Non-invasive fibrosis assessments of non-alcoholic fatty liver disease associated with low estimated glomerular filtration rate among CKD patients: the Fukuoka Kidney disease Registry Study

Clinical and Experimental Nephrology - A growing body of evidence has shown that non-alcoholic fatty liver disease (NAFLD) is associated with chronic kidney disease (CKD). Non-invasive fibrosis...     

Impact of Multivascular Disease on Cardiovascular Mortality and Morbidity in Patients Receiving Hemodialysis: Ten-Year Outcomes of the Q-Cohort Study

Aim: Multivascular disease, indicating concurrent arteriosclerotic lesions in a number of different vascular beds, is an independent risk factor for recurrent ischemic events in the general population. However, the impact of multivascular disease on the risk of developing cardiovascular disease has not been fully evaluated in patients receiving hemodialysis.Methods: A total of 3,504 hemodialysis patients were prospectively followed for 10 years. In this study, multivascular disease was defined as the coexistence of coronary artery disease and stroke. We examined the relationship between multivascular disease and the occurrence of composite cardiovascular endpoint, consisting of cardiovascular death, nonfatal coronary artery disease, nonfatal stroke, and peripheral artery disease.Results: The proportion of participants with multivascular disease was 5.7% (n = 200) at baseline. During follow-up (median, 106.6 months; interquartile range, 50.1–121.8 months), 1,311 patients experienced the composite endpoint, which was defined as at least one of the following: cardiovascular death (n = 620), nonfatal coronary artery disease (n = 318), nonfatal stroke (n = 340), and peripheral artery disease (n = 257). Compared with the group with no history of cardiovascular disease, the risk of experiencing the composite endpoint increased significantly with higher numbers of injured vascular beds in patients with single vascular disease (hazard ratio, 1.68; 95% confidence interval, 1.49–1.89) and in those with multivascular disease (hazard ratio, 2.11; 95% confidence interval, 1.71–2.60). In a multivariable analysis, multivascular disease was an independent predictor of cardiovascular events, in addition to diabetes, aging, and hypertension.Conclusions: This study clearly demonstrated that multivascular disease was a powerful predictor for cardiovascular mortality and morbidity in patients receiving hemodialysis.     

Effect of recirculation on the recovery of cerebral metabolism after experimental cerebral ischemia in male and female spontaneously hypertensive rats

Lactate, pyruvate and adenosine triphosphate (ATP) concentrations in the brain were measured at the end of various periods of cerebral ischemia induced by bilateral carotid occlusion at 1-hour recirculation after the ischemia in spontaneously hypertensive rates (SHR). In both male and female SHR, a progressive and consistent increase in lactate and lactate/pyruvate ratio and a concomitant decrease in ATP were observed in the ischemic periods of 1, 3 or 5 h. Changes of these cerebral metabolites in females were two thirds to one half of those in males at corresponding periods of ischemia. At 1 h after recanalization of the occluded carotid arteries, metabolic derangements of the ischemic brain were little recovered in male SHR exposed to only 1-hour ischemia, whereas in female SHR the decreased ATP levels were recovered close to the nonischemic control level even after 7-hour ischemia. Furthermore, the increased lactate in female was attenuated to only one sixth of that in male at 1-hour recirculation after 5-hour ischemia. It is concluded that the recovery of the cerebral ischemic metabolism by reperfusion is better in female than male SHR, probably because of the smaller metabolic changes during the ischemic insult, and the fact that the degree as well as the duration of ischemia seem to be important factors for sufficient recovery from ischemic impairment of the brain.     

Protective effects of angiotensin II type 1 receptor blocker on cerebral circulation independent of blood pressure

Angiotensin II type 1 receptor (AT1R) blocker (ARB) has been reported to modify hypertensive cerebrovascular changes; however, it is not clear whether its protective effects are independent of blood pressure. The aim of this study was to clarify the role of AT1R-mediated signals in cerebral circulation by the chronic treatment with telmisartan, an ARB, at a dose that did not lower the blood pressure. Male spontaneously hypertensive rats (SHR) and Wistar Kyoto rats (WKY) were treated for 4 weeks from 16 weeks of ages with telmisartan (SHR-L: 0.3 mg/kg/day, SHR-H: 3 mg/kg/day, WKY-H: 3 mg/kg/day) or vehicle (SHR-V, WKY-V). Superoxide measured by a chemiluminescent assay or dihydroethidium fluorescence and vascular morphology were examined for the thoracic aorta (Ao), common carotid (CCA), middle cerebral (MCA) and basilar arteries (BA). After 4 weeks of treatment, the blood pressure significantly declined in SHR-H but not in SHR-L in comparison to SHR-V. The lower limit of cerebral blood flow (CBF) autoregulation, evaluated by hemorrhagic hypotension, was significantly lower in SHR-L and SHR-H than SHR-V. In both SHR and WKY, the superoxide levels in the arteries were significantly attenuated by both doses of ARB. ARB also reversed vascular hypertrophy in Ao, CCA and BA and the inward remodeling in MCA. These results suggest that chronic treatment with telmisartan may therefore improve CBF autoregulation with a restoration of the vascular structure and an attenuation of superoxide generation, even at a dose that does not lower the blood pressure.     

Effects of alpha- and beta-adrenergic blockers on the lower limits of cerebral blood flow autoregulation in spontaneously hypertensive rats

The effects of alpha- and beta-adrenergic blockers (phenoxybenzamine, PBZ and propranolol, PPL, respectively) on the cerebral (CBF) and cerebellar (CeBF) blood flow autoregulations were examined in spontaneously hypertensive rats. CBF and CeBF were measured during stepwise hemorrhagic hypotension using hydrogen clearance method. The lower limits of autoregulation for CBF beyond which blood flow was decreased steeply were 72% of the resting blood pressure level in the control, 56% in the PBZ treated group, and 80% in the PPL group. Similar tendency was observed in CeBF. These results indicate that PBZ leads to a downward shift while PPL to a slight upward shift of the lower limits of CBF and CeBF autoregulations, suggesting that alpha-adrenergic blockade has a favorable effect for the maintenance of cerebral blood flow during acute reduction of blood pressure.     

Hypothermia inhibits ischemia-induced efflux of amino acids and neuronal damage in the hippocampus of aged rats

Brain hypothermia has been reported to protect against ischemic damages in adult animals. Our goal in this study was to examine whether brain hypothermia attenuates ischemic neuronal damages in the hippocampus of aged animals. We also determined effects of hypothermia on ischemia-induced releases of amino acids in the hippocampus. Temperature in the hippocampus of aged rats (19–23 months) was maintained at 36°C (normothermia), 33°C (mild hypothermia) or 30°C (moderately hypothermia) using a thermoregulator during 20 min of transient forebrain ischemia. Cerebral ischemia increased extracellular concentrations of glutamate and aspartate by 6- and 5-fold, respectively, in the normothermic group. Mild and moderate hypothermia, however, markedly inhibited the rise of these amino acids to less than 2-fold. Elevation of extracellular taurine, a putative inhibitory amino acid, was 16-fold in the normothermic rats. Mild hypothermia attenuated ischemia-induced increase in taurine (10-fold), and moderate hypothermia inhibited the increase. Ischemic damages, evaluated by histopathological grading of hippocampal CA1 area 7 days after ischemia, was significantly ameliorated in the mild (1.3±0.5, mean±S.E.M.) and moderate hypothermic rats (0.8±0.3) compared with the normothermic ones (3.4±0.4). These results suggest that brain hypothermia protects against ischemic neuronal damages even in the aged animals, and the protection is associated with inhibition of excessive effluxes of both excitatory and inhibitory amino acids.     

A case of acute disseminated encephalomyelitis after renal transplantation]

We report a patient of acute disseminated encephalomyelitis (ADEM) in a recipient of renal transplantation. A 43-year-old man suffered from generalized convulsion and consciousness disturbance followed by coma on day 53 of after the transplantation. He was receiving several immunosuppressants, and an increase of serum antigen for cytomegalovirus was observed one day before the ictus. T2 and diffusion-weighted image of MRI showed high intensity lesions in the bilateral cerebral white matter, basal ganglia, thalamus, midbrain, pons and cerebellum. Examination of cerebrospinal fluid revealed elevated myelin basic protein level. The patient was diagnosed as having ADEM and was treated with methylpredonisolone pulse therapy in combination with intravenous immune globulin. He gradually recovered and became capable to eat and sit on a wheel chair. White matter lesions on MRI were also diminished. ADEM may occur in recipients of organ transplantation even if they have immunosuppressive treatment.     

Mortality and histological findings of the brain during and after cerebral ischemia in male and female spontaneously hypertensive rats

Mortality and pathological changes of the brain during and after cerebral ischemia induced by bilateral carotid artery occlusion (BCO) were studied in male and female spontaneously hypertensive rats (SHR). Systolic arterial blood pressure at rest was significantly higher in male SHR (228 +/- 13 mm Hg, mean +/- S.E.M.) than female (192 +/- 12) (P less than 0.05). The average survival time during permanent occlusion was 11 +/- 6 h (mean +/- S.D.) in male SHR and 17 +/- 7 in female (P less than 0.005), though the cumulative mortality during 24-h ischemia was not different between male (88%) and female SHR (84%). Severe ischemic changes of nerve cells in the brain, especially in the cortex and hippocampus, were observed in 50% of male SHR at 3-h ischemia, while only 15% was observed in female SHR even after 7-h ischemia. After the temporary ischemia followed by reperfusion for 24 h, the mortality was varied between male and female SHR; 0, 31 and 100% after 1-, 3- and 5-h ischemia, respectively, in male SHR and 0% after 1- to 3-h ischemia and 33% after 5- to 7-h ischemia, respectively, in female. Ischemic changes of the brain tissue, such as acidophilic cytoplasm, nuclear degeneration and intercellular edema, were more frequent and severe in male SHR than female after recirculation following 3- or 5-h ischemia. It is concluded that the mortality and post-ischemic viability seem to be determined by the duration of ischemia and also by the degree of the neuronal damage, and female SHR is more tolerated for ischemic insult in comparison to male SHR.     

Postischemic gene transfer of soluble Flt-1 protects against brain ischemia with marked attenuation of blood-brain barrier permeability.

Brain edema is a major and often mortal complication of brain ischemia. Vascular endothelial growth factor (VEGF) is also known as a potent vascular permeability factor and may play detrimental roles at the acute stage of brain infarction. Our goal in this study was to explore protective effects of gene transfer of soluble flt-1 (sFlt-1), a natural inhibitor of VEGF, on focal brain ischemia. Adenoviral vector encoding sFlt-1 or beta-galactosidase as control was injected into the lateral ventricle 90 mins after photochemical distal middle cerebral artery occlusion in male spontaneously hypertensive rats. The transduced sFlt-1 was released to the cerebrospinal fluid from the ventricular wall and significantly increased 6 h, 1 and 7 days after sFlt-1 transfection. One day after brain ischemia, sFlt-1 gene transfer significantly reduced infarct volume (by 35%), brain edema (by 35%), and blood-brain barrier permeability (Evans blue extravasation; by 69%) with diminished phosphorylation of focal adhesion kinase (FAKtyr397 and FAKtyr861) in the ischemic vessels. Seven days after ischemia, sFlt-1 gene transfer also significantly attenuated infarct volume (by 29%) and monocyte/macrophage infiltration (by 27%), although there were no reductions in angiogenesis by sFlt-1 overexpression. These results suggest that sFlt-1 gene therapy targeting brain edema in acute stage of brain ischemia may be useful for brain infarction.