Discrepancies between the Cockcroft-Gault and Chronic Kidney Disease Epidemiology (CKD-EPI) Equations: Implications for Refining Drug Dosage Adjustment Strategies.

INTRODUCTION: The dosages of many medications require adjustment for renal function. There is debate regarding which equation, the Chronic Kidney Disease Epidemiology (CKD-EPI) equation vs. the Cockcroft-Gault (CG) equation, should be recommended to estimate glomerular filtration rate. METHODS: We used a mathematical simulation to determine how patient characteristics influence discrepancies between equations and analyzed clinical data to demonstrate the frequency of such discrepancies in clinical practice. In the simulation, the modifiable variables were sex, age, serum creatinine, and weight. We considered estimated glomerular filtration rate results in mL/min, deindexed for body surface area, because absolute excretory function (rather than per 1.73 m2 body surface area) determines the rate of filtration of a drug at a given plasma concentration. An absolute and relative difference of maximum (±) 10 mL/min and 10 %, respectively, were considered concordant. Clinical data for patients aged over 60 years (n = 9091) were available from one hospital and 25 private laboratories. RESULTS: In the simulation, differences between the two equations were found to be influenced by each variable but age and weight had the biggest effect. Clinical sample data demonstrated concordance between CKD-EPI and CG results in 4080 patients (45 %). The majority of discordant results reflected a CG result lower than the CKD-EPI equation. With aging, the CG result became progressively lower than the CKD-EPI result. When weight increased, the opposite occurred. DISCUSSION: The choice of equation for excretory function adjustment of drug dosage will have different implications for patients of different ages and body habitus. CONCLUSIONS: The optimum equation for drug dosage adjustment should be defined with consideration of individual patient characteristics.

Deep Hypothermic Cardiac Arrest Treated by Extracorporeal Life Support in a Porcine Model: Does the Rewarming Method Matter?

OBJECTIVES: Extracorporeal life support (ECLS) is the reference rewarming technique of accidental deep hypothermic cardiac arrest (DHCA). This study was designed to examine the impact of different rewarming blood flow rates and temperature setting of ECLS on cardiopulmonary lesions after DHCA in a porcine model of accidental hypothermia. METHODS: Twenty-four pigs were cannulated for ECLS, cooled until DHCA occurred, and subjected to 30 minutes of cardiac arrest. During the rewarming phase, we compared a low blood flow rate of 1.5 L/min versus a high flow rate of 3.0 L/min as well as two-temperature-setting rewarming strategies: a temperature during ECLS adjusted to 5°C above the central core temperature versus 38°C maintained throughout the rewarming phase. Cardiac output, hemodynamics and pulmonary function parameters were evaluated. Biologic markers of ischemia-reperfusion injuries were analyzed at baseline and at the end of the experiment. RESULTS: DHCA occurred at 21.2 ± 2°C. There was a trend for better cardiac output in groups with high blood flow (p = 0.053), with no interaction between ECLS flow and temperature (p = 0.63), a trend toward lower pulmonary vascular resistance (PVR; p = 0.075) and a significant decrease in arterial PVR in groups with high blood flow (p = 0.013) with no interaction (p = 0.47 and p = 0.60 for PVR and arterial PVR, respectively). Serum interleukin-6, tumor necrosis factor-α, receptor for advanced glycation end products (RAGE), and neuron-specific enolase were significantly increased between baseline and endpoint. The increase in the serum RAGE concentration was higher in the 38°C rewarming temperature groups compared to 5°C above adjusted temperature. There were no other significant differences in biomarkers. CONCLUSIONS: We developed a porcine model of DHCA treated by ECLS. Our data suggest that cardiac output tended to improve with a high-flow-rate rewarming strategy while a high-temperature delta between core temperature and ECLS increased the RAGE markers of lung injury.

Post-conditioning with Cyclosporine A after a 24-hour cold ischemia in ex vivo reperfused pig lungs.

OBJECTIVE: To evaluate the effects of 1 and 5 µM of Cyclosporine A (CsA), administered 24 hours after a cold ischemic period, in an ex vivo reperfused pig lung model. METHODS: The experiments were performed in 15 pigs. Each pair of lungs was surgically separated. Extracorporeal perfusion and mechanical ventilation were started after a cold ischemia of 2 hours for one lung and 24 hours for the contralateral. We constituted three groups (n = 5 each): two groups for which the lung underwent a 24-hour ischemia received either 1 or 5 µM of CsA at the time of reperfusion, and a control group without CsA. For each group, lungs undergoing a 2-hour ischemia did not receive CsA. RESULTS: Reperfusion with either CsA increased the PO2 levels in a dose dependent manner, and reduced concentrations of the receptor for advanced glycation endproducts, compared to the control. The pulmonary arterial pressure, the capillary pressure, and the pulmonary vascular resistances were not increased, even with 5 µM of CsA. No significant change was shown on cytokines levels. DISCUSSION: Postconditioning with CsA improves lung function, after a 24-hour cold ischemic period. Either 1 or 5 µM seemed to be safe regarding the pulmonary vascular pressures and resistances.

Toxoplasma gondii infection can regulate the expression of tumour necrosis factor-alpha receptors on human cells in vitro.

The in vitro regulation of tumour necrosis factor (TNF)-alpha receptors during Toxoplasma gondii infection of human MRC5 fibroblasts and human myelomonocytic THP-1 cells was investigated. Cells were infected with the virulent RH of T. gondii. TNFR membrane receptors were analysed by flow cytometry with biotinylated TNF-alpha. Shedding of the soluble form of TNFR1 and TNFR2 in cell culture supernatants was measured by enzyme-linked immunosorbent assay, and expression of mRNA production of TNFR1 and TNFR2 was analysed by quantitative real-time polymerase chain reaction, 1 h after infection. In the MRC5 cell line, T. gondii infection did not induce any up- or down-regulation of membrane TNFRs, soluble TNFRs or mRNA of TNFRs. However, THP-1 cell infection with living parasites induced a significant soluble TNFR1 release by THP-1 cells after 1 h. We detected an approximately 50% up-regulation (P < 0.01) of soluble TNFR1 in infected THP-1 cells compared to controls. No change in soluble TNFR2 levels was observed in the same conditions. Moreover, infection decreased the level of TNF membrane receptors, but had no effect on TNFR1 and TNFR2 mRNA levels. TNFR modulation by T. gondii infection, in vitro, depends on the cell type. Furthermore, our data suggest that living parasites control the shedding of the soluble form of TNFR1. This mechanism may influence the role of TNF-alpha in toxoplasmosis.