were absent. Hepatocellular injury inS. pneumoniae-associated HUS likely results from mechanisms involved in sepsis and pneumonia-induced jaundice, combined with severely increased bilirubin production following massive hemolysis. The hepatic injury in all three patients resolved within 9, 5, and 10 days. Our experience suggests that an extensive evaluation including liver biopsy is not indicated.

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.

Pseudotumor cerebri with vision impairment in two children with renal transplantation

The syndrome of pseudotumor cerebri consists of headaches, difficulty with vision and papilledema associated with raised intracranial pressure (ICP) without localizing neurological mass lesions. Recently, an association of pseudotumor cerebri and renal insufficiency, chronic dialysis or renal transplantation has been noted. Loss of vision remains a serious threat in children with pseudotumor cerebri. We report two children who developed pseudotumor cerebri with impairment of vision 5 years after renal transplantation. An awareness of this association should prompt the nephrologist to investigate and treat the symptoms of raised ICP to prevent visual loss.

Implementation of standardized follow-up care significantly reduces peritonitis in children on chronic peritoneal dialysis.

The Standardizing Care to improve Outcomes in Pediatric End stage renal disease (SCOPE) Collaborative aims to reduce peritonitis rates in pediatric chronic peritoneal dialysis patients by increasing implementation of standardized care practices. To assess this, monthly care bundle compliance and annualized monthly peritonitis rates were evaluated from 24 SCOPE centers that were participating at collaborative launch and that provided peritonitis rates for the 13 months prior to launch. Changes in bundle compliance were assessed using either a logistic regression model or a generalized linear mixed model. Changes in average annualized peritonitis rates over time were illustrated using the latter model. In the first 36 months of the collaborative, 644 patients with 7977 follow-up encounters were included. The likelihood of compliance with follow-up care practices increased significantly (odds ratio 1.15, 95% confidence interval 1.10, 1.19). Mean monthly peritonitis rates significantly decreased from 0.63 episodes per patient year (95% confidence interval 0.43, 0.92) prelaunch to 0.42 (95% confidence interval 0.31, 0.57) at 36 months postlaunch. A sensitivity analysis confirmed that as mean follow-up compliance increased, peritonitis rates decreased, reaching statistical significance at 80% at which point the prelaunch rate was 42% higher than the rate in the months following achievement of 80% compliance. In its first 3 years, the SCOPE Collaborative has increased the implementation of standardized follow-up care and demonstrated a significant reduction in average monthly peritonitis rates.