Investigation of new biomarkers of kidney injury in renal transplant recipients undergoing graft biopsy.

AIM: Urinary and blood kidney biomarkers (BM) remain insufficient for early kidney injury detection. We aimed to compare new kidney BM with histopathological data in kidney allograft recipients. METHODS: Blood and urine samples were collected from consecutive adult patients just before graft biopsy. All kidney samples were classified according to the Banff 2007 classification. The diagnostic performance of 16 new BM was compared to those of urinary proteins, blood urea nitrogen, eGFR, and serum creatinine to identify histopathological groups. RESULTS: Two hundred and twenty-three patients were analyzed. Microalbuminuria and urinary proteins performed well to discriminate glomerular injury from slightly modified renal parenchyma (SMRP). Urinary neutrophil gelatinase-associated lipocalin (NGAL) had the best performance relative to SMRP (AUROC .93) for acute tubular necrosis (ATN) diagnosis. Other BM had a slightly lower AUROC (.89). For the comparison of ATN to acute rejection, several new urinary BM (NGAL, cystatin C, MCP1) and classical BM (eGFR, serum creatinine) gave similar AUROC values (from .80 to .85). Urinary NGAL values in patients with ATN were 10-time higher than those with acute rejection (P=.0004). CONCLUSION: The new BM did not outperform classical BM in the context of renal transplantation. Urinary NGAL may be useful for distinguishing between ATN and acute rejection.

Endothelial-protective effects of a G-protein-biased sphingosine-1 phosphate receptor-1 agonist, SAR247799, in type-2 diabetes rats and a randomized placebo-controlled patient trial.

AIMS: SAR247799 is a G-protein-biased sphingosine-1 phosphate receptor-1 (S1P1 ) agonist designed to activate endothelial S1P1 and provide endothelial-protective properties, while limiting S1P1 desensitization and consequent lymphocyte-count reduction associated with higher doses. The aim was to show whether S1P1 activation can promote endothelial effects in patients and, if so, select SAR247799 doses for further clinical investigation. METHODS: Type-2 diabetes patients, enriched for endothelial dysfunction (flow-mediated dilation, FMD <7%; n = 54), were randomized, in 2 sequential cohorts, to 28-day once-daily treatment with SAR247799 (1 or 5 mg in ascending cohorts), placebo or 50 mg sildenafil (positive control) in a 5:2:2 ratio per cohort. Endothelial function was assessed by brachial artery FMD. Renal function, biomarkers and lymphocytes were measured following 5-week SAR247799 treatment (3 doses) to Zucker diabetic fatty rats and the data used to select the doses for human testing. RESULTS: The maximum FMD change from baseline vs placebo for all treatments was reached on day 35; mean differences vs placebo were 0.60% (95% confidence interval [CI] -0.34 to 1.53%; P = .203) for 1 mg SAR247799, 1.07% (95% CI 0.13 to 2.01%; P = .026) for 5 mg SAR247799 and 0.88% (95% CI -0.15 to 1.91%; P = .093) for 50 mg sildenafil. Both doses of SAR247799 were well tolerated, did not affect blood pressure, and were associated with minimal-to-no lymphocyte reduction and small-to-moderate heart rate decrease. CONCLUSION: These data provide the first human evidence suggesting endothelial-protective properties of S1P1 activation, with SAR247799 being as effective as the clinical benchmark, sildenafil. Further clinical testing of SAR247799, at sub-lymphocyte-reducing doses (≤5 mg), is warranted in vascular diseases associated with endothelial dysfunction.

Inadequacy of current pediatric epinephrine autoinjector needle length for use in infants and toddlers.

BACKGROUND: Epinephrine injection represents the standard of care for anaphylaxis treatment. It is most effective if delivered intramuscularly, whereas inadvertent intraosseous injection may be harmful. The needle length in current pediatric epinephrine autoinjectors (EAIs) is 12.7 mm; however, the ideal needle length for infants and toddlers weighing less than 15 kg is unknown. OBJECTIVE: To determine the skin-to-bone distance (STBD) and skin-to-muscle distance (STMD) at baseline and after simulated EAI application in infants and toddlers (weighing 7.5-15 kg). METHODS: Study participants recruited from 2 North American allergy clinics underwent baseline and compression (10-lb pressure) ultrasonography of the anterolateral thigh with a modified ultrasound transducer mimicking the footprint and maximum pressure application of an EAI device. Ultrasound images, with clinical data masked, were analyzed offline for STBD and STMD in short-axis approach. RESULTS: Of 53 infants (mean age, 18.9 months; 54.7% male; 81.1% white; mean weight, 11.0 kg), 51 had adequate images for short-axis STBD measurements. In these infants, the mean (SD) baseline STBD was 22.4 (3.8 mm), and the mean (SD) STMD was 7.9 (1.7) mm. With 10-lb compression, the mean (SD) STBD was 13.3 (2.1) mm, and the mean (SD) STMD was 6.3 (1.2) mm. An EAI with a needle length of 12.7 mm applying 10-lb pressure could strike the bone in 43.1% of infants and toddlers in this cohort. CONCLUSION: Our data suggest that the optimal EAI needle length for infants and toddlers weighing 7.5 to 15 kg should be shorter than the needle length in currently available pediatric EAIs to avoid accidental intraosseous injections.

A generic operational strategy to qualify translational safety biomarkers.

The importance of using translational safety biomarkers that can predict, detect and monitor drug-induced toxicity during human trials is becoming increasingly recognized. However, suitable processes to qualify biomarkers in clinical studies have not yet been established. There is a need to define clear scientific guidelines to link biomarkers to clinical processes and clinical endpoints. To help define the operational approach for the qualification of safety biomarkers the IMI SAFE-T consortium has established a generic qualification strategy for new translational safety biomarkers that will allow early identification, assessment and management of drug-induced injuries throughout R&D.