Cerebral hyperperfusion is a relatively rare syndrome with significant and potentially preventable clinical consequences. The pathophysiology of cerebral hyperperfusion syndrome (CHS) may involve dysregulation of the cerebral vascular system and hypertension, in the setting of increase in cerebral blood flow. The early recognition of CHS is important to prevent complications such as intracerebral hemorrhage. This review will focus on CHS following carotid endarterectomy and carotid artery stenting. We will discuss the typical clinical features of CHS, risk factors, pathophysiology, diagnostic modalities for detection, identification of patients at risk, and prevention and treatment. Although currently there are no specific guidelines for the management of CHS, identification of patients at risk for CHS and aggressive treatment of hypertension are recommended. Occurrence within 30 days post-CEA; Clinic features such as new onset headache, seizure, hemiparesis, and glasgow coma scale (GCS) <15 or radiological features including cerebral edema or intracerebral hemorrhage (ICH); Evidence of hyperperfusion  on imaging studies  or systolic blood pressure >180 mmHg ; and No evidence of new cerebral ischemia, postoperative carotid occlusion and metabolic or pharmacologic cause.Cerebral hyperperfusion syndrome (CHS) is a relatively rare condition after carotid endarterectomy (CEA) or carotid artery stenting (CAS) but is potentially preventable. CHS may be defined as focal cerebral damage following a revascularization procedure, usually as a result of hyperperfusion. Bouri et al. suggest the following four criteria to define post-CEA CHS : OccurreHyperperfusion has been reported in 0.2 to 18.9 % of cases following CEA .The term CHS has often been used interchangeably with cerebral reperfusion injury, and some authors argue that the latter term is more appropriate.The pathophysiology of reperfusion related injury is not entirely clear, however, it is believed that dysregulation of the cerebral vascular system and hypertension resulting in an increase of CBF play a significant role.Early recognition of CHS is important as it may be reversed at an early stage. Initially the edema associated with CHS is reversible, however, if CHS progresses to ICH the prognosis is not nearly as favorable as up to 30 % of patients remain at least partially disabled, and mortality rates are up to 50 % , 5.This review will focus on CHS following CEA and CAS. Specifically, we will discuss the pathophysiology, diagnostic modalities for detection and identification of patients at risk, and prevention and treatment of CHS.The exact mechanism of CHS after CAS or CEA remains unclear but seems to be multi-factorial.The normal brain has the ability to maintain constant intracranial pressure by an autoregulatory mechanism, when a change in blood flow occurs. Waltz in 1968 first described the impact of changes of systemic blood pressure on CBF in ischemic and non-ischemic cortex in a cat model of middle cerebral artery occlusion [Sundt and colleagues reviewed CBF in 1145 patients who underwent carotid endarterectomy from 1972 to 1981 [Bernstein and colleagues described a 56-year-old man with a high-grade left carotid stenosis who had left CEA . The patPostoperative hypertension in the setting of impaired autoregulation may cause an increase in cerebral perfusion pressure (CPP) as CPP is dependent on mean arterial pressure. Acute increase in CPP in areas of infarcted/necrotic or hypoperfused tissue can lead to ICH. This may be more pronounced when there is impaired vasoreactivity of cerebral vasculature and inability of arterioles to constrict in the setting of increased perfusion resulting in ICH .In general, patients with severe carotid artery stenosis often have underlying systemic hypertension and undergo CEA to reduce the risk of stroke in a vascular bed that may be subject to chronic cerebral ischemia. Baseline chronic hypertension might play a major role in the development of CHS. Preoperative longstanding hypertension leads to endothelial dysfunction and microangiopathy which can result in a breakdown of the blood brain barrier (BBB). Breakdown of the BBB was observed previously in an animal model of cerebral hyperperfusion . There iA presumed mediator of impairment of autoregulation and dysfunction of BBB in CHS is nitric oxide, which leads to vasodilatation and increases in cerebral vessel permeability . Dohare Baroreceptor dysfunction is also known as baroreflex failure syndrome (BFS). This can be related to baroreceptor denervation after bilateral CEA and may lead to CHS. Baroreceptor dysfunction can also cause a progressive increase in blood pressure after CEA which is challenging to control even with blood pressure lowering therapy. Fluctuations in blood pressure after CEA can last up to 12 weeks due to baroreceptor denervation. One study showed that 6.6 % of patients with bilateral CEA developed CHS as compared to 1.1 % of patients with unilateral CEA. Therefore, contralateral CEA performed within 3 months of CEA on the other side increases the risk of CHS –18.Sometimes, there is carotid baroreceptor stimulation during a carotid artery endovascular procedure via a balloon or carotid stent manipulation. The stimulation results in transient bradycardia and hypotension leading to cerebral ischemia. In some situations, the stimulation can be quite prolonged even more than that seen in patients with CEA during clamping of the internal carotid artery. These patients are at risk of CHS due to rebound arterial hypertension and also due to cerebral ischemia that occurs during the procedure , 19.Key points about the pathophysiology of CHS are listed in Table There are several imaging modalities and techniques used to investigate patients for CHS. These include but are not limited to transcranial doppler (TCD), computerized tomography (CT), magnetic resonance imaging (MRI), MR perfusion (MRP) and single-photon-emission CT (SPECT).TCD is the most commonly and widely available technique that can be used for the evaluation and prediction of the risk of CHS in preoperative, perioperative and postoperative phases. The main advantage of TCD is that it is non-invasive and provides real-time information. One may observe preoperative cerebral hypoperfusion and postoperative cerebral hyperperfusion. Also, TCD detects cerebral embolic signals that may lead to ischemia , 3.TCD measures CBF velocity in the middle cerebral artery (MCA) and can be of value in predicting a difference in CBF in patients with CHS. Auto-regulation has no effect on the diameter of the MCA. Therefore, changes in MCA flow velocity correlate nicely with changes in MCA perfusion. If there is a significant reduction in CBF velocity of intracranial blood vessels in the preoperative phase as compared to baseline values, it will be associated with postoperative hyperperfusion. On the other hand, a 1.5-fold postoperative increase of MCA mean flow velocity compared with preoperative levels may predict the occurrence of CHS , 20.Other TCD criteria for the prediction of postoperative hyperperfusion in patients with recent CEA have been defined. These include low perioperative distal carotid artery pressure (<40 mmHg), and an increase in peak blood flow velocity and pulsatility index of >100 % after declamping of the carotid artery in CEA , 21, 22.Moreover, cerebral vasoreactivity can predict the risk of CHS, and this can be measured using TCD. In a normal person, the administration of carbon dioxide or acetazolamide will lead to a rapid increase in CBF ranging from 20 to 80 % due to dilatation of cerebral blood vessels. In patients with chronic cerebral ischemia, the cerebral blood vessels are already maximally dilated, and there is no significant change in CBF after the administration of carbon dioxide or acetazolamide. This is called low or impaired cerebral hemodynamic reserve. Using TCD, patients with low preoperative cerebrovascular reserve are at risk of developing cerebral hyperperfusion and CHS , 23, 24.Also, it has been shown that TCD-derived low intraoperative distal internal carotid artery pressure (d ICAP) (<40 mmHg) has a high predictive value for postoperative hyperperfusion and CHS . MoreoveThe limitations of TCD should be kept in mind, and these include but are not limited to various technical problems such as an insufficient cranial window for insonation, variations of intracranial blood vessels forming the circle of Willis making insonation difficult, and cervical vessels which can affect velocities of intracranial vessels.CT of the brain completed right after CEA can be completely normal in patients with CHS. Later on, findings develop which may include diffuse cerebral edema, patchy white matter changes, mass effect, and intracerebral hemorrhage Fig. . These cMRI of the brain is more sensitive to detect ischemic changes but not necessarily to predict the risk of CHS. MRI abnormalities can be similar to those seen on CT of the brain including white matter edema, focal infarction or hemorrhage Fig. . HoweverMR perfusion scan can show a difference in CBF in the cerebral hemispheres. Measurement of preoperative CBF by using perfusion-weighted imaging can help identify patients at risk of cerebral hyperperfusion after CEA in the absence of contralateral internal carotid artery stenosis. Fukuda et al. showed a significant correlation between preoperative CBF and increase in CBF immediately after CEA (p < 0.0001). They studied the relationship between hyperperfusion immediately after CEA and elevated preoperative cerebral blood volume and noted that no patient with normal preoperative cerebral blood volume showed post-CEA hyperperfusion. Furthermore, elevated preoperative cerebral blood volume was the only significant independent predictor of post-CEA hyperperfusion , 3, 25.Single-photon-emission CT of the brain is a sensitive method to identify patients at risk of hyperperfusion after CEA and for recognizing CHS. It helps to differentiate between brain ischemia and hyperperfusion. Similar to TCD, it can help determine CBF reserve after carbon dioxide or acetazolamide administration and also detect postoperative cerebral hyperperfusion, especially if hyperperfusion persists between the 1st and 3rd postoperative day. Ogasawara et al. showed that intraoperative MCA blood flow velocity monitoring by using TCD was a less reliable method to detect cerebral hyperperfusion after CEA than postoperative MCA blood flow velocity monitoring by SPECT. In this study, TCD monitoring could not be completed in one out of seven patients diagnosed with post-CEA hyperperfusion on SPECT imaging and who later developed CHS. SPECT technique is superior to TCD when there is occlusion or hemodynamically significant stenosis of the ipsilateral MCA –28.Features of key imaging modalities in the diagnosis of CHS are listed in Table Preventive strategies for CHS include proper blood pressure control in the perioperative period, and consideration of timing of surgery, type of anesthesia, and use of free radical scavengers. These strategies are discussed below.An important factor in the prevention of CHS is proper control of blood pressure. It may be prudent to carefully monitor blood pressure in patients with increased CBF as hypertension may subsequently develop postoperatively even in normotensive patients. Blood pressure control in patients with CHS may be challenging, and even when there is normal blood pressure, CHS can occur. Therefore, whereas it is recommended to have careful control of blood pressure, there are no definitive guidelines about the target blood pressure in these patients and for how long blood pressure needs to be controlled , 29, 30.One should be cautious when selecting a drug for blood pressure control in these patients as some of the anti-hypertensives with vasodilatory effects may worsen the outcome. Medications in the latter group include calcium channel blockers, sodium nitroprusside, glycerol trinitrate, and angiotensin II inhibitors. Beta-blockers reduce arterial blood pressure and have little effect on the intracranial pressure within the autoregulatory range. Therefore, beta-blockers potentially can be used to treat hypertension in patients with brain injury. A limitation to some of the early generation beta-blockers is that they may be associated with blood pressure variability. However, other medications which may be more suitable for these patients include mixed alpha-adrenergic antagonists and beta-adrenergic antagonists such as labetalol. These medications help reduce cerebral perfusion pressure and mean arterial pressure without any direct effect on CBF. Patients with CHS may have elevated catecholamine concentrations. Therefore, medications like clonidine, a centrally acting sympatholytic, may be useful. Blood pressure in patients with CHS should be controlled with either labetalol or clonidine, which do not increase CBF , 19, 21.According to the American Heart Association and American Stroke Association Guidelines, the benefit of CEA is greatest if it is done within 2 weeks of the ischemic stroke or transient ischemic attack . HoweverSome of the general anesthetics may lead to cerebral hyperperfusion and increase the risk of CHS. Therefore, one should be careful when selecting an anesthetic and its dose as high doses of a volatile halogenated hydrocarbon anesthetic may lead to the development of CHS. Some anesthetics such as isoflurane are favorable when used in patients with cerebral injury as these have a vasodilatory effect on cerebral blood vessels. However, the effects of isoflurane on the cerebral metabolic rate and cerebral autoregulation are dose dependent, and this should be kept in mind as higher doses can potentially lead to CHS. Similarly, nitrous oxide is a safe anesthetic at a concentration of less than 70 % and has no significant effect on cerebral autoregulation. A combination of anesthetics may lead to complications. For example, nitrous oxide combined with isoflurane may cause cerebral vasodilation. Other anesthetics, such as propofol, normalize CBF which may result from its effect on cerebral metabolism, and thus, it can potentially be used in patients with CHS , 33–35.There is no indication for prophylactic use of anti-epileptic drugs in patients with CHS. However, if a patient has periodic lateralized epileptiform discharges on EEG or a clinical seizure spell, treatment with an anti-epileptic drug may be indicated , 3, 36.As mentioned above, oxygen-derived free radicals can lead to brain injury in patients with CHS. Free radical scavengers such as edaravone may minimize this damage. Edaravone inhibits lipid peroxidation and vascular endothelial damage. In one case series, use of edaravone helped to reduce the incidence of CHS after CEA as measured by SPECT . The eviIn patients with cerebral edema, mannitol and hypertonic saline may be used. However, the evidence for the use and potential beneficial effect of these medications in patients with CHS and their effect on long-term prognosis is not clear. Other treatments such as corticosteroids and barbiturates have been administered in select patients. In patients with cerebral edema, adequate sedation and hyperventilation may also be effective , 28, 38.Strategies for the prevention and treatment of CHS are listed in Table CHS is a potentially life-threatening complication of CEA and carotid stenting. It can happen within a few days postoperatively, but presentation can be delayed for weeks. Timely diagnosis and treatment are necessary. If these patients are treated early, they may do better as there may be minimal complications and a good recovery. However, with a delay in diagnosis, the mortality rate may be up to 50 %, especially in those patients who develop ICH. Patients with CHS may develop headache, focal neurological deficits, cerebral edema, brain hemorrhage and seizures. Most of the patients have hyperperfusion. However, a minimal to moderate increase in brain perfusion can lead to CHS.Clinicians should be aware of the main putative risks for CHS such as high-grade carotid artery stenosis, poor collateral blood flow, post-operative hypertension and hyperperfusion, impaired cerebrovascular reserve, intra-operative distal carotid pressure of <40 mmHg, intraoperative ischemia, and recent contralateral CEA. TCD is the most commonly and widely available technique used in the perioperative period to monitor for cerebral hyperperfusion. Control of blood pressure with labetalol and clonidine may be useful for the prevention and treatment of CHS , 3, 18.


After birth asphyxia, a variety of hemodynamic disorders may be noted in the neonatal intensive care unit; these require appropriate recognition and management. The present study was designed to demonstrate the prevalence of heart complications amongst asphyxiated newborns.Through a cohort study, 29 asphyxiated term neonates were followed since birth until amelioration of pulmonary hypertension and compared with 31 well born neonates. Both groups were evaluated for their heart anatomy and hemodynamic with meticulous assessment through echocardiography. This study was conducted in Besat Medical Center since August 2010 until February 2012.Hemodynamic and anatomic disorders including myocardial dysfunction, pulmonary hypertension and patent arterial duct (PDA) were strongly associated with birth asphyxia (P< 0.05).Birth asphyxia was associated with systolic and diastolic dysfunction and pulmonary hypertension which demands precise evaluation, early recognition and appropriate management. Birth asphyxia is defined as metabolic acidemia due to decreased oxygen transfer through the placenta or neonatal respiratory tract with intrapartum pH of less than 7.00 and base deficit greater than 12 mmol/l.6The aim of this study was to evaluate asphyxiated neonates for possible occurrence of cardiovascular disorders.Overall, 29 asphyxiated term neonates were followed since birth and compared with 31 well newborns for cardiovascular complications in the neonatal intensive care unit of Besat hospital since August 2010 until February 2012. In both groups first echocardiography was performed in the first or second day after birth. Follow up echocardiography was done at least once a week until improvement of pulmonary hypertension or minimum one month. In a few patients (2 patients) echocardiography evaluation was scheduled for more than one month due to prolongation of pulmonary hypertension. All neonates were between 38 to 41 weeks of gestational age determined by the last menstrual period (LMP) or ultrasound method. Besat hospital is the referral center for the neonatal intensive care in Sanandaj, the capital of Kurdistan province. Asphyxiated neonates were categorized into two groups of moderate and severe types.8We excluded neonates with congenital heart disease other than patent arterial duct and patent foramen oval from this study. Likewise, patients with congenital or acquired lung disease were omitted. Moreover, patients with other organ anomaly or chromosomal disorders and those with early septicemia were not considered in this study.t- test for normally distributed variables. The Chisquare and Fisher exact test were used to compare categorical variables. All P-values lower than 0.05 were considered significant with SPSS 20. The study was approved by the Ethical Committee of Kurdistan University of Medical Sciences.Univariate analysis was used to compare variables for the outcome groups of interest. Continuous variables were compared using Student’s In birth asphyxia group eleven patients (37.9%) were female and eighteen (62%) males. Comparing with healthy controls, although asphyxia was numerically more common in males, it was not statistically significant (P=0.132).Patent arterial duct was a common finding in asphyxiated neonates (62%), whereas, only one normal newborn had patent arterial duct which shows significant relationship between asphyxia and this complication (P<0.001)  and II. There was a prominent relationship between tricuspid valve regurgitation and asphyxia (P=0.003) . On the Mitral valve regurgitation was relatively rare among the asphyxiated group; however, moderate regurgitation was found in one patient with moderate asphyxia and in two others with severe type (P=0.06) .About one third of asphyxiated neonates had different levels of systolic dysfunction. Statistical assessment showed positive relationship between severity of asphyxia and systolic dysfunction (P=0.01 and 0.001) Tables  and II. Pulmonary hypertension was present in near two-thirds of asphyxiated neonates. All of our patients with severe asphyxia had different levels of pulmonary hypertension, whereas, pulmonary hypertension was present in 57% of those with moderate asphyxia. Statistical analysis showed significant relationship between increased pulmonary hypertension and asphyxia (P<0.001) .There was no statistical relationship between weight and other variables including patent arterial duct, tricuspid regurgitation, and pulmonary hypertension, systolic and diastolic dysfunction. Antero posterior chest X ray was commonly abnormal in asphyxiated neonates particularly those with severe type (P<0.001) showing increased cardio thoracic ratio or pulmonary vascular marking.In this study, we tried to evaluate cardiovascular complications after birth asphyxia especially by accurate echocardiographic assessment. Ventricular diastolic dysfunction was present in more than half of the neonates with either moderate or severe asphyxia; however, patients with severe asphyxia had higher grade of diastolic dysfunction. Likewise, systolic dysfunction was statistically affected by asphyxia. The degree of asphyxia determines the severity of cardiac dysfunction as it may be ignorable in mild hypoxia.Patent arterial duct is a common finding after birth asphyxia, as indicated in this study (62%). Its mechanism has been studied on the asphyxiated lambs.10Our study showed high prevalence of pulmonary hypertension in asphyxiated neonates. Likewise, higher pulmonary pressure was associated with more hemodynamic instability. Pulmonary hypertension of neonates may play a role in rapid development of right and left ventricular dysfunction by their remodeling through reduced cardiolipin biosynthesis and remodeling enzymes.21Neonatal asphyxia causes a variety of cardiovascular disturbances including myocardial dysfunction and “transient pulmonary hypertension”. These hemodynamic abnormalities are real risks to the neonate; therefore, they deserve enough attention and early recognition for timely and appropriate management. Echocardiographic evaluation is warranted and the importance is emphasized


Objective: To evaluate association of blood and seminal plasma lead and cadmium with sperm quality of non-occupationally exposed male partners of couples with infertility. Materials and methods: A cross-sectional study was conducted on 75 men aged 20-45 years (mean = 37.1 ± 7.0 yrs.) with infertility recruited from the Fertility Clinic of a hospital in Abakaliki. Sperm count done in accordance with the WHO guidelines was used to classify the participants as normospamia, oligospermia and azospermia. Atomic absorption spectrophotometer was used to determine lead and cadmium levels in plasma from blood and semen.Results: There were 15 azospermics, 22 oligospermics and 36 normospermics. Seminal and blood plasma cadmium as well as blood plasma lead were significantly (p < 0.01) higher in azospermic and oligospermic men compared to normospermic men. However, while seminal plasma lead was significantly (p < 0.05) higher in oligospermic and normospernic men than in azospermic men, the seminal plasma lead was comparable between oligospermic and normospermic men. Significant inverse associations (p < 0.01) were found between blood and seminal cadmium levels and sperm count, motility and morphology; blood lead was inversely correlated with sperm count only.Conclusion: The study suggests that environmental exposure to cadmium and lead may contribute to development of poor sperm quality and infertility in men of reproductive age in Nigeria. Infertility presents a worldwide reproductive health problem and its etiologic cause remains elusive. According to the WHO, infertility is the inability of a sexually active couple to achieve spontaneous pregnancy in one year of regular unprotected intercourse . EpidemiThere is growing reproductive health concern about the considerable decrease in sperm quality and fertility. Although the cause of male infertility is understood in some cases of underlying pathological conditions, most cases are due to poor semen quality or sperm abnormalities of unknown causes . In receThe cause for the over 12 million infertile men and women in Nigeria is largely unknown . AlthougRecruitment of subjects: This cross-sectional study investigated men aged 20–45 years. Seventy-five (75) male partners of women consulting for infertility at the Fertility Clinic Unit, Department of Obstetrics and Gynecology of Our Lady’s Hospital, Abakaliki, South-East Nigeria between July and November, 2014 were recruited for enrolment in this study. The men with primary and secondary infertility were referred for semen analysis. Sociodemographic data and obstetric history were obtained by structured questionnaire. Body mass index (BMI) for each participant was calculated based on height and weight. Inclusion criteria: We included males of couples living together with regular unprotected coitus for at least a period of ≥ 1 year without conception.Exclusion criteria: Medical examination of potential participants was performed. Males with genital infection, use of contraceptives, and testicularvaricocele, and smoking/chronic alcohol intake, micronutrient supplementation for the last three months, surgery, and chronic illness including endocrine diseases were excluded from the study. Men currently on fertility drugs and those that are occupationally exposed to toxic metals were also excluded.Study consent/Ethical approval: A written consent of each participant that merited our selection criteria was taken after explaining the aim and objectives of the study and its benefits on individual and society. Also, the Ethics and Research Committees of the Federal Teaching Hospital, Ebonyi State University, Abakaliki approved the study protocols.Collection of Blood and Semen: Semen samples were obtained in private by masturbation into a sterile wide-mouth and metal-free glass container after 3 days of sexual abstinence. Collection of spilled semen and prior use of antibiotics were avoided. Fasting venous blood (5.0 ml) was also collected from each participant into heavy metal-free lithium-heparin sample bottle for determination of lead and cadmium. The samples were centrifuged at 2000 g for 5 minutes after which plasma was isolated and stored frozen (-20OC) until analysis.Semen parameter analysis: Standard semen parameters  were immediately evaluated according to guidelines of the WHO Laboratory Manual for the Examination of Human Semen  was used to determine the concentrations of lead and cadmium in seminal and blood plasma.Statistical analysis: The data obtained were statistically evaluated using statistical package for Social Science Program (SPSS®) for Windows® version 20.0. Values are represented as mean ± standard deviation for all variables. One-way analysis of variance (one-way ANOVA) was used to compare the means while relationships between parameters were determined using Pearson correlation analysis. Values were considered statistically significant at p value <0.05.Demographic characteristics: Seventy-three (73) males conforming to the inclusion criteria were recruited in the study. All participants were married and infertile couples without occupational exposure to Pb and Cd. Based on sperm concentration, we found normospermia , oligospermia (22 men) and azoospermia (15 men). The males ranged in age from 20 to 45 years with a mean age of 37.1 (SD = 7.0 yrs). As shown in Seminal parameters: From 6 cell/ml) was significantly higher (p = 0.00) than the azoospermics (0.00 ×106 cell/ml) and oligospermics (10.86 × 106 cell/ml), whereas the percentage total motility and morphology were not significantly different except in azoospermics.Cadmium and lead levels in blood and seminal plasma: From Correlation of lead and cadmium with seminal parameters:However, in Correlation of lead and cadmium with seminal parameters:Trends in male reproductive health have been reported for acute decline in semen quality and fertility, which have been associated with occupational and environmental chemical exposure based on animal and human studies . AlthougThis study investigated association of blood and seminal plasma Cd and Pb concentrations with semen quality in non-occupationally exposed infertile Nigerian men undergoing infertility evaluation. The overall results of this study indicate that even considerably low levels of blood and seminal plasma Pb (0.44–2.05 μg/dl) and Cd (0.43–1.14 μg/dl) might reduce the human semen quality. We found that Cd and Pb levels in azoospermic and oligospermic blood and seminal plasma were significantly higher compared to normospermic men . This maOmu et al. reported non-significant association of Cd with semen parameters in normozoospermic, oligozoospermic and azoospermic men . ReportsExisting reports on the role of Pb in male infertility is still unclear and available papers are controversial , 26, 34.Conclusion: We found some significant relationships between Pb and Cd and semen quality in the present study. Our results suggest that environmental exposure to Pb and Cd may adversely affects fertility in men resident in Abakaliki, Southeastern Nigeria.


P = 0.014), ejection duration (P = 0.045), and lower SEVR (P = 0.035) than DD homozygotes. Multiple regression analysis adjusted for age, body mass index, heart rate, and blood pressure confirmed these results. Further sex stratified analysis showed that the associations existed only in men (n = 33) whereas in women (n = 30) the differences were suggestive (P < 0.1). It is concluded that in a northern Russian population men carrying I allele have stiffer arteries, shorter diastole duration, and impaired coronary perfusion and seem to be at higher risk for cardiovascular diseases than DD carriers.The ADRA2B gene 301–303 I/D polymorphism is associated with various cardiovascular phenotypes. However, an association of genotypes with the timing structure of cardiac cycle remains unclear. The central hemodynamic parameters were assessed by pulse wave analysis in 63 residents of the Kola Peninsula (68 N) aged 27–65 yr. The genotypes were determined by PCR. The paired comparisons revealed that II genotype carriers had higher values of augmentation index ( Vascular alpha2-adrenergic receptors (ADR) postsynaptically mediate physiological responses to endogenous catecholamines and cause arterial and venous vasoconstriction in skeletal muscles and in the heart . It is tUnlike the majority of genetic studies that have investigated or reviewed pressure amplitudes  or pulseNOS3, beta-adrenergic receptor genes. The latter are known to mediate positive inotropic and chronotropic effects and are responsible for differences in cardiac autonomous nervous system functions.The contribution of gene polymorphisms to the variance of arterial distensibility phenotypes has been addressed in many studies. Among them are those describing the influence of angiotensin-aldosterone genes, matrix metalloproteinase genes, endothelial cell-related genes, e.g., ADRA2B gene polymorphisms have been found to determine physiological parameters other than cardiovascular phenotypes but indirectly influencing them. This consideration illustrates the complexity of the genetic regulation of the parameters explored in the present study and explains the supposed weakness of effects.In their turn, We examined 63 apparently healthy Russian individuals of Caucasoid race  working at an underground loparite mine in the Kola Peninsula  in December 2014. The participants were selected if they were normotensive or prehypertensive (<140/90 mmHg) and had no cardiovascular, respiratory or metabolic diseases. All provided written consent, and the Institute's Ethic Committee approved the study protocol.This is a population-based observational study.radial/PPaortic × 100. As described elsewhere, higher AIx and lower Ampl indicate greater arterial stiffness . The mean blood pressure was obtained from an integration of the waveform. The pulse pressure amplification from the aorta to radial artery was calculated according to the formula Ampl = PPtiffness . The leftiffness .ADRA2B gene (rs28365031) was detected by polymerase chain reaction followed by agarose gel electrophoresis.Genomic DNA was extracted from the blood using commercial kits  at the Genetic Laboratory at the Institute of Physiology and Basic Medicine. The 301–303 insertion/deletion polymorphism in P ≤ 0.05 was considered statistically significant, but the value ≤0.1 was also indicated to note a suggestive effect.Individuals with homozygous and heterozygous haplotypes were grouped, and mean values ± SD for tonometric parameters were calculated. Using SPSS-19 software (IBM), we analyzed differences among genotype groups by the Kruskal-Wallis test since the data were not normally distributed in the studied sample. The post hoc Dunnett's T3 test was used for multiple comparisons. Multivariable linear regression models were created (GLM option) for genotype-dependent outcomes to adjust for the effects of potential confounding variables including age, body mass index (BMI), heart rate (HR), and aortic systolic blood pressure (SBP). A value of P = 0.039) and PP (P = 0.022), greater AIx value (P = 0.003), lower PP amplification (P = 0.013), and hence stiffer peripheral arteries compared with DD carriers .  The higher ED indicates the shortened diastole, low SEVR, and therefore worse conditions for afterload myocardial perfusion. In women, the differences among genotypes for ED, AIx, and SEVR, though weak, are similar to those observed in men. For the entire sample, the differences remain significant for ED, AIx, and SEVR. For these variables, the paired comparisons revealed significant differences between II and DD genotype but not among ID and DD haplotypes. The SEVR value in the joint sex group varies across genotypes irrespective of major confounders  in the multiple regression model . The effect of haplotypes explains 12% of the total variation of SEVR and exceeds that of age and BMI.For both sexes, no significant differences in age, BMI, HR, and BPs were observed between haplotypes. Homozygous male carriers of I allele had higher aortic systolic


Urinary miRNAs may potentially serve as noninvasive biomarkers in various kidney diseases to reflect disease activity, severity and progression, especially those correlated with the pathogenesis of kidney diseases. This study demonstrates that urinary miR-196a, a kidney-enriched miRNA, can predict progression of chronic kidney disease (CKD).Focal segmental glomerulosclerosis (FSGS) cohorts were used as the representative example of CKD. First, correlation of miR-196a with disease activity was analyzed using paired urine and plasma samples from FSGS patients with nephrotic-range proteinuria (FSGS-A), complete remission (FSGS-CR) and normal controls (NCs). Then, the value of urinary miR-196a in predicting disease progression was validated using another cohort of 231 FSGS patients who were followed-up until over 36 months or reaching end-stage renal disease (ESRD). MiR-196a levels were analyzed by quantitative reverse transcription-polymerase chain reaction.The results showed that urinary miR-196a significantly increased in FSGS-A compared with FSGS-CR and NCs, clearly distinguishing FSGS-A from FSGS-CR and NCs, whereas plasma miR-196a showed no difference among these groups. Moreover, urinary miR-196a, which was associated with proteinuria, estimated glomerular filtration rate (eGFR), interstitial fibrosis and tubular atrophy, significantly increased in patients progressed to ESRD compared to those not. Furthermore, patients with higher urinary miR-196a displayed poorer renal survival than those with lower urinary miR-196a. Multivariate Cox analysis confirmed urinary miR-196a as an independent risk factor for FSGS progression after adjusting for age, sex, proteinuria and eGFR. Prediction accuracy of ESRD was significantly improved by combining urinary miR-196a with other indicators including eGFR and proteinuria.Urinary miR-196a may serve as a biomarker for predicting CKD progressionThe online version of this article (10.1186/s12967-018-1470-2) contains supplementary material, which is available to authorized users. Chronic kidney disease (CKD) represents a major public health problem and is an important cause of global mortality . StudiesMicroRNAs (miRNAs), a class of ~ 22-nt non-coding RNAs, play important roles in various physiologic and pathologic processes through post-transcriptional gene silencing . Recent In the present study, FSGS cohorts were used as the representative example of CKD. To illustrate the origin of urinary miR-196a, we measured the paired urinary and plasma miR-196a levels simultaneously from 100 each of FSGS patients with nephrotic-range proteinuria (FSGS-A), complete remission (FSGS-CR) and normal controls (NCs). To prove that urinary miR-196a is a biomarker associated with kidney injury and can be used for risk stratification of ESRD and predicting disease progression, we assessed the relationship of urinary miR-196a level with IF/TA and the risk of progression to ESRD using another separate cohort consisting of 231 patients with FSGS. Our study has identified that urinary miR-196a is a kidney-derived, and injury related biomarker for predicting the progression of CKD.All case patients and healthy controls were recruited at the National Clinical Research Center of Kidney Diseases of Jinling Hospital  between January 2005 and December 2011. A total of 100 FSGS-A patients, 100 FSGS-CR patients and 100 age- and sex-matched NCs were recruited. In addition, another 231 patients with FSGS were enrolled at the time of kidney biopsy. FSGS was defined as follows : (1) foc2, the initiation of renal replacement therapy or receiving kidney transplantation, or 40% reduction of baseline eGFR) .As the IF/TA scores can predict long-term renal outcome of CKD patients , we nextr = − 0.369, p = 0.012) or TA .Our previous study indicated that miR-196a is predominantly expressed in human kidney and protects from renal fibrosis . To testp < 0.0001). Using the first tertile as the referent, patients in tertile 3 had greater hazard ratio (HR) for progression to ESRD  even after adjustment for age, sex, proteinuria and eGFR. There was a trend of higher HR for ESRD in tertile 2, but not significant .We further investigated whether urinary miR-196a level was a factor influencing risk stratification of ESRD and disease progression in FSGS. We conducted the analyses modeling urinary miR-196a in tertiles as well as a continuous exposure as previously reported –37. Evalp < 0.0001). The finding remained consistent after adjustment for age, sex, proteinuria and eGFR in multivariate Cox analysis (Table p < 0.001).When analyzed as a continuous variable, urinary miR-196a was significantly associated with progression to ESRD in univariate Cox analysis (Table p = 0.001), as well as an improvement in model fit, as the C-statistic increased from 0.61 (model1) to 0.68 (model2) and the AIC decreased from 461 (model1) to 448 (model2)  using proteinuria and eGFR that were adjusted for age and sex was compared with the “full” models using urinary miR-196a (model2) in addition to proteinuria and eGFR. Notably, model2 demonstrated a significant covariate effect on the likelihood ratio test (2) Table . FinallyIn the present study, we have shown that urinary miR-196a is a kidney-derived biomarker for renal injury. The negative correlation between intrarenal miR-196a and IF/TA observed in the biopsy specimens from FSGS patients also supports that urinary miR-196a is a renal injury marker. Our results further demonstrate that urinary miR-196a may serve as a biomarker for predicting the disease progression in patients with FSGS.We previously found that FSGS-A patients had an elevation of urinary miR-196a level compared to FSGS-CR patients or healthy donors . In addiRenal fibrosis is a hallmark of CKD progression. Previous studies by others and us have demonstrated that miR-196a is a kidney-enriched miRNA and plays an important role in tissue fibrosis –26, 38. Previous studies have showed tubular cell loss, inflammatory cells infiltration, fibroblast proliferation, inflammatory pathways activation in the process of renal fibrosis –41. It iTo assess the predictive value of urinary miR-196a on risk stratification of ESRD and disease progression of FSGS patients, we set the progression to ESRD or 40% eGFR reduction as composite end points, which reflect the current concept of clinical trial end points in CKD . The cohMore and more studies have shown that biomarker panels can significantly improved prediction accuracy compared with a single biomarker –51. We fkipI. Our previous study showed that urinary miR-196a levels are associated with DN and membranous nephropathy (MN) [miR-196a has also been shown to play a role in other kidney diseases. Wang et al.  showed tthy (MN) . These rSeveral previous studies have explored the potentials of miRNA levels as biomarkers for CKD progression. Wang et al. showed that the levels of miR-192 in kidney and miR-200b in urine, two microRNAs that are involved in CKD , 54, areOn the other hand, there are a few limitations in this study. First, our findings were based on Chinese patients with FSGS and it may be difficult to generalize our results to other races. Second, the present study focused on a single miRNA level in urine and the predictive value of urinary miR-196a level in other kidney diseases remains unknown.Our results demonstrate that urinary miR-196a level may serve as a new risk factor for disease progression in patients with CKD. This identification will not only provide a novel biomarker to predict CKD progression, but also exploit a new intervention tool for slowing CKD progression.Additional file 1. Additional methods, figures and tables.


Effective treatments in heart failure (HF) patients with ischemic etiology have not been fully established. Nicorandil, combination of nitrate component and sarcolemmal adenosine triphosphate-sensitive potassium channel opener, is a potent vasodilator of coronary and peripheral vessels and has been used as an antianginal agent. Therefore, we examined impacts of nicorandil on cardiac mortality in ischemic HF patients.n = 116) and non-nicorandil group (n = 218). We retrospectively examined cardiac mortality.Consecutive 334 HF patients with ischemic etiology were retrospectively registered and divided into 2 groups based on oral administration of nicorandil: nicorandil group (P = 0.032). In the Cox proportional hazard analysis, usage of nicorandil was a suppressor of cardiac mortality , and this result was consistent in several subgroup analyses, such as left ventricular ejection fraction, percutaneous coronary intervention, coronary artery bypass graft, diabetes, β-blockers, and statins.In the Kaplan-Meier analysis (mean follow-up period 963 days), cardiac mortality was significantly lower in the nicorandil group than in the non-nicorandil group (11.2% vs. 19.7%, Nicorandil is potentially effective for reducing mortality in patients with ischemic heart failure.This was a retrospective study. Recent standard pharmacotherapy for heart failure (HF), such as beta-blockers and renin angiotensin system inhibitors, have much improved mortality in HF patients –3. HF win = 116) and non-nicorandil group . While the prescription of nicorandil was determined by the attending physician freely, patients with advanced coronary artery disease tended to be prescribed nicorandil in our hospital. Diagnosis of decompensated HF was defined based on the Framingham criteria [This was a retrospective study. Consecutive 334 HF patients with ischemic etiology at Fukushima Medical University between 2009 and 2014 were divided into two groups based on oral administration of nicorandil at hospital discharge: a nicorandil group .The chi-square test was used for comparisons of categorical variables. Data of the two groups were compared using the independent Student’s t-test for normally distributed data, and the Mann-Whitney U test for non-normally distributed data. To assess the potential heterogeneity of nicorandil treatment effects on cardiac mortality, we conducted subgroup analyses. Interactions between nicorandil and the following clinically relevant variables, which are different between the two groups and/or generally known risk factors, were estimated by a Cox proportional hazards regression model: age, sex, left ventricular ejection fraction (LVEF), presence of left main trunk lesion, three-vessel disease, history of percutaneous coronary intervention or CABG, presence of diabetes, chronic kidney disease, dialysis, and use of β-blockers, statins, anti-platelet agents, and nitrate. A value of P = 0.032). In the Cox proportional hazard analysis (Table P = 0.035). Interactions between nicorandil use and clinically relevant variables were modeled using Cox regression and are shown in Table P = 0.019), and remained in a tendency in patients without CABG (P = 0.133).As shown in Table In the present study, we firstly demonstrated that oral administration of nicorandil was associated with lower cardiac mortality in ischemic HF patients, and this result was consistent in several subgroup analyses, such as LVEF, percutaneous coronary intervention, coronary artery bypass graft, diabetes, β-blockers, and statins.Intravenous nicorandil for decompensated HF patients, regardless of ischemic etiology, improves cardiac pump function, New York Heart Association class, left ventricular function, myocardial microvascular circulation, pulmonary capillary wedge pressure, pulmonary arterial pressure, and peripheral resistance , and ora2+ overload by opening adenosine triphosphate-sensitive potassium channels, anti-inflammatory and anti-proliferative effects, anti-apoptosis, anti-arrhythmic effects, protection of endothelial, mitochondrial, and energy-modulating functions, and preservation of kidney function [Several favorable effects of nicorandil on cardiovascular system have been reported, such as reduction in preload and afterload, improvement of myocardial perfusion, protection of cardiomyocytes from ischemic damage, prevention of Cafunction , 13, 14.There are several limitations in the present study. First, it is a nonrandomized and retrospective study of a single institution, so the number of subjects was relatively small and there are potential biases and confounders that may be responsible for our findings. Second, we have conducted this study using only variables on hospitalization, without consideration for changes in medical parameters and post-discharge treatment. Third, our results has not established a cause-effect relationship between the usage of nicorandil and improvement of cardiac mortality. Thus, the results of the present study should be viewed as preliminary, and further studies with larger populations and randomization are needed.In conclusion, nicorandil potentially reduces cardiovascular mortality in patients with ischemic HF.


Persistent pulmonary hypertension of the newborn (PPHN) is a syndrome of failed circulatory adaptation at birth due to delay or impairment in the normal fall in pulmonary vascular resistance (PVR) that occurs following birth. The fetus is in a state of physiological pulmonary hypertension. In utero, the fetus receives oxygenated blood from the placenta through the umbilical vein. At birth, following initiation of respiration, there is a sudden precipitous fall in the PVR and an increase of systemic vascular resistance (SVR) due to the removal of the placenta from circulation. There is dramatic increase in pulmonary blood flow with a decrease in, and later reversal of shunts at the foramen ovale and ductus arteriosus. The failure of this normal physiological pulmonary transition leads to the syndrome of PPHN. PPHN presents with varying degrees of hypoxemic respiratory failure. Survival of infants with PPHN has significantly improved with the use of gentle ventilation, surfactant and inhaled nitric oxide (iNO). PPHN is associated with significant mortality and morbidity among survivors. Newer agents that target different enzymatic pathways in the vascular smooth muscle are in different stages of development and testing. Further research using these agents is likely to further reduce morbidity and mortality associated with PPHN. During fetal life, pulmonary vascular resistance (PVR) is high and pulmonary blood flow (Qp) is low . Followi2) contribute to high PVR  − PaO2.○Where R is the respiratory quotient .○2 is 4–20 mm of Hg. A-aDO2 can be above 600 mm Hg in very severe cases of HRF. An online calculator is available at http://perinatology.com/calculators/A-a%20gradient.htm.The normal A-aDOA-aDO2/ FiO2P/F ratio is the ratio of the partial pressure of oxygen (in mm Hg) in the arterial blood to the fractional inspired oxygen concentration. P/F ratio = PaO○Mild >200 to ≤300.○Moderate >100 to ≤200 and ○Severe ≤100 mm Hg.Severity assessment based on P/F ratio:2 accurately predicts oxygen delivery to vital organs such as the brain and heart and is not altered by right to left shunting at the PDA. However, many patients with PPHN have umbilical arterial access  resulting in lower PaO2 and higher OI and lower P/F ratio compared to preductal evaluation.Note: For calculation of OI and P/F ratios, it is preferable to use preductal blood gases . Preduct○2 × 100/Preductal SpO2.OSI = Mean airway pressure × FiO○OSI has been shown to correlate well in infants with HRF, OI ≈ 2 × OSI .Oxygen saturation index (OSI)—All of the above indices require arterial blood gas for evaluation and hence the need for arterial access. OSI is a noninvasive index of gas exchange and is calculated as follows:Objective assessment of oxygenation in infants with PPHN/HRF can be performed with one of the following indices:The goals of therapy in PPHN are to promote lung recruitment, pulmonary vasodilation, improve oxygenation and provide adequate oxygen delivery to the tissues while minimizing oxidative stress and free radical injury.Maintaining normal body temperature, glucose level, ionic calcium and sedation/ analgesia are important for optimal outcomes in patients with PPHN.A common cause of failure to respond to treatment in HRF with impaired oxygenation and ventilation is inadequate lung recruitment. Optimizing lung recruitment with the use of PEEP to achieve lung expansion to functional residual capacity (FRC) approximately 8–9 ribs expansion on anteroposterior chest X-ray) often ensures adequate lung recruitment. Underinflation and overinflation increase PVR due to the mechanical effects on the extra-alveolar and intra-alveolar pulmonary blood vessels. Atelectasis increases intrapulmonary right to left shunting leading to worsening hypoxia and hypercarbia. Overinflation can impede venous return and cause systemic hypotension.2 between 50 and 80 mmHg) . In. In38]. e to iNO .Cyclic mononucleotides cGMP and cAMP are degraded by phosphodiesterase (PDE) enzymes in the pulmonary artery smooth muscle cells. Milrinone is a PDE3A inhibitor and enhances cAMP levels in the arterial smooth muscle cells and cardiac myocytes resulting in vasodilation and inotropy . MilrinoSildenafil is a PDE5 inhibitor, which decreases breakdown of cGMP resulting in pulmonary vasodilation  40]. Si. Si40]. (1)In the presence of systemic hypotension without cardiac dysfunction, the agents of choice are dopamine, norepinephrine and vasopressin (pressor support).(2)When systemic hypotension is associated with cardiac dysfunction, epinephrine or a combination of dopamine/vasopressin and milrinone are the agents of choice.(3)In the presence of stable systemic blood pressure and cardiac dysfunction, milrinone is the agent of choice.(4)Studies in the lamb model of PPHN have shown increase in pulmonary arterial pressure and decreased pulmonary blood flow following initiation of dopamine. In control lambs with normal pulmonary vasculature, dopamine increases the systemic blood pressure with relatively small increase in pulmonary arterial pressure. In contrast, lambs with remodeled pulmonary vasculature and PPHN induced by antenatal ductal ligation, dopamine, especially at doses >10 µg/kg/min, results in a greater increase in pulmonary arterial pressure .(5)The use of dobutamine is often associated with a fall in systemic blood pressure resulting in exacerbation of right to left shunting and systemic desaturation. Dobutamine causes increase in myocardial oxygen requirement which may worsen myocardial dysfunction in PPHN.Systemic hypotension due to low systemic vascular resistance or left ventricular dysfunction is common in infants with PPHN. Right ventricular dysfunction and failure occurs due to increased afterload in infants with severe PPHN. Optimizing cardiac output with adequate volume expansion and inotropic support is important for achieving optimal gas exchange and systemic oxygen delivery.Maintaining adequate  systemic blood pressure decreases systemic oxygen desaturation by decreasing the pulmonary to systemic shunt through the ductus arteriosus. It is a common practice to increase systemic blood pressure to supraphysiological levels above pulmonary arterial pressures to prevent right-to-left shunting and desaturation . IatrogeIn PPHN, episodes of pulmonary vasoconstriction can be induced by external stimuli. Hence, these infants should be nursed in an environment with minimal stimulation and provided adequate sedation with fentanyl/morphine. The routine use of paralyzing agents should be avoided  and reseThe goal is to provide adequate parenteral calories and maintaining adequate ionic calcium levels for optimal cardiac function by providing a parenteral nutrition solution with glucose, calcium, amino acids and lipids.2 should be maintained between 40 and 55 mm Hg.Acidosis promotes pulmonary vasoconstriction and hence it is important to maintain pH in the normal range 7.25–7.4). Metabolic alkalosis by sodium bicarbonate infusion and respiratory alkalosis by hyperventilation should be avoided . Metabol. PaCO2 s2 ≥ 630 for >4 h. Hypoxemia to this degree is predictive of 60–80% mortality in the absence of access to ECMO. The risk of rapid deterioration and death is high in patients with severe PPHN and HRF and hence discussions and initiation of transfer should be undertaken in patients at an OI of 30 on pulmonary vasodilator therapy. Contraindications to ECMO include gestational age <34 weeks (due to high risk of intraventricular hemorrhage (IVH)), significant IVH, persistent bleeding diathesis, irreversible neurological injury, major chromosomal abnormalities and irreversible major organ dysfunction.About 30–40% of infants do not achieve a sustained oxygenation response to iNO. ECMO may be lifesaving in infants who fail maximal conventional therapy. Hence, access to ECMO or ability to transfer patients in a timely manner to an ECMO center should be available to centers that manage patients with HRF/PPHN. The indications for ECMO are OI >40 for >2 h in 3 out of 5 arterial blood gases or A-aDOFollow-up studies comparing therapies for PPHN demonstrate that neurodevelopmental impairments are present in about 25% of infants, sensorineural hearing loss in 6–23% and persisting respiratory illness in 25%. It is important to ensure long-term multidisciplinary follow up care following discharge for these infants.l-Citrulline, endothelin receptor antagonists, soluble guanylyl cyclase stimulators and activators, Rho kinase inhibitors, peroxisome proliferator activated receptor gamma (PPAR ɤ) agonists, and antioxidants are in different stages of development and testing [Survival of infants with PPHN has significantly improved with the use of gentle ventilation, surfactant and iNO. However, due to the limited availability of iNO, high cost, and lack of efficacy in about a third of patients with PPHN, there is a need to develop better agents that target different enzymatic pathways in the vascular smooth muscle. Newer agents such as  testing . Further


In multivariable Cox analysis, a low GNRI, female sex, high systolic blood pressure, high fasting glucose, and low estimated glomerular filtration rate were independently associated with progression to dialysis. A low GNRI was independently associated with progression to dialysis in our study cohort. The GNRI may be useful in predicting the risk of adverse renal outcomes in patients with CKD stages 3–5. Additional studies are needed to explore whether an improvement in GNRI delays CKD progression.Evaluating nutritional status is crucial to detecting malnutrition in patients with chronic kidney disease (CKD). The Geriatric Nutritional Risk Index (GNRI) has been associated with overall and cardiovascular mortality in the dialysis population. The aim of this study was to evaluate whether the GNRI is associated with progression to dialysis in patients with moderate to advanced CKD. We enrolled 496 patients with stage 3–5 CKD who had received echocardiographic examinations, and categorized them according to baseline GNRI values calculated using the serum albumin level and body weight. The renal end-point was defined as the commencement of dialysis. During follow-up , 106 (21.4%) of the patients progressed to dialysis. The GNRI was positively correlated with the left ventricular ejection fraction (LVEF) ( Nutritional management is important for patients with chronic kidney disease (CKD). The degree of malnutrition increases as CKD progresses and is closely associated with major adverse clinical outcomes, thereby resulting in increased rates of hospitalization and mortality . EstabliThe GNRI is calculated using serum albumin level and body weight, and it was originally introduced as a simple tool to assess the nutritional status of elderly hospitalized patients . BesidesDespite these findings, whether or not the GNRI is a strong predictor of adverse renal outcomes has never been investigated. Therefore, the aim of this study was to investigate whether the GNRI was independently associated with progression to dialysis in these patients.2; stage 4, eGFR 15 to 29 mL/min/1.73 m2; and stage 5, eGFR < 15 mL/min/1.73 m2. The patients who had significant mitral valve disease and those on maintenance hemodialysis (HD) were excluded. The study protocol was approved by the Institutional Review Board of the hospital, and all patients provided informed consent to participate in this study.This study enrolled 496 patients with stage 3–5 CKD from the Outpatient Department of Internal Medicine at a regional hospital in southern Taiwan from January 2007 to May 2010. The patients were followed up for more than three months to confirm the presence of CKD, and they were classified into three groups based on the stage of CKD according to the National Kidney Foundation-Kidney Disease Outcomes Quality Initiative (K/DOQI) guidelines at entry to the study  as follo3 − LVIDd3] − 13.6 g [2 in the male and female patients, respectively, according to previously reported cut-off values [Echocardiographic parameters were evaluated by two independent experienced cardiologists who were blinded to the patients’ clinical data using standard two-dimensional and M mode images , and included the left ventricular (LV) end-diastolic volume (LVEDV), LV end-systolic volume (LVESV), left atrial diameter (LAD), LV internal diameter in diastole (LVIDd), LV posterior wall thickness in diastole (LVPWTd), and interventricular septal wall thickness in diastole (IVSTd). LV systolic function was evaluated according to the LV ejection fraction (LVEF), with a cutoff of <50% based on previous studies of preserved systolic function ,19. LV m− 13.6 g . The leff values . Offline2).Based on the original nutritional risk index for elderly subjects , the GNRAll demographic data and relevant medical histories of the patients including age, sex, smoking history, and comorbidities were recorded from medical records. Blood and urine samples were collected from the patients after a 12-h fast within one month of enrollment. All laboratory examinations were performed using an automated analyzer . Serum creatinine levels were calculated using the compensated Jaffé method  , and eGFThe renal end-point was defined as starting dialysis, as determined by the regulations of the National Health Insurance program for dialysis therapy based on laboratory data, nutritional status, and symptoms and signs of uremia. Of those who reached the renal end-point, eGFR data were recorded until the commencement of dialysis, and the other patients were followed up until February 2011.p < 0.05) in univariable analysis were entered into a multivariable model 1: GNRI, gender, diabetes mellitus, hypertension, and systolic blood pressure , and a multivariable model 2: GNRI, fasting glucose, hemoglobin, eGFR, CaXP product, uric acid, proteinuria, LAD > 4.7 cm, and LVH . We analyzed the time to the renal end-points using Kaplan-Meier survival curves with the log-rank test among the tertiles of GNRI. A direct comparison between albumin, BMI, and GNRI was performed in multivariable models. Incremental model performance was assessed using a change in the χ2 value. A p value < 0.05 was considered to indicate statistical significance. All statistical analyses were performed using SPSS software for Windows version 19.0  Inc., Chicago, IL, USA).Descriptive statistics are presented as percentages, means ± standard deviations, or medians (25th–75th percentiles) for triglycerides. Differences between study groups were assessed using one-way analysis of variance (ANOVA) for continuous variables and the chi-square test for categorical variables. Pearson’s correlation analysis was used to evaluate associations between the echocardiographic parameters and the GNRI. Multivariable linear regression analysis was used to determine the factors for GNRI. Multivariable Cox proportional hazards analysis was used to evaluate associations between baseline variables and progression to dialysis, with the results expressed as hazard ratios (HRs) and corresponding 95% confidence intervals (CIs). Baseline variables that were statistically significant , and negatively correlated with LVMI , LVH , and LVEF < 50% . However, the GNRI was not correlated with LVEDV, LVESV, or LAD > 4.7 cm.p = 0.017), coronary artery , high triglyceride , high hemoglobin , and LVEF ≧ 50%  were significantly associated with high GNRI.p < 0.001), female sex, a history of diabetes and hypertension, high systolic blood pressure, high levels of fasting glucose, CaXP product and uric acid, low hemoglobin, low eGFR, proteinuria, LAD > 4.7 cm, and LVH were associated with a significantly higher risk of progression to dialysis. In the multivariable model, a lower GNRI , male sex, diabetes, high systolic blood pressure, low eGFR, and high CaXP product were independently associated with progression to dialysis. p < 0.001), being female, and a high systolic blood pressure were independently associated with progression to dialysis. In the multivariable model 2, a low GNRI , high fasting glucose, low hemoglobin, and low eGFR were independently associated with progression to dialysis. p < 0.001). The unadjusted HR for tertile 2 versus quartile 1 was 0.509 , compared to 0.310  for quartile 3 versus quartile 1. The patients in the highest two tertiles had a better dialysis-free survival than those in the lowest tertile of GNRI.Over a mean follow-up period of 25.2 ± 12.5 months (range 3.3 to 50.1 months), 106 patients (21.4%) started dialysis. p < 0.001) and model 2 .We further performed analysis using Lorentz’s formula, and still found that a low GNRI was still significantly associated with progression to dialysis in model 1 , and found a low GNRI was still significantly associated with progression to dialysis in model 1  and model 2 . Similarly, after the exclusion of patients with BMI < 18.5 kg/m2 (n = 13), we still found that a low GNRI was significantly associated with progression to dialysis in model 1  and model 2 .To avoid interaction with BMI, we further performed multivariable analysis after the exclusion of patients with BMI ≧ 30 kg/mn = 50), and found that GNRI was significantly related to progression to dialysis  and outperformed albumin and BMI of the model. In a direct comparison, the multivariable model without albumin, BMI, and GNRI was not significantly improved by adding albumin  and BMI , respectively. Whereas adding GNRI resulted in significant improvement .Because malnutrition may influence CKD progression, we further performed multivariable analysis in patients with albumin <3.5 g/dL  [There are several limitations to this study. First, we used baseline GNRI rather than mean GNRI. In addition, we did not obtain data of time-dependent changes in albumin and BMI, and we were thus not able to investigate the association between weight variation and outcomes. In addition, BMI is limited to differentiating fat and lean mass, and therefore we will use body composition analysis using dual-energy X-ray absorption to elucidate this issue in future studies. Second, we did not include inflammatory markers such as C-reactive protein into the analysis because of missing data. Chronic inflammation has been linked to malnutrition, and this is a potential confounder of the associations observed in this study. Third, BMI may be misleading in the presence of edema, which is common in patients with advanced CKD. Finally, GNRI was originally developed by modifying the nutritional risk index for elderly subjects. As Yamada et al. has reported, the ideal body weight was calculated from the patient’s height and a BMI of 22, which was a simpler equation than Lorentz’s original formula. He also demonstrated that there was only little difference between two formulas (< 0.001) .In conclusion, in patients with stages 3–5 CKD, a low GNRI was an independent determinant of progression to dialysis. Using the GNRI to evaluate and manage nutritional status in patients with CKD may be important in predicting the commencement of dialysis. Additional studies are needed to explore whether an improvement in GNRI delays CKD progression.


Almonds can decrease glycemic index of co-consumed foods and are a rich source for oleic acid and α-tocopherol. The aim of the randomized, crossover, controlled feeding trial was to examine whether as compared to NCEP step II diet as control (CON), ~60 g/d almonds (ALM) added to CON would improve glucoregulation and cardiovascular disease (CVD) risk factors in 33 Chinese T2DM patients.Forty T2DM patients were enrolled and randomly assigned to receive CON or ALM for 12 wks after a 2-wk. run-in period. Blood and urine samples were collected in the beginning and at the end of each dietary intervention phase for the assessment of biomarkers of glucoregulation, lipid profile, inflammation, and oxidative stress.P = 0.01 and 0.04). Mean total and LDL-cholesterol concentrations were not changed by both diets.While ALM had a better overall nutritional quality than CON, neither ALM nor CON improved the glycemic status as the primary study outcome and other CVD risk factors, except the circulating nitric oxide being decreased by ALM compared to CON. Among 27 of 33 patients with the baseline HbA1c ≤8, ALM decreased post-interventional fasting serum glucose and HbA1c by 5.9% and 3.0% as compared to that of CON, respectively (These results suggest almonds incorporated into healthful diets can improve glycemic status in diabetic patients with a better glycemic control.NCT01656850, registered 13 January 2012. Diabetes is associated with the development and progression of cardiometabolic diseases . AccordiPatients with T2DM are generally instructed by medical professionals to follow a nutrition therapy of their own preference, in which monitoring consumption of carbohydrate-rich foods and increasing fruits, legumes, vegetables, whole grains, and dairy products are generally recommended to control wide blood glucose swings . Though Our previous 4-week controlled feeding study with Chinese patients with T2DM and mild hypercholesterolemia  showed t2, HbA1c: 6.5–10%, and regular use of prescribed oral hypoglycemic agents . The exclusion criteria included regular use of insulin, oral steroids or anti-inflammatory agents, ≥5% body weight change in the last 6 mo, diagnosed CVD, stroke, gastrointestinal diseases, inflammatory bowel disease, chronic kidney disease, hepatobiliary disease, renovascular disease, endocrine diseases, hyperuricemia, autoimmune diseases, active treatment for cancer of any type ≤1 y, poor hypertension control (systolic blood pressure ≥ 150 mmHg and/or diastolic blood pressure ≥ 95 mmHg), known allergies to nuts of any kind, frequent nut consumption (≥3 oz./wk), regular use of any dietary supplements or homeopathic remedies, daily ethanol intake of ≥2 drinks and smoking. Due to insulin dosage is normally adjusted with carbohydrate intake, there might be a safety concern with the decrease of carbohydrate intake from 56% to 47% when fat-rich almonds were incorporated into study diet. Thus, patients using insulin were excluded from the study.Patients previously diagnosed with T2DM by an attending physician of the Endocrine Clinic of either the Taipei Medical University Hospital (TMUH) or the Taipei Medical University-Shuang-Ho Hospital in Taiwan were recruited for the trial. The inclusion criteria included age between 40 and 70 y, BMI: 24 to 35 kg/mClinicalTrials.gov (no. NCT01656850).After enrollment, subjects were asked to adhere with medication regimens and to refrain from consuming nuts during the 2-wk. run-in period and during the intervention. The study protocol was approved by the Institutional Review Board of the Taipei Medical University, and written informed consent was obtained from participants before study procedures were performed. The study was registered at The study was a 28-wk. randomized, crossover, controlled feeding trial with a 2-wk. run-in period and a 2-wk. washout between alternative diets. The study duration was selected because it was required for the assessment of HbA1c, which is indicative of the long-term glycemic status. The enrolled patients were randomly assigned to receive one of the study diets for 12 wks after the run-in period, during which they consumed CON . The % fat mass was measured up to a 0.1% accuracy. After ≥10 min of rest in a quiet room, blood pressure was measured twice with 10 min rest between measurements, using a FT-500 R automatic blood pressure meter . The final blood pressure values are the mean of 2 measurements.Fasting and postprandial blood samples were collected from a venous vein of one arm into vacutainers with and without anticoagulant (EDTA or NaF). Plasma and serum were collected after centrifugation at 1400 × g for 10 min at 4 °C, aliquoted, and then stored in −80 °C until analyses. Morning spot urine was also collected at the study sites after overnight fast and stored at −80 °C until analysis.Serum AST and ALT, creatinine, and magnesium were all determined using a Siemens Advia 1800 automated chemical analyzer .electrochemiluminescence immunoassay , and inter-day coefficient of variation (CV) was 8%. Homeostasis model assessment-Insulin Resistance (HOMA-IR) was calculated according to the formula: insulin × glucose/22.5, with insulin expressed as μU/mL and glucose as mmol/L [Glucose in NaF plasma and lipid profile in serum were determined using a SYNCHRON LX20 Pro clinical chemistry analyzer . Serum insulin was determined by an s mmol/L . C-peptis mmol/L  A-1 and High sensitivity C-reactive protein (hsCRP) in serum was determined in TBA-40FR chemistry analyzer using a latex-enhanced turbidimetric immunoassay , and inter-day CV was 7.2%. Plasma intracellular adhesion molecule-1 (ICAM-1), E-selectin, and endothelin-1 were assessed using human sICAM-1/CD54 Quantikine ELISA kit , human E-selectin/CD62E ELISA kit, (R and D Systems) and endothelin-1 Quantikine ELISA kit (R and D Systems), respectively. Serum nitric oxide (NO) was determined by a colorimetric total nitric oxide assay kit (R and D Systems). Intra-day CV for ICAM-1, E-selectin, endothelin-1, and NO was 2.6, 2.2, 2.8, and 2.9%, respectively, and inter-day CV was 3.9, 12.5, 11.1, and 10.0%.2α-isoprostanes in urine were determined using our routine HPLC-GC/MS method [Total FS method . The finPlasma α-tocopherol was determined using a reverse-phase HPLC method, according to Bieri et al. . BrieflyP ≤ 0.05 (2-tailed). All analyses were performed using SAS 9.3 .The sample size was calculated using the HOMA-IR data of our previous study . A samplA total of 40 patients were enrolled and 33 of them completed the whole intervention with full compliance. The compliance to the study protocol was assessed by measuring the amount of unconsumed foods during the trial and checking the compliance calendar of almond consumption Fig. . Two subP ≤ 0.0001). ALM and CON provided 16 and 7% calories from MUFA, respectively. As 60 g almonds provide 7.2 g fiber, ALM had 37.5% more fiber than CON. As almonds are rich in Mg and α-tocopherol, ALM contained 62 and 179% more than CON, respectively.Average caloric intake was comparable between CON and ALM phases Table . SubjectAt the end of the 12-wk. intervention, both ALM and CON did not affect body weight, BMI, waist and hip circumferences, waist/hip ratio, % body fat, as compared to the respective baseline/washout values Table . AverageP = 0.082). There was no difference between ALM and CON in blood glucose excursion for 3 h post breakfast, and the highest blood glucose at 246.6 and 239.4 mg/dl for ALM and CON, respectively, was noted at 90 min. The AUC of serum insulin kinetics after the breakfast did not differ between 2 diets. ALM decreased postprandial insulin level at 30, 60, and 90 min by 19, 15, and 17%, respectively, as compared to CON at the same time point. The highest postprandial blood insulin at 31.5 and 37.8 mU/l for ALM and CON, respectively, was noted at 90 min.Mean HbA1c of 2 pre-intervention values was 7.5%. At the end of ALM and CON, both diets did not change HbA1c as compared to the corresponding pre-intervention value. Similarly, both diets did not affect fasting serum glucose, insulin, and HOMA-IR values. However, as compared to the value at the end of CON, there was a trend that ALM increased C-peptide by 4.6% (n = 27) with the initial HbA1c ≤8% , but the post ALM value was more comparable to the pre ALM value with a 5.1% increase.Lipid profile did not differ between 2 diets in all subjects and the subset subjects Table . During P = 0.121) and significantly decrease the value by 7.9% in subset subjects. Both ICAM-1 and endothelin-1 contents remained similar during the course of the trial.Serum hsCRP below 0.5 mg/dl in all 4 measurements was not affected by the diets Table . While tP = 0.15). ALM did not lead to a significant increase in plasma α-tocopherol. α-Tocopherol value of all 33 subjects at the end of both ALM and CON phases was ~8% higher than the corresponding pre-intervention value, and the percent increase in the subset subjects was 8.6 and 3.5%, respectively.Circulating oxidized LDL was not affected by the diets Table . ALM decApproaches to protecting against CVD risk have been intensively sought for patients with T2DM. Among all evidence based approaches, a healthful dietary pattern and regular physical activity are appreciated to be the key components of diabetes management after pharmacotherapy . In thisAmerican Diabetes Association (ADA), a variety of nutrient-dense foods in appropriate portion sizes shall be incorporated into their daily diet to improve overall health and specifically to attain individualized glycemic, blood pressure, and lipid goals [P = 0.04).Nutrition therapy is defined as the treatment of a disease or condition through the modification of nutrient or food intake . Accordiid goals . Both ofid goals . As incoid goals , 33. As id goals . HbA1c iid goals . Chen etid goals  reportedid goals , 18, 35 id goals  showed tid goals  did not id goals  found thLow density lipoprotein (LDL)-cholesterol levels have been shown to rise in response to the increased intake of dietary cholesterol and saturated fats . TherefoAlmonds and other tree nuts have been appreciated for their hypocholesterolemic benefit, mainly due to their fiber, phytosterols, polyphenolics, and a high unsaturated to saturated fat ratio , 42. TheInflammation has become one of most appreciated mechanisms accountable for the development and progression of CVD , 45. InfNitric oxide (NO) plays a pivotal role in endothelial dysfunction and hypertension. In this study, we found that the circulating NO concentration was significantly lower at the end of ALM than CON, but it shall be noted that compared to the pre-ALM value, the post value was not significantly decreased. Given that blood pressure remained steady during the almond consumption period, clinical plausibility of the observed NO reduction in endothelial health seems not clinically important.Traber (2014) indicated that it is very difficult to adequately interpret the circulating α-tocopherol status [The unchanged plasma α-tocopherol after almond consumption was unexpected even though the dose of almonds provided 179% more α-tocopherol than the control diet. Since all subjects who completed the trial had a full compliance to the study regimen during the intervention, the unchanged circulating α-tocopherol status could be ascribed to unknown mechanism(s). Further, l status .n = 33) may impose an obstacle in the detection of significant changes of the study measures. For example, we infer that a larger sample size would enhance the likelihood of detecting the benefits of almonds on LDL-cholesterol, E-selectin, protein carbonyl, and urinary isoprostanes. Second, the study was a controlled feeding trial. Thus, any potential benefits, e.g., the improved glycemic management in diabetic patients with HbA1c ≤8%, are not readily generalizable to people who add almonds to their own nutritional therapy. Third, the same batch of almonds was used in the whole study to eliminate the impact of variation in almond nutrient composition between batches on the study outcomes. However, it is unclear whether different forms of almonds would affect the study outcomes. Nevertheless, we anticipate that adding almonds to patients’ diet will definitely improve nutritional quality because of their favorable nutrient profile and potential food displacement effect.All volunteers didn’t display any gastrointestinal symptoms and other side effects during the whole trial. There are a few limitations in this study. First, the small sample size (Nutrition therapy is very crucial for managing blood glucose in patients with the diabetes. Previously, we reported that almonds added to replace 20% energy intake in Chinese patients with T2DM and mild hypercholesterolemia improved glycemic control, lipid profile, inflammation, and oxidative stress. However, the present study did not show almonds at ~60 g/d which was incorporated into the NCEP step 2 diet affected HbA1c, fasting blood glucose and insulin, postprandial glycemic response, lipid profile, and biomarkers of inflammation and oxidative stress in Chinese patients with T2DM and normocholesterolemia. In a subset analysis, the benefits of almonds in glycemic control were noted in the patients with the baseline HbA1c ≤8%.In conclusion, our findings suggest almonds incorporated to healthful diets may help improve glycemic status in diabetic patients with a better glycemic control.


Based on the % change in urinary albumin, patients were divided into two groups, responders (<−50%) and non-responders (≥−50%), and a logistic analysis of urinary angiotensinogen before treatment showed the area under the curve as 0.694. When the cutoff value of urinary angiotensinogen before the treatment of 13.9 µg/g Cr was used, the maximum Youden index  was obtained. When all patients were re-divided into two groups, those with higher values of urinary angiotensinogen before the treatment  and those with lower values, Group H showed significantly decreased urinary albumin (p < 0.05). Therefore, urinary angiotensinogen could be a prognostic marker of the albuminuria reduction effects of olmesartan in patients with metabolic syndrome.This study was performed to demonstrate urinary angiotensinogen as a potential prognostic marker of the albuminuria reduction effects of olmesartan in patients with metabolic syndrome. In 24 patients , 5–40 mg/day of olmesartan were given. Urinary concentrations of albumin and angiotensinogen  and plasma renin activity were measured before and after the 12- and 24-week marks of olmesartan treatment. Olmesartan treatment increased plasma renin activity and decreased urinary albumin and urinary angiotensinogen significantly ( Obesity is a risk factor for a variety of diseases ,2, incluThe angiotensin II receptor blocker (ARB) is reported to prevent the progress of renal injury in an experimental model for metabolic syndrome . HoweverThe Reduction of End points in Non-insulin-dependent diabetes with the Angiotensin II Antagonist Losartan (RENAAL) study  reportedThe intrarenal RAS is regulated by multiple independent mechanisms . Others Initially, 33 patients were recruited. Afterwards, nine patients were excluded , and consequently, 24 patients were analyzed . Clinicap < 0.05; p < 0.05; Olmesartan significantly decreased blood pressure  ratio (UAlbCR) (N = 16) and the lower (Group L) group. Clinical characteristics  in population screening of individuals who are at risk for accelerated GFR loss . MicroalR2 = 0.000609, r = −0.0247, p = 0.909; correlation with UAGTCR and DBP: R2 = 0.00635, r = −0.0797, p = 0.711; correlation with UAlbCR and SBP: R2 = 0.0178, r = 0.133, p = 0.534; correlation with UAlbCR and diastolic blood pressure (DBP): R2 = 0.0114, r = 0.107, p = 0.620). These data suggest that in patients with metabolic syndrome, the albuminuria reduction effects of ARB are independent of the anti-hypertensive actions of ARB, but exert themselves via other mechanisms. Their mechanisms are the RAS/angiotensin II type I receptor pathway beyond the anti-hypertensive actions of ARB, which do not pass through the blood pressure-lowering effect of ARB. One of the possible mechanisms of CKD in metabolic syndrome patients is the activation of the RAS. Several mechanisms of the activation of the RAS are sympathetic stimulation [There was no correlation between UAGTCR or UAlbCR and blood pressure (correlation with UAGTCR and systolic blood pressure (SBP): mulation , synthesmulation  and renamulation  despite mulation ,31. The mulation . Kidneysmulation , renin [mulation . Once anmulation . In rat mulation ,37. The mulation ,22. The mulation ,13. ThisThere may be a correlation between UAGTCR and Cr clearance. AGT mRNA in the kidneys has been localized on the proximal tubule cells. This locally-formed and secreted AGT could dictate the intratubular angiotensin II ,39. It wThere were several possible explanations for how the activation of RAS in the proximal tubule cells could lead to glomerular injuries, such as albuminuria. The following three interpretations may explain this issue. First, the increase of AGT in proximal tubular cells may lead to the increase in angiotensin II in renal tissues , which mSecondly, the AGT produced in proximal tubular cells appears to be secreted directly into the apical side of the tubular lumen . In addiFinally, AGT was mainly expressed in proximal tubular cells in the kidney . HoweverThis experimental protocol was approved on 29 November 2007 by the Institutional Review Board of Kagawa University School of Medicine  and registered (UMIN 000001030). Participants with metabolic syndrome were recruited from Kagawa University, Toyama University, or Kansai Medical University from February 2008–June 2011, and written informed consent forms were obtained. Participants were patients with metabolic syndrome who met the following conditions: patients were between 20 and 70 years old, untreated by ARBs, ACE inhibitors or diuretics for the preceding 4 weeks, body mass index (BMI) ≥ 25 or (waist ≥ 85 cm (Men) or ≥ 90 cm (Women)), clinic SBP ≥ 130 mmHg or DBP ≥ 85 mmHg. In addition, at least one criterion from the following conditions was required: TG ≥ 150 mg/dL, high-density lipoprotein-cholesterol (HDLc) ≤ 40 mg/dL and/or FBS ≥ 110 mg/dL. Exclusion criteria for patients included pregnancy, treatment with ARBs, ACE inhibitors or diuretics within 4 weeks, patients with diabetes mellitus who were treated with anti-diabetic drugs, severe hypertension (SBP ≥ 160 mmHg or DBP ≥ 110 mmHg), secondary hypertension, severe renal disease , severe hepatic disease (AST ≥ 150 IU/L or ALT ≥150 IU/L), history of major cardiac or cerebrovascular events, endocrine diseases and patients with malignancies.The participants took olmesartan 5–40 mg/day for 24 weeks. Blood pressure was checked every 4 weeks, and the amount of olmesartan was adjusted based on blood pressure (less than 130/85 mmHg and more than 100/50 mmHg). If blood pressure in patients who took 40 mg/day olmesartan over 8 weeks reached more than 150/100 mmHg, they were excluded. Blood and urine samples were collected at baseline (0 weeks) and at 12 and 24 weeks after treatment. Blood pressure was measured at baseline (0 weeks) and 4, 8, 12, 16, 20 and 24 weeks after treatment in clinic.AGT, renin activity at rest, aldosterone, FBS and TG were measured in the 0-, 12- and 24-week blood samples. Albumin, AGT and Cr were measured in the 0-, 12- and 24-week urine samples. Blood pressure and body weight were measured in the 0-, 4-, 8-, 12-, 16-, 20- and 24-week samples. Plasma and urinary AGT concentrations were measured by the human AGT ELISA kit  .t-test. p < 0.05 was considered as statistically significant.All statistical analyses were performed with JMP software Version 10  and GraphPad Prism software Version 6 . Clinical characteristics and laboratory data of all patients at baseline are reported as the mean ± S.E.M. One-way repeated measures ANOVA followed by Tukey’s multiple comparisons test were used to compare values over the time course. Logistic analysis was conducted based on whether or not UAlbCR decreased less than −50% by olmesartan treatment. The ROC curve was developed; the AUC was calculated; and the optimal cutoff value was determined. Based on this cutoff value of UAGTCR before the treatment, patients were subdivided into 2 groups. Then, the % changes in UAlbCR and ΔUAlbCR were compared between the 2 groups using the unpaired Our data demonstrate that olmesartan, an ARB, could decrease urinary excretions of albumin, as well as AGT in patients with metabolic syndrome. In addition, we show that urinary AGT excretion could be a prognostic marker of the albuminuria reduction effects of ARB in patients with metabolic syndrome. Based on the findings in this study, treatment with ARB might be recommended in untreated patients with metabolic syndrome who showed a higher value of urinary AGT before treatment.We used only one ARB, olmesartan, but did not use multiple ARBs in this study. If we used multiple ARBs in the first study, we would not be able to judge a specific action of a specific ARB or a class-effect of ARBs. We realize that the sample size is relatively small, and there is not a control group. These are limitations of this study. Unfortunately, however, the patient recruitment in this registered clinical trial was ended, and it is not possible to increase the sample size in this study. In order to address these issues, we are now planning larger scale prospective clinical studies using multiple ARBs.