Barriers and Advances in Kidney Preservation.

Despite the fact that a significant fraction of kidney graft dysfunctions observed after transplantation is due to ischemia-reperfusion injuries, there is still no clear consensus regarding optimal kidney preservation strategy. This stems directly from the fact that as of yet, the mechanisms underlying ischemia-reperfusion injury are poorly defined, and the role of each preservation parameter is not clearly outlined. In the meantime, as donor demography changes, organ quality is decreasing which directly increases the rate of poor outcome. This situation has an impact on clinical guidelines and impedes their possible harmonization in the transplant community, which has to move towards changing organ preservation paradigms: new concepts must emerge and the definition of a new range of adapted preservation method is of paramount importance. This review presents existing barriers in transplantation (e.g., temperature adjustment and adequate protocol, interest for oxygen addition during preservation, and clear procedure for organ perfusion during machine preservation), discusses the development of novel strategies to overcome them, and exposes the importance of identifying reliable biomarkers to monitor graft quality and predict short and long-term outcomes. Finally, perspectives in therapeutic strategies will also be presented, such as those based on stem cells and their derivatives and innovative models on which they would need to be properly tested.

Liver fibrosis staging with contrast-enhanced ultrasonography: prospective multicenter study compared with METAVIR scoring.

We prospectively assessed contrast-enhanced sonography for evaluating the degree of liver fibrosis as diagnosed via biopsy in 99 patients. The transit time of microbubbles between the portal and hepatic veins was calculated from the difference between the arrival time of the microbubbles in each vein. Liver biopsy was obtained for each patient within 6 months of the contrast-enhanced sonography. Histological fibrosis was categorized into two classes: (1) no or moderate fibrosis (F0, F1, and F2 according to the METAVIR staging) or (2) severe fibrosis (F3 and F4). At a cutoff of 13 s for the transit time, the diagnosis of severe fibrosis was made with a specificity of 78.57%, a sensitivity of 78.95%, a positive predictive value of 78.33%, a negative predictive value of 83.33%, and a performance accuracy of 78.79%. Therefore, contrast-enhanced ultrasound can help with differentiation between moderate and severe fibrosis.

Effect of human head flexion on the control of peripheral blood flow in microgravity and in 1 g.

This study evaluated, in six healthy subjects, whether head flexion, which stimulates the vestibular system and the tonic neck receptors, interferes with cardiovascular regulation. Arterial parameters were measured continuously using a pulsed Doppler ultrasound probe during parabolic flights with subjects either in the supine craned-head position (control) or in the supine anterior neck flexion bent-neck position. Exposure to 0 g induced a fluid shift towards the head (stroke volume +8%, P<0.05). Compared to the control situation the mean (SD) blood flow in the femoral artery decreased [ -10 (9)% vs +1 (10)%; P<0.05], and the ratio cerebral artery:femoral artery blood flow ( : ) increased [+8 (14)% vs -4 (7)%; P<0.05], in the bent-neck position. Thus, neck flexion without otolith loading (subject in 0 g) favoured cerebral perfusion during the exposure to 0 g. The return to 1 g, even in the supine position, induced a fluid shift towards the lower limbs. From 0 to 1 g, reduced less [ +6 (8)% vs -1 (8)%; P<0.05], and the : decreased more [-11 (9)% vs 0 (10)%; P<0.05], in the bent-neck position than in the control position. Thus the redistribution of peripheral blood flow in response to the fluid shift towards the legs was less efficient in the bent-neck position. In 0 g environment the passive flexion of the neck (neck receptor stimulation only) increased resistance in the femoral artery [ R(fa) +20 (21)%; P<0.05] and reduced the [-15(10)%; P<0.07] which increased the redistribution of flow towards the brain [; +12 (7)%; P<0.07]. This response was of lower amplitude when both otoliths and neck muscle were stimulated (neck flexion in 1 g) [ R(fa)+9 (7)%, P<0.05; -9 (12), NS; : 0 (12), NS]. We suggest that otolith and neck muscle stimulation (by neck flexion) trigger opposite vascular effects in response to a fluid shift towards the legs.

Influence of otoliths and neck muscle receptors on peripheral hemodynamic regulation.

To evaluate the cardiovascular changes induced by otoliths and neck mechanoreceptors stimulation during head movements, nine subjects in supine prone position performed passive head-down neck flexion (P.Ext) and head up P.Extension (P.Flex) As the lower limbs vasoconstricted from P.Ext to P.Flex, it is suggested that the otoliths stimulation towards the base of the head (like in standing position) contribute to reduce the vasoconstriction whereas when stimulated towards the top of the head (head flexion) they increase it.

Venous stagnation induced by 7 days in HDT, in the cerebral, ophthalmic, renal and splanchnic territories.

The scientific objectives was to quantify the vascular changes in the brain, eye fundus, renal parenchyma, and splanchnic network. Heart, portal, jugular, femoral veins were investigate by Echography. The cerebral mesenteric, renal and ophthalmic arteries were investigated by Doppler. Eye fundus vein an papilla were investigated by optical video eye fundus. The left ventricle volume decreased as usual in HDT. The cerebral and ophthalmic vascular resistances didn't change whereas the eye fundus papilla and vein, and the jugular vein increased. These arterial and venous data confirm the existence of cephalic venous blood stasis without sign of intracranial hypertension. On the other hand the kidney volume increased which is in agreement with blood flow stagnation at this level. At last the mesenteric vascular resistance decreased and the portal vein section increased in HDT which is in favor of an increase in flow and flow volume through the splanchnic area.

Effect of the thigh-cuffs on the carotid artery diameter jugular vein section and facial skin edema: HDT study.

OBJECTIVE: To evaluate the distal arterial, venous and skin changes in a group using thigh cuffs during daytime and in a control group. METHOD: Cardiac, arterial, venous parameters were measured by echography and Doppler. Skin thickness was measured by high frequency echography. RESULTS & DISCUSSION: Head down position induced plasma volume reduction, increased cerebral resistance, reduced lower limb resistance. The jugular vein increased whereas the femoral and popliteal veins decreased. All these changes were already observed in previous HDT. Common carotid diameter decreased, Front head skin thickness increased and Tibial skin thickness decreased. Eight hours with thigh cuffs increased the cardiac and carotid sizes which is in agreement with the plasma volume increase. Conversely they reduced the cerebral vascular resistance, jugular section and front head edema which may explain the sensation of comfort reported by the subjects. At the lower limb level the thigh cuffs restored the skin thickness to pre-HDT level but enlarged markedly the femoral and popliteal veins. HR, BP, CO, TPR did not change.

Effect of a venotonic agent on the main arteries and veins during a 5 day HDT.

OBJECTIVE: To evaluate the cardiac, arterial and venous effect of a venotonic drug (Cirkan "Ck") administrated orally daily to 6 subjects in HDT position during 5 days. These subjects underwent a second 5d HDT without Ck treatment one month later. Pre and post HDT the subjects were submitted to a stand test. METHOD: The cardiovascular parameters were measured by echography and Doppler. RESULTS AND DISCUSSION: The Cirkan treatment contributed to reduce the increase in cerebral resistance, and to maintain the lower limb resistance at a higher level than on controls. It reduces the vein section at the extremities (Jugular, femoral) and in the central vein system connected to the right heart (sub hepatics). On the other hand it increases the portal vein section which means that the blood stagnation at the splanchnic level is increased. Despite these arterial and venous significant modifications the clinical and ECG and Blood pressure response to the Stand test was similar in both groups.

Cardiac, cerebral & lower limb hemodynamic changes, during HDT (5 days to 42 d) & space flights (7 days to 6 months).

The objective was to identify the major cardiovascular changes induced by exposure to real or simulated 0 g (spaceflights: 6 days, 14 d, 21 d, 25 d, 6 months; Head Down Tilt: 10 h, 4 d, 5 d, 7 d, 30 d, 42 d), with a minimum of countermeasure (Daily exercise in space, no exercise in HDT).

3D realtime echography and echography assisted by a robotic arm for investigating astronauts in the ISS from the ground.

As human will stay for long duration in isolated sites like ISS there will be a need to perform quick and reliable diagnosis to evaluate the gravity of the pathology in presence of clinical symptoms. Many pathological situations (abnormal heart rate, pericardic collection, mitral prolaps, cholecystis, renal lithiasis, normal and ectopic pregnancies, ovarian cyst, acute appendicitis, phlebitis ... ) may occur even if all the astronauts are absolutely normal and healthy preflight. Ultrasound echography and Doppler are non invasive methods easy to use in space and very well adapted and used in routine for such diagnosis at the hospital. The objective of the present project was to design a method that guarantee a reliable echographic diagnostic in an isolated site (space station or earth site) by a Medical Doctor located at the expert site that should be the Nasa control center for ISS. It is supposed that there is only a non sonographer person in the isolated site and that the transmission system (audio, video, numeric..) is the only link between the 2 sites. Two options are proposed: (a) A 3D realtime acquisition echograph that can record quickly all the echos of a volume containing the organ suspected to have a lesion, all these echo information being sent to the ground and processed by the ground experts, (b) A robotic arm that hangs the echo probe in the isolated site tele-operated (through sattelite network) from the ground by an expert in clinical ultrasound. (As the expert moves the joystick of his ground computer the robotic arm reproduces the same movements on the probe).

Doppler measurement of cerebral and lower limb flow during a lower body negative pressure test for predicting orthostatic intolerance.

OBJECTIVE: To quantify the cardiovascular response to an orthostatic test for predicting orthostatic intolerance. METHODS: Cerebral and lower limb arterial flow and resistance were assessed by Doppler ultrasonography during lower body negative pressure (7 minutes each at -25 and -45 mm Hg). Cardiovascular deconditioning was induced by 42 days in head-down tilt at -6 degress (7 subjects) and 6-month spaceflights (10 cosmonauts). RESULTS: Orthostatic intolerance during a stand test was observed in 57% of the head-down-tilt subjects and 83% of the cosmonauts. At the lower body negative pressure after head-down tilt and during or after flight, the average cerebral flow velocity and vascular resistance did not change significantly from before head-down tilt and before flight. Conversely, there was a lack of lower limb arterial vasoconstriction (-24% from before head-down tilt and -43% from before flight; P < .01), and the cerebral-femoral flow ratio increased less (-27% from before head-down tilt and -52% from before flight; P < .01). The lack of vasoconstriction was more pronounced in intolerant subjects (-25% from before head-down tilt and -48% from before flight) compared with tolerant subjects (-22% from before head-down tilt and -14% from before flight; P > .01). Also, the lack of a cerebral-femoral flow ratio increase was more pronounced in intolerant subjects (-49% from before head-down tilt and -55% from before flight; P < .01) than in tolerant subjects (-1% from before head-down tilt and -33% from before flight; P < .01). The cerebral flow deficit at the lower body negative pressure before head-down tilt was greater than 8% in 3 of the 4 intolerant head-down-tilt subjects and less than 8% in the 3 tolerant subjects. The 3 cosmonauts who were intolerant after flight had a preflight cerebral flow deficit greater than 8%, whereas the tolerant cosmonaut had a cerebral flow deficit less than 8%. CONCLUSION: Lack of lower limb vasoconstriction and a lower cerebral-femoral flow ratio during lower body negative pressure in disadapted subjects were associated with orthostatic intolerance. A cerebral flow deficit during lower body negative pressure before disadaptation allowed measurement of the predisposition of the subjects to become intolerant.

Adaptation of the left heart, cerebral and femoral arteries, and jugular and femoral veins during short- and long-term head-down tilt and spaceflights.

The objective of this investigation was to identify the major cardiovascular changes induced by exposure to real or simulated Og (spaceflights: 6, 14, 21 and 25 days, and 6 months; head down tilt, HDT: 10 h, 4, 5, 7, 30 and 42 days), with a minimum of counter-measures. The following cardiovascular data were measured by echocardiography and Doppler ultrasonography: left ventricle end-diastolic volume (LVDV), stroke volume (SV), cardiac output (CO), ejection fraction (EF), middle cerebral artery flow velocity (Qca), femoral artery flow velocity (Qfa), cerebral vascular resistance (Rca), femoral vascular resistance (Rfa), jugular vein cross-sectional area (Ajv), femoral vein cross-sectional area (Afv), heart rate (HR), and mean blood pressure (MBP). LVDV remained decreased compared to pre-HDT or pre-flight levels after 1 week of spaceflight or HDT (-8 to -13%, P<0.05), EF did not change. HR tended to increase (5-10%) during spaceflight and HDT, whereas MBP tended to decrease during flight, but did not change in HDT. These findings are consistent with the existence of a moderate and stable hypovolemia. Qca and Rca fluctuated between +10 and -10% from pre-HDT or pre-flight values, and always showed opposing variations. There was no significant decrease in cerebral perfusion. Lower-limb resistance (Rfa) remained decreased (-5% to -18%, P<0.05) throughout the flights or HDT after week 1. Ajv remained significantly enlarged (+40% P < 0.05) after 1 week in spaceflight or in HDT. Afv was enlarged in spaceflight after week 1 (+15% to +35%, P<0.05), whereas it decreased after 4-5 days of HDT (-20% to -35%, P<0.05). The cardiovascular system reached a new and stable equilibrium during flight and HDT within less than 1 week. With the exception of the femoral vein, there was no significant difference in either the amplitude or the time course of the cardiovascular changes in both situations after 1 week.

Influences of thigh cuffs on the cardiovascular system during 7-day head-down bed rest.

Thigh cuffs, presently named "bracelets," consist of two straps fixed to the upper part of each thigh, applying a pressure of 30 mmHg. The objective was to evaluate the cardiac, arterial, and venous changes in a group of subjects in head-down tilt (HDT) for 7 days by using thigh cuffs during the daytime, and in a control group not using cuffs. The cardiovascular parameters were measured by echography and Doppler. Seven days in HDT reduced stroke volume in both groups (-10%; P < 0.05). Lower limb vascular resistance decreased more in the cuff group than in the control group (-29 vs. -4%; P < 0.05). Cerebral resistance increased in the control group only (+6%; P < 0.05). The jugular vein increased (+45%; P < 0.05) and femoral and popliteal veins decreased in cross-sectional area in both groups (-45 and -8%, respectively; P < 0.05). Carotid diameter tended to decrease (-5%; not significant) in both groups. Heart rate, blood pressure, cardiac output, and total resistance did not change significantly. After 8 h with thigh cuffs, the cardiac and arterial parameters had recovered their pre-HDT level except for blood pressure (+6%; P < 0.05). Jugular vein size decreased from the pre-HDT level (-21%; P < 0.05), and femoral and popliteal vein size increased (+110 and +136%, respectively; P < 0.05). The thigh cuffs had no effect on the development of orthostatic intolerance during the 7 days in HDT.

Effect of the thigh-cuffs on the carotid artery diameter jugular vein section and facial skin edema: HDT study.

Thigh cuffs, currently named "bracelets", consist of 2 straps fixed to the upper part of each thigh, applying a pressure of approximately 30 mmHg. Initially the thigh cuffs were designed and used to improve th comfort of the cosmonauts during their stay in zero g. Except a reduction of the "puffy face" aspect no other morphological nor hemodynamic significant change was reported even when the cosmonauts weared these thigh cuffs inflight for 10h per day during several weeks or months. The objective was to evaluate the distal arterial, venous and skin changes in a group of 8 subjects in HDT for 7 days and using thigh cuffs 8h during daytime, and in a control group also in HDT for 7d but not using cuff.