Effect of beta blockers on optical coherence tomography angiography in normal, suspect, and glaucomatous eyes: A prospective study.

PURPOSE: The study aimed to assess the effect of hypertension, and use of systemic beta blockers (BB) and other antihypertensives on ocular perfusion by optical coherence tomography angiography (OCTA) in normal, suspect, and glaucomatous eyes. METHODS: Cross-sectional study in tertiary eye care center. Prospectively recruited consenting subjects between 18 and 90 years with or without glaucoma. Measured the optic nerve peripapillary perfusion and flux and macular vessel density (MVD: 6 × 6 and 3 × 3 mm) in the superficial retinal layer using OCTA. RESULTS: Included 200 eyes (112 patients). Compared to nonhypertensives or those on non-BB antihypertensives (NBB), hypertensives on BB had lower peripapillary perfusion (43.45,43.40, 42.05%, P = 0.003), and MVD (6 × 6 mm: 16.65, 16.70,15.75 mm/mm 2 , P = 0.002; 3 × 3 mm: 18.70, 18.50, 18.00 mm/mm 2 , P = 0.025). Those on systemic BB with vasodilatory properties had similar perfusion parameters as nonhypertensives and NBB. Those on systemic BB without vasodilating properties had significantly lower peripapillary perfusion (42.05 vs 43.30%, P = 0.011) and MVD (6 × 6 mm: 15.15 vs 16.60 mm/mm 2 , P < 0.001; 3 × 3 mm: 17.40 vs 18.70 mm/mm 2 , P = 0.005) compared to nonhypertensives. On multivariate analysis, peripapillary perfusion increased with increase in diastolic blood pressure (ß:0.051, p: 0.04) and increasing age was the only factor found to be significantly associated with decreased peripapillary and macular perfusion parameters. CONCLUSION: Systemic BB users have worse ocular perfusion parameters compared to those on other medications or nonhypertensives on univariate analysis but similar perfusion on multivariate analysis. Those on BB with vasodilation have better ocular perfusion parameters. All BB cannot be considered equally detrimental to ocular perfusion. Further well-controlled prospective studies are needed to reassess the effects of BB with or without vasodilation on ocular perfusion.

Overcoming Barriers to Drug Development in Children with CKD.

Like all sick children, children with CKD need access to safe and effective medicines that have been formulated and examined specifically for them. Despite legislation in the United States and the European Union that either mandates or incentivizes programs for children, conducting trials to advance the treatment of children continues to prove to be a challenge for drug developers. This is also the case for drug development in children with CKD, where trials face challenges in recruitment and completion and where there remains a substantial time lag between initial approval of a medicinal product for use in adults and completion of studies that result in the addition of pediatric-specific labeling for the same indication. The Kidney Health Initiative commissioned a workgroup of diverse stakeholders ( https://khi.asn-online.org/projects/project.aspx?ID=61 ), including participants from the Food and Drug Administration and the European Medicines Agency, to think carefully through the challenges in drug development for children with CKD and how to overcome them. This article provides an overview of the regulatory frameworks in the United States and the European Union that govern pediatric drug development, the current landscape of drug development and approval for children with CKD, the challenges in conduct and execution of these drug trials, and the progress that has been made to facilitate drug development for children with CKD.

Comparison of conjunctiva-related complications between scleral and corneal patch grafts in Ahmed glaucoma valve implantation.

Purpose: Comparison of the conjunctiva related complication rates and success rates among eyes with Ahmed glaucoma valve (AGV) implantation in which eye bank derived scleral and corneal patch grafts had been used to cover the tube. Methods: Retrospective comparative study. Patients who underwent AGV implantation between January 2000 to December 2016 were included. Demographic, clinical data, intra and post operative data was obtained from electronic medical records. Conjunctiva related complications were divided into two groups: with and without implant exposure. Conjunctiva related complication rates, success rate, risk factors among eyes with corneal and scleral patch graft were compared. Results: Three hundred and twenty three eyes of 316 patients underwent AGV implantation. Scleral patch graft was used in 214 eyes of 210 patients (65.9%) and corneal patch graft was used in 109 eyes of 107 patients (34%). Median follow up was 14 months. There was no significant difference in the conjunctiva related complication rate (7.3 % in corneal patch graft versus 7.0% in scleral patch graft;p=0.5) and conjunctival dehiscence rate (3.7% versus 4.6%, P = 0.7) among the two groups. Success rate was significantly higher in the corneal patch graft group versus the scleral patch graft group (98% versus 72%; p=0.001). Eyes with corneal patch graft had a higher survival rate (P = 0.01). Conclusion: There was no significant difference in the rate of conjunctiva related complications following corneal and scleral patch grafts used to cover the AGV tube. Eyes with corneal patch graft had a higher success rate and survival rate.

Long Anterior Zonules and Angle Closure Disease.

PRCIS: Angle closure disease was present in 59.3% of eyes with long anterior zonules (LAZ). The cause is multifactorial including a thick anteriorly positioned crystalline lens, shorter axial length, and increased lens thickness to axial length factor. PURPOSE: To study the profile of eyes with LAZ presenting in a glaucoma clinic in a tertiary eye care centre and understand the pathogenesis of angle closure disease in these eyes. METHODS: This was a retrospective cross-sectional study.All patients with LAZ seen from January 2014 to December 2018 were included. Demographic and clinical characteristics were noted. LAZ eyes (177 eyes of 177 patients) were compared with an equal number of age and sex-matched controls. LAZ was defined as radially oriented zonular fibers (both pigmented and nonpigmented), extending central to the normal zonular termination zone on the anterior lens surface >1 mm beyond their usual insertion of 1.42±0.24 mm from the lens equator onto the mid peripheral zone or central to it, as seen on slit-lamp examination, following pupillary dilation by a single examiner. Glaucoma was defined according to the International Society for Geographical and Epidemiological Ophthalmology classification. The following biometric parameters were compared: anterior chamber depth (ACD), axial length (AXL), lens thickness (LT), lens position (LP=ACD+0.5×LT), relative lens position (RLP=LP/AXL); lens thickness to axial length factor (LAF=(LT/AXL)×10). LAZ eyes without angle closure disease were also compared with controls. RESULTS: Mean age of patients with LAZ was 64.8±8.1 years. Of these, 63.3% were females. Angle closure disease was present in 59.3% (105/177) patients. Majority of these eyes were primary angle closure suspects (PACS) (53.3%, n=56). Significant differences were found between LAZ eyes and controls for LT (4.8±0.38 mm vs. 4.49±0.40 mm, P<0.0001), ACD (2.68±0.39 mm vs. 3.0±0.32 mm, P<0.0001), AXL (22.37±0.79 mm vs. 22.94±1.1, P<0.0001), LAF (2.14±0.19 vs. 1.96±0.21, P<0.0001), and LP (5.07±0.37 vs. 5.3±0.25, P<0.0001). CONCLUSIONS: Angle closure was present in more than half the eyes with LAZ. Majority of these eyes were PACS or had primary angle closure. LAZ eyes had a thicker lens, shallow AC, a shorter axial length and an increased LAF as compared with age and sex matched normal controls. The presence of LAZ may be an indicator of increased risk for angle closure.

Pediatric formulation development - Challenges of today and strategies for tomorrow: Summary report from M-CERSI workshop 2019.

A workshop on "Pediatric Formulation Development: Challenges of Today and Strategies for Tomorrow" was organized jointly by the University of Maryland's Center of Excellence in Regulatory Science and Innovation (M-CERSI), the U.S. Food and Drug Administration (FDA) and the International Consortium for Innovation and Quality in Pharmaceutical Development (IQ) Drug Product Pediatric Working Group (PWG). This multi-disciplinary, pediatric focused workshop was held over a two-day period (18-19 Jun 2019) and consisted of participants from industry, regulatory agencies, academia and other organizations from both US and Europe. The workshop consisted of sequential sessions on formulation, analytical, clinical, and regulatory and industry lessons learned and future landscape. Each session began with a series of short framing presentations, followed by facilitated breakout sessions and panel discussion. The formulation session was dedicated to three main topics pertaining to drug product acceptability, excipients in pediatrics and oral administration device considerations. The analytical session discussed key considerations for dosing vehicle selection and analytical strategies for testing of different dosage forms, specifically mini-tablets (multiparticulates). The clinical session highlighted the influence of pediatric pharmacokinetics prediction on formulation design, pediatric drug development strategies and clinical considerations to support pediatric formulation design. The regulatory and industry lessons learned and future landscape session explored the regional differences that exist in regulatory expectations, requirements for pediatric formulation development, and key patient-centric factors to consider when developing novel pediatric formulations. This session also discussed potential collaboration opportunities and tools for pediatric formulation development. This manuscript summarizes the key discussions and outcomes of all the sessions in the workshop with a broadened review and discussion of the topics that were covered.

Tube Obstruction of a Nonvalved Glaucoma Drainage Device by a Dislocated Soemmering's Ring.

The authors report a case of tube obstruction of a nonvalved glaucoma drainage device (Aurolab aqueous drainage implant; AADI) with a dislocated Soemmering's ring (SR) leading to a postoperative intraocular pressure (IOP) spike after an initial IOP reduction. A 24-year-old man with bilateral aphakia, bilateral secondary glaucoma developed corneal decompensation in the left eye. The IOP in the left eye was 22 mm Hg with 3 topical IOP-lowering medications (timolol 0.5%, brimonidine 0.2%, and latanoprost 0.005%). To control the IOP before performing a penetrating keratoplasty, AADI was implanted. A good bleb and an IOP of 10 mm Hg were noted at 6.5 weeks postoperatively. The following day the patient developed an acute rise in IOP (42 mm Hg) because of tube obstruction of the AADI by a SR. The IOP spike was initially controlled with oral acetazolamide and topical IOP-lowering medications (fixed combination of timolol 0.5% and brimonidine 0.2%). Six days later, pars plana vitrectomy, SR removal, penetrating keratoplasty, and tube trimming were performed. Following this, the patient had good IOP control and a clear corneal graft at 1-year follow-up. In aphakic eyes undergoing nonvalved glaucoma drainage device implantation, a complete pars plana vitrectomy combined with any lens remnant removal may be considered. It helps to avoid tube obstruction because of these lens remnants, which can migrate anteriorly along with the aqueous currents.

Creatinine-Based Renal Function Assessment in Pediatric Drug Development: An Analysis Using Clinical Data for Renally Eliminated Drugs.

The estimated glomerular filtration rate (eGFR) equations based on serum creatinine (SCR) have been used for pediatric dose adjustment in drug labeling. This study evaluated the performance of those equations in estimating individual clearance of drugs that are predominantly eliminated by glomerular filtration, using clinical data from the renally eliminated drugs gadobutrol, gadoterate, amikacin, and vancomycin. The eGFR was compared with the observed drug clearance (CL) in 352 pediatric patients from birth to 12 years of age. Multiple eGFR equations overestimated the drug CL on average, including the original and bedside Schwartz equations, which showed an average eGFR/CL ratio between 1 and 3. Further analysis with bedside Schwartz equation showed a higher eGFR/CL ratio in the subjects with a lower SCR or CL. Supraphysiological eGFR as high as 380 mL/min/1.73 m2 was obtained using the bedside Schwartz equation for some of the subjects, most of whom are children < 2 years of age with SCR < 0.2 mg/dL. Excluding the subjects with supraphysiological eGFR from the analysis did not change the overall trend of overestimation. In conclusion, Schwartz equations led to an overestimation of drug clearance for the drugs evaluated. When greater precision is required in predicting eGFR for pediatric patients, such as in drug dosing, revised k constants for the Schwartz equation or new methods of glomerular filtration rate estimation may be necessary.

Dosing Recommendations for Pediatric Patients With Renal Impairment.

A treatment gap exists for pediatric patients with renal impairment. Alterations in renal clearance and metabolism of drugs render standard dosage regimens inappropriate and may lead to drug toxicity, but these studies are not routinely conducted during drug development. The objective of this study was to examine the clinical evidence behind current renal impairment dosage recommendations for pediatric patients in a standard pediatric dosing handbook. The sources of recommendations and comparisons included the pediatric dosing handbook (Lexicomp), the U.S. Food and Drug Administration-approved manufacturer's labels, and published studies in the literature. One hundred twenty-six drugs in Lexicomp had pediatric renal dosing recommendations. Only 14% (18 of 126) of Lexicomp pediatric renal dosing recommendations referenced a pediatric clinical study, and 15% of manufacturer's labels (19 of 126) described specific dosing regimens for renally impaired pediatric patients. Forty-two products had published information on pediatric renal dosing, but 19 (45%) were case studies. When pediatric clinical studies were not referenced in Lexicomp, the renal dosing recommendations followed the adult and pediatric dosing recommendations on the manufacturer's label. Clinical evidence in pediatric patients does not exist for most renal dosing recommendations in a widely used pediatric dosing handbook, and the adult renal dosing recommendations from the manufacturer's label are currently the primary source of pediatric renal dosing information.

Phacoemulsification in eyes with long anterior zonules.

PURPOSE: To study the safety of phacoemulsification in eyes with long anterior zonules (LAZs). SETTING: Institute. DESIGN: Retrospective interventional case series. METHODS: All patients with clinically proven LAZs who had undergone phacoemulsification by a single surgeon from January 2014 to December 2018 were included. All cases of LAZs with cataract extraction by procedures other than phacoemulsification or combined with any other ocular surgery were excluded. Sixty-five eyes of 52 patients were analyzed. Phacoemulsification with capsulorhexis that involves sacrificing the LAZs was performed. The primary outcome measures were the incidence of capsulorhexis extension or the need to rescue intraoperatively and the rate of intraoperative complications. Secondary outcomes assessed were the percentage of eyes within ±0.5 diopters (D) and ±1 D of the target refraction. RESULTS: Sixty-five eyes (52 patients) were analyzed; the mean age of patients was 67.3 ± 7.4 years. The successful completion of an adequately sized capsulorhexis without extension or rescue was seen in 100% of cases. The incidence of intraoperative complications was 1.5% (posterior capsular rupture in 1 eye). The mean postoperative corrected distance visual acuity was 0.05 ± 0.1 (logarithm of the minimum angle of resolution) at a mean of 26.8 ± 7.6 days. The mean spherical equivalent was -0.15 ± 0.7 D. Eyes within ±0.5 D and ±1.00 D of the target refraction were 77% and 94%, respectively. CONCLUSIONS: Phacoemulsification in eyes with LAZs can be safely performed through an adequately sized capsulorhexis by sacrificing, ie, cutting or breaking, the anteriorly inserted zonules 360 degrees without significant intraoperative complications.

Exposure-Response Assessment in Pediatric Drug Development Studies Submitted to the US Food and Drug Administration.

Exposure-response (E-R) modeling provides a quantitative tool to leverage adult data to support pediatric trial design and drug approval. The pediatric E-R studies submitted to US Food and Drug Administration (FDA) between 2007 and 2018 were surveyed in the context of various types of trial designs supporting drug approval in the pediatric population. The applications of E-R evaluation in pediatric drug development programs are mainly focused on three areas: (i) supporting pediatric extrapolation when the E-R relationships are similar between the pediatric and adult populations; (ii) dose selection to balance the risk-benefit profile based on the change in efficacy and safety response with different exposure levels; and (iii) approval of a new formulation, new dosing regimen, or new route of administration, where E-R evaluation helps quantify the change in clinical response between the old and new strategies. E-R modeling will continue to play an expanded role in pediatric drug development in the future.

Decompression Retinopathy Following Trabeculectomy: A Case Report.

INTRODUCTION: Decompression retinopathy (DR) can have varied manifestations as retinal and vitreous hemorrhage, disc edema, and macular edema. Vein occlusion associated with choroidal detachment (CD) has not been reported so far as a feature of DR. CASE: We report a case of a 78 year old male with bilateral primary open angle glaucoma (POAG) on maximal topical medication with progressive field loss. Trabeculectomy with mitomycin C was done in the left eye, and the patient developed hypotony in the immediate postoperative period which was managed conservatively. After six weeks he developed CD, vein occlusion and macular edema. Thus, Anti VEGF was given and in other eye filtration surgery was done with all measures to avoid sudden hypotony. Patient still developed CD in the right eye. For which, he was given oral and topical steroids in tapering dose. After one month there was resolution of macular edema in the left eye and choroidal detachment resolved in both eyes and IOP was in lower teens in both eyes. CONCLUSION: Venous stasis retinopathy and choroidal detachment can be the manifestations of decompression retinopathy following glaucoma filtering surgery. The advancement in imaging modalities now can help us find the pathogenesis of the condition and validation of previous hypothesis proposed. Early identification and management of retinopathy helps in resolution with good visual recovery.

Intraocular Pressure in the Eyes of Patients With Carotid-Cavernous Fistulas: Profile, Intereye Asymmetry, and Treatment Outcomes.

PRECIS: Secondary ocular hypertension (OHT) is common in carotid-cavernous fistulas (CCFs). Management of elevated intraocular pressure (IOP) is possible with a multidisciplinary approach. The ipsilateral normal eyes may have higher IOP than the contralateral eyes. PURPOSE: To study the IOP profile of the eyes of patients with a CCF, treatment outcomes for elevated IOP, and intereye IOP asymmetry in the eyes with normal IOP. METHODS: This was a retrospective case series. A total of 64 eyes of 60 patients with digital subtraction angiography-proven CCF diagnosed from the year 2000 to 2016 were included. The demographics, clinical features, management, and outcomes were recorded. The primary outcome included understanding of the cause of elevated IOP. The secondary outcomes included comparison of the IOP between contralateral eyes and ipsilateral normal eyes (IOP <21 mm Hg) and management outcomes for elevated IOP. RESULTS: The mean age of the patients was 45.6±18.2 years. In the study population, 70% of the patients were males. Indirect CCF was present in 55% of the eyes. It was found that 64.06% (n=41) of the eyes had elevated IOP, glaucoma, or were glaucoma suspects. Among all the eyes, 40.62% (n=26) of the eyes had secondary OHT due to elevated episcleral venous pressure, whereas 7.81% (n=5) of the eyes had secondary open-angle glaucoma. The mean IOP was higher in the ipsilateral eyes than in the other eyes (22.95±7.1vs. 15.11±2.99 mm Hg; P<0.001). The mean IOP in the ipsilateral normal eyes was higher than that in the contralateral eyes, with a mean difference of 2.92±2.29 mm Hg (confidence interval of the mean difference: 1.90-3.94 mm Hg; P<0.0001). IOP reduction (<21 mm Hg) was achieved in 70.7% of the patients following CCF management with intermittent carotid massage, endovascular treatment, IOP-lowering medications, or a combination among these. CONCLUSIONS: Secondary OHT due to elevated episcleral venous pressure was more common than secondary open-angle glaucoma. Ipsilateral normal eyes had higher IOP than contralateral eyes. IOP-lowering agents and management of CCF resulted in IOP control in most patients.

Research Gaps in Primary Pediatric Hypertension.

Hypertension affects >40% of the US population and is a major contributor to cardiovascular-related morbidity and mortality. Although less common among children and adolescents, hypertension affects 1% to 5% of all youth. The 2017 Clinical Practice Guideline for the Diagnosis and Management of High Blood Pressure in Children and Adolescents provided updates and strategies regarding the diagnosis and management of hypertension in youth. Despite this important information, many gaps in knowledge remain, such as the etiology, prevalence, and trends of hypertension; the utility and practicality of ambulatory blood pressure monitoring; practical goals for lifestyle modification that are generalizable; the long-term end-organ impacts of hypertension in youth; and the long-term safety and efficacy of antihypertensive therapy in youth. The Eunice Kennedy Shriver National Institute of Child Health and Human Development, in collaboration with the National Heart, Lung, and Blood Institute and the US Food and Drug Administration, sponsored a workshop of experts to discuss the current state of childhood primary hypertension. We highlight the results of that workshop and aim to (1) provide an overview of current practices related to the diagnosis, management, and treatment of primary pediatric hypertension; (2) identify related research gaps; and (3) propose ways to address existing research gaps.

Comparison between broadband and monochromatic photopic negative response in full-field electroretinogram in controls and subjects with primary open-angle glaucoma.

PURPOSE: A prospective, cross-sectional, case-control study was conducted to investigate the role of broadband and monochromatic photopic negative response (PhNR) of the full-field flash electroretinogram (ERG) in the evaluation of ganglion cell damage in primary open-angle glaucoma (POAG) subjects. METHODS: Subjects with POAG and age-matched normal subjects were recruited from the outpatient department of a tertiary eye care center in South India. A total of 25 patients with POAG and 50 age-matched normal subjects were recruited. ERG was recorded using broadband (3.5 cd.s/m2 white stimulus on 10 cd/m2 white background) and monochromatic (3.5 cd.s/m2 red stimulus on 10 cd/m2 blue background and 1 cd.s/m2 blue stimulus on 10 cd/m2 yellow background) stimuli. RESULTS: The reduction in PhNR amplitude in POAG compared to normal individuals was higher in red-on-blue PhNR [26.37 µV; p < 0.001, confidence interval (CI) 19.34 to 33.4] as compared to broadband stimuli (16.41 µV; p < 0.001, CI 8.68 to 24.13), and blue on yellow (21.96 µV; p < 0.001, CI 10.12 to 33.8). Red-on-blue PhNR amplitudes correlated better with mean deviation (MD; r = - 0.66, p < 0.05), pattern standard deviation (PSD; r = - 0.4, p = 0.04), visual field index (VFI; r = - 0.58, p < 0.05), and retinal nerve fiber layer thickness (r = - 0.67, p < 0.05) in comparison with broadband and monochromatic blue-on-yellow PhNR. Receiver operating characteristic curve revealed largest area under the curve (0.89) in red-on-blue PhNR compared to broadband (0.76) and blue on yellow (0.74). The sensitivity and specificity was also higher in red-on-blue PhNR (72% and 80%, respectively) as compared to the other stimuli (sensitivity and specificity of broadband 0.68 and 0.7, blue on yellow 0.64 and 0.7, respectively). CONCLUSION: Correlation of PhNR with Humphrey visual field parameters and retinal nerve fiber layer thickness showed that red-on-blue PhNR can be a useful additional tool for clinical assessment of retinal ganglion cell dysfunction in glaucoma patients. Red-on-blue PhNR was more sensitive as compared to white-on-white and blue-on-yellow PhNR in identifying ganglion cell dysfunction and correlates well with other structural and functional tests for glaucoma such as MD, PSD, VFI, and RNFL thickness.

Effects of deferasirox dose and decreasing serum ferritin concentrations on kidney function in paediatric patients: an analysis of clinical laboratory data from pooled clinical studies.

BACKGROUND: Serious and fatal deferasirox-induced kidney injury has been reported in paediatric patients. This study aimed to investigate the effects of deferasirox dose and serum ferritin concentrations on kidney function and the effect of impaired kidney function on dose-normalised deferasirox minimum plasma concentration (Cmin). METHODS: We did a case-control analysis using pooled data from ten clinical studies. We identified transfusion-dependent patients with thalassaemia, aged 2-15 years, who were receiving deferasirox and had available baseline and follow-up serum creatinine and ferritin measurements. Cases of acute kidney injury (AKI) were defined according to an estimated glomerular filtration rate (eGFR) threshold of 90 mL/min per 1·73 m2 or less (if baseline eGFR was ≥100 mL/min per 1·73 m2), an eGFR of 60 mL/min per 1·73 m2 or less (if baseline eGFR was <100 mL/min per 1·73 m2), or an eGFR decrease from baseline of at least 25%. Cases were matched to control visits (eGFR ≥120 mL/min per 1·73 m2) on age, sex, study site, and time since drug initiation. We calculated rate ratios for AKI using conditional logistic regression, and evaluated the effect of eGFR changes on Cmin. FINDINGS: Among 1213 deferasirox-treated paediatric patients, 162 cases of AKI and 621 matched control visits were identified. Patients with AKI had a mean 50·2% (SD 15·5) decrease in eGFR from baseline, compared with a 6·9% (29·8) decrease in controls. A significantly increased risk for AKI (rate ratio 1·26, 95% CI 1·08-1·48, p=0·00418) was observed per 5 mg/kg per day increase in deferasirox dispersible tablet dose (equivalent to a 3·5 mg/kg per day dose of film-coated tablets or granules), above the typical starting dose (20 mg/kg per day). An increased risk (1·25, 1·01-1·56, p=0·0400) for AKI was also observed per 250 µg/L decrease in serum ferritin, starting from 1250 µg/L. High-dose deferasirox (dispersible tablet dose >30 mg/kg per day) resulted in an increased risk (4·47, 1·25-15·95, p=0·0209) for AKI when serum ferritin was less than 1000 µg/L. Decreases in eGFR were associated with increased Cmin. INTERPRETATION: Deferasirox can cause AKI in a dose-dependent manner. The increased AKI risk with high-dose deferasirox and lower serum ferritin concentration is consistent with overchelation as a causative factor. Small decreases in eGFR correlate with increased deferasirox Cmin, especially in younger patients. Physicians should closely monitor renal function and serum ferritin, use the lowest effective dose to maintain acceptable body iron burden, and interrupt deferasirox treatment when AKI or volume depletion are suspected. FUNDING: None.

Etiology and management of dyslipidemia in children with chronic kidney disease and end-stage renal disease.

Lipids are essential components of cell membranes, contributing to cell fuel, myelin formation, subcellular organelle function, and steroid hormone synthesis. Children with chronic kidney disease (CKD) and end-stage renal disease (ESRD) exhibit various co-morbidities, including dyslipidemia. The prevalence of dyslipidemias in children with CKD and ESRD is high, being present in 39-65% of patients. Elevated lipid levels in children without renal disease are a risk factor for cardiovascular disease (CVD), while the risk for CVD in pediatric CKD/ESRD is unclear. The pathogenesis of dyslipidemia in CKD features various factors, including increased levels of triglycerides, triglyceride-rich lipoproteins, apolipoprotein C3 (ApoC-III), decreased levels of cholesterylester transfer protein and high-density lipoproteins, and aberrations in serum very low-density and intermediate-density lipoproteins. If initial risk assessment indicates that a child with advanced CKD has 2 or more co-morbidities for CVD, first-line treatment should consist of non-pharmacologic management such as therapeutic lifestyle changes and dietary counseling. Pharmacologic treatment of dyslipidemia may reduce the incidence of CVD in children with CKD/ESRD, but randomized trials are lacking. Statins are the only class of lipid-lowering drugs currently approved by the U.S. Food and Drug Administration (FDA) for use in the pediatric population. FDA-approved pediatric labeling for these drugs is based on results from placebo-controlled trial results, showing 30-50% reductions in baseline low-density lipoprotein cholesterol. Although statins are generally well tolerated in adults, a spectrum of adverse events has been reported with their use in both the clinical trial and post-marketing settings.

Drug development for pediatric neurogenic bladder dysfunction: dosing, endpoints, and study design.

Pediatric drug development is challenging when a product is studied for a pediatric disease that has a different underlying etiology and pathophysiology compared to the adult disease. Neurogenic bladder dysfunction (NBD) is such a therapeutic area with multiple unsuccessful development programs. The objective of this study was to critically evaluate clinical trial design elements that may have contributed to unsuccessful drug development programs for pediatric NBD. Trial design elements of drugs tested for pediatric NBD were identified from trials submitted to the U.S. Food and Drug Administration. Data were extracted from publically available FDA reviews and labeling and included trial design, primary endpoints, enrollment eligibilities, and pharmacokinetic data. A total of four products were identified. Although all four programs potentially provided clinically useful information, only one drug (oxybutynin) demonstrated efficacy in children with NBD. The lack of demonstrable efficacy for the remainder of the products illustrates that future trials should give careful attention to testing a range of doses, using objectively measured, clinically meaningful endpoints, and selecting clinical trial designs that are both interpretable and feasible. Compiling the drug development experience with pediatric NBD will facilitate an improved approach for future drug development for this, and perhaps other, therapeutic areas.