OBJECTIVE

To investigate characteristics of clinical trials and results on safety and effectiveness reported in US Food and Drug Administration (FDA) documents for recently approved high risk cardiovascular devices compared with the characteristics and results reported in peer reviewed publications.

DESIGN

A search of the publicly available FDA database was performed for all cardiovascular devices that received premarket approval from 1 January 2000 to 31 December 2010. For each study listed in the premarket approval documents, a Medline search was conducted to obtain the corresponding publication.

MAIN OUTCOME MEASURES

Clinical trial characteristics, primary endpoints, and safety and efficacy results in the FDA documents and corresponding publications.

RESULTS

106 cardiovascular devices received premarket approval from 1 January 2000 to 31 December 2010. FDA premarket approval documents for these devices contained 177 studies, of which 86 (49%) had been published by 1 January 2013. These 86 publications corresponded to 60 distinct devices. The mean time from FDA approval to publication in a peer reviewed journal was 6.5 months (range -4.8-7.5 years). In 22 (26%) of the 86 compared studies the number of participants enrolled in the study differed in the FDA summary and the corresponding publications. Of 152 primary endpoints identified in the FDA documents, in the corresponding publications three (2%) were labeled as secondary, 43 (28%) were unlabeled, and 15 (10%) were not found. Among the primary results, 69 (45%) were identical, 35 (23%) were similar, 17 (11%) were substantially different, and 31 (20%) could not be compared.

CONCLUSIONS

Many clinical trials for high risk cardiovascular devices approved by the FDA remain unpublished. Even when trials are published, the study population, primary endpoints, and results can differ substantially from data submitted to the FDA.

INTRODUCTION

Several studies have demonstrated that renal transplantation in HIV positive patients is both safe and effective. However, none of these studies have specifically examined outcomes in patients with HIV-associated nephropathy (HIVAN).

METHODS

Medical records of all HIV-infected patients who underwent kidney transplantation at Johns Hopkins Hospital between September 2006 and January 2014 were reviewed. Data was collected to examine baseline characteristics and outcomes of transplant recipients with HIVAN defined pathologically as collapsing focal segmental glomerulosclerosis (FSGS) with tubulo-interstitial disease.

RESULTS AND DISCUSSION

During the study period, a total of 16 patients with HIV infection underwent renal transplantation. Of those, 11 patients were identified to have biopsy-proven HIVAN as the primary cause of their end stage renal disease (ESRD) and were included in this study. They were predominantly African American males with a mean age of 47.6 years. Seven (64%) patients developed delayed graft function (DGF), and 6 (54%) patients required post-operative dialysis within one week of transplant. Graft survival rates at 1 and 3 years were 100% and 81%, respectively. Acute rejection rates at 1 and 3 years were 18% and 27%, respectively. During a mean follow up of 3.4 years, one patient died.

CONCLUSIONS

Acute rejection rates in HIVAN patients in this study are higher than reported in the general ESRD population, which is similar to findings from prior studies of patients with HIV infection and ESRD of various causes. The high rejection rates appear to have no impact on short or intermediate term graft survival.

BACKGROUND

Tenofovir disoproxil fumarate (TDF) may cause acute kidney injury and proximal tubular dysfunction. However, no detailed studies document urinary phosphate wasting as a marker of TDF-induced tubulopathy.

METHODS

Records of HIV-infected patients with presumed TDF toxicity were reviewed. We describe the characteristics and clinical course of 15 patients who had documented elevated (>20%) fractional excretion of phosphate (FEphos).

RESULTS

Patients were predominantly Caucasian and male (73 and 80%, respectively), with a mean age of 56 years (range 38-76). Of the 15 patients, 11 had a estimated glomerular filtration rate (eGFR) of >90 mL/min/1.73(2) at time of TDF initiation. The mean duration of TDF therapy prior to diagnosis of TDF toxicity was 64 months. Mean FEphos was 34% (range 20-62). The mean eGFR at TDF initiation was 104 mL/min/1.73 m(2) [standard deviation (SD) 17.0] with a gradual decline to 69 mL/min/1.73 m(2) (SD 19.0) by the time of TDF discontinuation. Of 10 patients with repeated FEphos after TDF discontinuation, 9 had improvement of their FEphos. Of these individuals, 6 had normalization of their FEphos. Estimated GFR improved in 12 patients after discontinuation of TDF, though importantly, none returned to their baseline eGFR.

CONCLUSIONS

Urinary phosphate wasting is a sensitive marker for TDF-induced proximal tubulopathy and is associated with unrecognized and permanent renal function decline. Tubular dysfunction can develop after years of TDF therapy in those with normal kidney function at the time of drug initiation. This suggests that continuing vigilance be maintained in all those on TDF.

BACKGROUND

Inhalation of ambient levels of ozone causes airway inflammation and epithelial injury.

METHODS

To examine the responses of airway cells to ozone-induced oxidative injury, 19 subjects (7 with asthma) were exposed to clean air (0ppb), medium (100ppb), and high (200ppb) ambient levels of ozone for 4h on three separate occasions in a climate-controlled chamber followed by bronchoscopy with bronchoalveolar lavage (BAL) 24h later. BAL cell mRNA expression was examined using Affymetrix GeneChip Microarray. The role of a differentially expressed gene (DEG) in epithelial injury was evaluated in an in vitro model of injury [16HBE14o- cell line scratch assay].

RESULTS

Ozone exposure caused a dose-dependent up-regulation of several biologic pathways involved in inflammation and repair including chemokine and cytokine secretion, activity, and receptor binding; metalloproteinase and endopeptidase activity; adhesion, locomotion, and migration; and cell growth and tumorigenesis regulation. Asthmatic subjects had 1.7- to 3.8-fold higher expression of many DEGs suggestive of increased proinflammatory and matrix degradation and remodeling signals. The most highly up-regulated gene was osteopontin, the protein level of which in BAL fluid increased in a dose-dependent manner after ozone exposure. Asthmatic subjects had a disproportionate increase in non-polymerized osteopontin with increasing exposure to ozone. Treatment with polymeric, but not monomeric, osteopontin enhanced the migration of epithelial cells and wound closure in an α9β1 integrin-dependent manner.

CONCLUSIONS

Expression profiling of BAL cells after ozone exposure reveals potential regulatory genes and pathways activated by oxidative stress. One DEG, osteopontin, promotes epithelial wound healing in an in vitro model of injury.