In recent years, the diagnostic utility of urinary protein levels has been demonstrated for the early detection and progression of kidney disease. This study aimed to evaluate the associations of the non-albumin protein (NAP) with different urinary marker for tubular and glomerular damage in patients with type 2 diabetes (T2D).In this observational cross-sectional study, 424 patients with T2D duration > 10 years were classified into two groups according to estimated glomerular filtration rate (eGFR). The ratios of different urinary markers , and neutrophil gelatinase-associated lipocalin (NGAL) to creatinine were analyzed.p = 0.033).The levels of urinary biomarkers increased significantly with decrease in eGFR levels. In the group with moderately decreased eGFR, the albumin to-creatinine ratio (ACR), non-albumin protein-to-creatinine ratio (NAPCR), and total protein-to-creatinine ratio (PCR) were independently associated with all urinary markers after being adjusted for risk factors. The area under the receiver operating characteristics (ROC) curve for ACR and PCR had a better diagnostic value than other urinary biomarkers. Comparing ROC curve of NAPCR with other urinary biomarkers, it was significantly better than NGAL/Cr (The findings of the present study confirm that ACR and PCR are diagnostic biomarkers in T2D patients with decreased eGFR. NAPCR in these patients diagnostically only outperformed NGAL/Cr. Diabetes mellitus (DM) is a growing public health problem throughout the world. In 2017, 425 million people worldwide were estimated to have diabetes, and the number of cases is predicted to increase to 629 million by 2045. Diabetic nephropathy (DN) is one of the major microvascular complications of diabetes and represents the leading cause of end-stage kidney disease. The prevalence of diabetes among the Saudi population has been reported to be 17.7%, and 40% of end stage renal diseases in hemodialysis patients is caused by diabetic nephropathy [Proteinuria is a condition characterized by the presence of increased amounts of protein in the urine, and it is an important indicator of kidney disease in diabetic patients. The condition can be classified on the basis of the type of protein that is detected  or the underlying pathological damage  . UrinaryIn current practice, the albumin-to-creatinine ratio (ACR) is the most commonly used and well-standardized biomarker for the diagnosis of kidney disease in diabetic patients, and several studies have reported the clinical significance of urinary total protein, transferrin, RBP and NGAL levels in DN –10. MethThis is a cross-sectional study conducted at University Diabetes Center, King Saud University between 1 April 2014 and 18 June 2015. The study was approved by the Institutional Review Board (IRB) of the King Saud University and was conducted in accordance with the Declaration of Helsinki . WrittenT2D patients aged between 35 and 70 years and with diabetes duration > 10 years were recruited for this study. Patients with diabetic complications including vasculopathy and retinopathy, or other associated diseases such as hypertension and hyperlipidemia, were included in this study, as these complications are more prevalent among T2D patients having longer duration of diabetes. Diabetes was managed with oral antidiabetic therapy with or without insulin therapy. Hypertension was managed with medications including angiotensin II receptor antagonists, thiazide diuretics, angiotensin-converting enzyme inhibitors, beta blockers and calcium channel blockers. Hyperlipidemia was managed with statins. Details of the exclusion and inclusion criteria have been reported in a previous study .2 [2), Group 2 (eGFR: <60 mL/min/1.73 m2).In accordance with the Standards for Reporting Diagnostic Accuracy Studies (STARD), a diagram illustrating the flow of participants through the study is shown in Fig. 2 . A totalAfter overnight fasting, 5 mL of venous blood was collected from each patient in a plain tube. Serum was separated and immediately stored at −20 °C for further analysis. Biochemical assessment of fasting blood sugar (FBS), HbA1c, serum creatinine, and lipid levels , low-density lipoprotein (LDL) and total cholesterol (TC)) were carried out using the Randox RX Daytona Clinical Chemistry Analyzer .2). Systolic blood pressure (SBP) and diastolic blood pressure (DBP) were measured using a digital blood pressure monitor. Random spot urine samples were obtained from patients during their clinic visits. Urine samples were stored at −80 °C. Urinary albumin, creatinine, and total protein levels were analyzed using the Randox RX Daytona Clinical Chemistry Analyzer. Urinary albumin excretion was estimated by calculating the ACR in units of mg/g, and urinary total protein excretion was estimated by calculating the PCR in units of mg/g. The NAPCR (mg/g) was calculated by subtracting the ACR value from the PCR [Body mass index (BMI) was calculated by dividing weight (kg) by height squared  were measured by solid phase enzyme-linked immunosorbent assay (ELISA) using commercially available standard kits designed for urine analysis .https://www.medcalc.org/manual/comparison_of_roc_curves.php A p value <0.05 was considered statistically significant.All statistical analyses were performed using SPSS version 21.0 . Data are presented as mean ± standard deviation for normally distributed variables and as median (interquartile range (IQR)) for skewed variables. Pearson or Spearman correlation analyses were performed using either ACR, PCR, or NAPCR as the dependent variable. For multiple linear regression analysis, either ACR, PCR, or NAPCR was considered as the dependent variable and other urinary markers were considered independent variables. Several models were built to adjust for confounding factors of kidney disease including age, gender, duration of diabetes, systolic blood pressure (SBP), HbA1c, LDL, and eGFR. Receiver operating characteristics (ROC) curves were plotted, and the area under the curve (AUC) was evaluated for different markers. The comparison of ROC curves of different urinary markers using online calculator p = 0.012). The PCR, ACR, NAPCR, transferrin -to- creatinine ratio (Transferrin/Cr), retinol binding protein-to-creatinine ratio (RBP/Cr) and neutrophil gelatinase-associated lipocalin-to-creatinine ratio (NGAL/Cr) values increased as eGFR decreased and showed a linear trend (p < 0.001). The median NAPCR of Group 1 was 88.15 mg/g, compared with 186.13 mg/g for Group 2 (p < 0.001).Table 2.The relationships between NAPCR and urinary markers as well as clinical and biochemical parameters of each group are summarized in Table The relationships of the PCR and ACR with urinary markers as well as clinical and biochemical parameters are summarized in Additional file Results of multiple linear regression analysis with NAPCR as the dependent variable Table  revealedThe results of multiple linear regression analyses with PCR and ACR as the dependent variables are summarized in Additional file 2) are illustrated in Fig. p=0.033 ROC curve areas in type 2 diabetes.The diagnostic performance of various urinary biomarkers in patients with T2D with reduced eGFR  and tubular (RBP/Cr and NGAL/Cr) markers. NAPCR in T2D with decreased eGFR diagnostically only outperformed NGAL/Cr.2 value among all urinary markers that were evaluated [The association of urinary NAP with tubular markers in normoalbuminuric patients has previously been reported, suggesting that urinary NAP can used as a marker for detecting tubular damage during the early stages of DN . Previouvaluated , 15. AltSeveral studies reported that urinary RBP and NGAL were associated with tubular damage that occurred during early stages of DN. The multivariate analysis revealed that NAPCR was associated with all the markers after adjusting for confounding factors. Even though, in Group 2, NAPCR was not significantly associated with transferrin/Cr after adjustment for confounding factors of age, gender, duration of diabetes, systolic blood pressure (SBP) in model 1 and 2. Urinary transferrin is considered a sensitive marker of glomerular damage, and a significant association with albumin excretion has been shown . UrinaryIn this study ACR and PCR had better diagnostic value than other urinary biomarkers in T2D with decreased eGFR levels. These markers outperformed tubular markers such as RBP/Cr and NGAL/Cr in terms of diagnostic accuracy, in patients with T2D with decreased eGFR. Levels of urinary RBP were significantly higher in microalbuminuric diabetics when compared with normoalbuminuric and controls, indicating impaired proximal renal tubular function in early stage of DN , 29. ButPrevious study has demonstrated the potential of a multiple-biomarker approach for diagnosis of DN . The useThis study demonstrates that ACR and PCR are diagnostic biomarkers in T2D patients with decreased eGFR. Nevertheless, these results also suggest that along with ACR and PCR, NAP may provide additional value for diagnosis of tubular damage in diabetic patients with decreased eGFR levels. Furthermore, this preliminary study will clearly need a validation with future prospective analysis on larger sample size.Additional file 1: Table S1. Correlation of total protein-to-creatinine ratio with clinical, anthropometric and biochemical characteristics and other urinary markers in type 2 diabetes subjects. Note. Group 1,eGFR ≥60 mL/min/1.73 m2; Group 2, eGFR < 60 mL/min/1.73 m2; BMI, body mass index; SBP, systolic blood pressure; DBP, diastolic blood pressure; FBS, fasting blood sugar; HbA1c, hemoglobin A1c; LDL, low-density lipoprotein; HDL, high-density lipoprotein; eGFR, estimated glomerular filtration rate; ACR, albumin-to-creatinine ratio; NAPCR, non-albumin protein-to-creatinine ratio; Transferrin/Cr, transferrin-to-creatinine ratio; RBP/Cr, retinol binding protein-to-creatinine ratio; NGAL/Cr, neutrophil gelatinase-associated lipocalin-to-creatinine ratio; r, coefficients of correlation; values of p < 0.05 were considered significant.Additional file 2: Table S2. Correlation of albumin-to-creatinine ratio with clinical, anthropometric and biochemical characteristics and other urinary markers in type 2 diabetes subjects. Note. Group 1,eGFR ≥60 mL/min/1.73 m2; Group 2, eGFR < 60 mL/min/1.73 m2; BMI, body mass index; SBP, systolic blood pressure; DBP, diastolic blood pressure; FBS, fasting blood sugar; HbA1c, hemoglobin A1c; LDL, low-density lipoprotein; HDL, high-density lipoprotein; eGFR, estimated glomerular filtration rate; PCR, total protein-to-creatinine ratio; NAPCR, non-albumin protein-to-creatinine ratio; Transferrin/Cr, transferrin-to-creatinine ratio; RBP/Cr, retinol binding protein-to-creatinine ratio; NGAL/Cr, neutrophil gelatinase-associated lipocalin-to-creatinine ratio; r, coefficients of correlation; values of p < 0.05 were considered significant.Additional file 3: Table S3. Multivariate regression analysis with total protein-to-creatinine ratio as the dependent variable. Note. Group 1, eGFR ≥60 mL/min/1.73 m2; Group 2, eGFR < 60 mL/min/1.73 m2; ACR, albumin-to-creatinine ratio; NAPCR, non-albumin protein-to-creatinine ratio; Transferrin/Cr, transferrin-to-creatinine ratio; RBP/Cr, retinol binding protein-to-creatinine ratio; NGAL/Cr, neutrophil gelatinase-associated lipocalin-to-creatinine ratio. Model 1, adjusted for age, gender and duration of diabetes. Model 2, adjusted for age, gender and duration of diabetes, SBP. Model 3, adjusted for age, gender, duration of diabetes, SBP, HbA1c, LDL and eGFR. Values of p < 0.05 were considered significant.Additional file 4: Table S4. Multivariate regression analysis with albumin-to-creatinine ratio as the dependent variable. Note. Group 1, eGFR ≥60 mL/min/1.73 m2; Group 2, eGFR < 60 mL/min/1.73 m2; PCR, total protein-to-creatinine ratio; NAPCR, non-albumin protein-to-creatinine ratio; Transferrin/Cr, transferrin-to-creatinine ratio; RBP/Cr, retinol binding protein-to-creatinine ratio; NGAL/Cr, neutrophil gelatinase-associated lipocalin-to-creatinine ratio. Model 1, adjusted for age, gender and duration of diabetes. Model 2, adjusted for age, gender and duration of diabetes, SBP. Model 3, adjusted for age, gender, duration of diabetes, SBP, HbA1c, LDL and eGFR. Values of p < 0.05 were considered significant.Additional file 5: Table S5. The comparison of ROC curves of different urinary markers in type 2 diabetes subjects. Note. ACR, albumin-to-creatinine ratio; PCR, total protein-to-creatinine ratio; NAPCR, non-albumin protein-to-creatinine ratio; Transferrin/Cr, transferrin-to-creatinine ratio; RBP/Cr, retinol binding protein-to-creatinine ratio; NGAL/Cr, neutrophil gelatinase-associated lipocalin-to-creatinine ratio; values of p < 0.05 were considered significant.


Portal hypertension is a severe complication caused by various chronic liver diseases. The standard methods for detecting portal hypertension  are available in only a few hospitals due to their technical difficulty and invasiveness; thus, non-invasive measuring methods are needed. This study aimed to establish and assess a novel model to calculate free portal pressure based on biofluid mechanics.Comparison of each dog’s virtual and actual free portal pressure showed that a biofluid mechanics-based model could accurately predict free portal pressure  and had a high AUC , sensitivity , specificity , positive likelihood ratio , and low negative likelihood ratio  for detecting portal hypertension.Our study suggests that the biofluid mechanics-based model was able to accurately predict free portal pressure and detect portal hypertension in canines. With further research and validation, this model might be applicable for calculating human portal pressure, detecting portal hypertensive patients, and evaluating disease progression and treatment efficacy. Portal hypertension is known as a severe disease with a poor outcome. It can threaten people’s lives if the gastroesophageal varices rupture and are not treated in time , 2. PortBiofluid mechanics is the study of biological flow mechanisms and the inter-relationships with physiological and pathological processes using the fundamental principles of fluid mechanics . Using bThe aim of this study was to establish and assess a biofluid mechanics-based model for predicting FPP and detecting portal hypertension in canines.4-treated groups developed liver fibrogenesis, had lower blood flow velocity, wider blood vessel diameters, and higher liver function and FPP values as compared with those from a control group. These results proved the success of our canine portal hypertensive model.To validate canine portal hypertensive models, we focused on canine liver fibrogenesis Fig. , liver fWe imported canine abdominal CT images into the IQQA-Liver system to produce a three-dimensional portal venous model, in which the portal vein and its main branches, including the left and right portal vein, the splenic vein, the superior mesenteric vein, and the inferior mesenteric vein, were visualized precisely. We used FLUENT software to divide the model . The concordance correlation coefficient was 0.97 (95% CI: 0.93 to 0.99). These results showed that the vFPP model provided a good prediction of FPP.To assess the numeric correlation between vFPP and FPP, we performed Bland and Altman’s limits of agreement analysis Fig. a, the inP < 0.0001). We selected vFPP = 12 mmHg as the criterion value. The sensitivity was 92.3 (95% CI: 64.0 to 99.8); the specificity was 91.7 (95% CI: 61.5 to 99.8); the positive likelihood ratio was 11.1 (95% CI: 1.7 to 72.8); the negative likelihood ratio was 0.08 (95% CI: 0.01 to 0.6).To evaluate the performance of vFPP in the diagnostics of portal hypertension, we carried out receiver operating characteristic (ROC) curve analysis Fig. d. The arAll canines survived and had no important adverse events during the experiment.Portal hypertension is a life-threatening disease. Portal pressure measurement is of great importance because it is the standard method for detecting portal hypertension. Moreover, portal pressure strongly correlates with severe complications, such as hepatocellular carcinomas, gastro-oesophageal variceal haemorrhaging, hepatic encephalopathy, and ascites . In thisThe IQQA system, the FLUENT software, and the Navier-Stokes equations have been widely used to reconstruct blood vessels, simulate blood flow, and precisely calculate the haemodynamics –24. In t4 to dogs for 1, 2, 3 or 4 months to represent different stages of portal hypertension. Our result showed that our model was suitable for not only severe but also mild portal hypertensive and even normal canine functionality. Moreover, our model was able to predict the vFPP value, which was another advantage over previous models. We used five time points , because there were few references reporting the adverse events for this method. We were concerned that some canines might be unable to survive 4 months of continuous injection of CCl4 and planned to terminate CCl4 injection if two dogs from the earliest group died. For example, if two dogs had lived for only 2 months during continuous injection of CCl4, then we would have terminated CCl4 injection at that time point; therefore, there would have been only three groups left: Control, CCl4 (1 month), and CCl4 (2 months). However, if we had designed only three time points  in this study, then in this situation, there would have been only two groups left: Control and CCl4 (2 months), which would have been insufficient to reflect different stages of cirrhosis and portal hypertension.Iranmanesh and Liu also established models for detecting portal hypertensive patients, which showed good diagnostic performance with high sensitivity and specificity , 28. AltOur non-invasive methods could calculate vFPP from CT, blood tests, and Doppler ultrasound results. Similarly, we could use these methods to simulate the blood flow of the inferior vena cava and hepatic veins, and calculate the virtual hepatic venous pressure (vHVP) and virtual HVPG (the difference between vFPP and vHVP). With further research and validation, this model might be applicable for calculating human vFPP and virtual HVPG, detecting portal hypertensive patients, and evaluating disease progression and treatment efficacy.There are some limitations in this study. Firstly, although we demonstrated a high correlation between vFPP and FPP, this result was acquired from canines, not humans. We chose beagles as experimental animals because they have a moderate body size and a digestive system similar to humans. It is also easy to perform examinations on them. In addition, the methods and results of this study might be applied to humans more appropriately. After this study, we applied this model to several portal hypertensive patients who underwent portosystemic shunts or splenectomy with periesophagogastric devascularisation and found similar results (unpublished observations). We are currently carrying out a prospective, randomised, non-controlled, multicentre trial  to further validate this model in humans . SecondlThe non-invasive and biofluid mechanics-based model could accurately predict FPP and had high sensitivity and specificity for detecting portal hypertension in canines. With further research and validation, this model might be applicable for calculating human FPP, detecting patients with portal hypertension, and evaluating disease progressions and treatment efficacies.4. The 25 dogs were divided randomly into five 5-member groups: Control, CCl4 (1 month), CCl4 (2 months), CCl4 (3 months), and CCl4 (4 months). Randomisation was based on a computer-generated random digits table. Each dog’s group was blind to the researchers responsible for histological staining, laboratory tests, Doppler ultrasound, CT, FPP measurement, and vFPP computation in order to prevent biases. The 20 dogs in the CCl4-treated groups began receiving CCl4 administration 1, 2, 3 or 4 months before the end of the study, so that all dogs reached the end of the study simultaneously. CCl4 was dissolved in olive oil (60% CCl4 and 40% olive oil) and injected subcutaneously in the dorsal area of the canines. This administration was repeated every 10 days at a dose of 1.0 to 1.3 ml/kg. Histological staining, laboratory tests, Doppler ultrasound, CT, FPP measurement, and vFPP computation were performed at the end of the study. All canines survived and continued to live in the laboratory animal department of Shanghai Jiagan Biotechnology Co., Ltd. after the study.The canines used in this study were purchased from the laboratory animal department of Shanghai Jiagan Biotechnology Co., Ltd. as experimental animals. The study protocol was reviewed and approved by the Animal Care and Use Committee of Shanghai Ninth People’s Hospital, School of Medicine, Shanghai Jiao Tong University. All procedures were conducted according to the Animal Experimentation Guidelines of Shanghai Jiao Tong University. The study was performed on 25 adult male beagles (10.5 to 12.5 kg), which were caged with constant temperature (25 °C), humidity (60 ± 10%), and circadian-rhythmic lighting in the laboratory animal department of Shanghai Jiagan Biotechnology Co., Ltd. To reflect different stages of cirrhosis and portal hypertension, canine portal hypertensive models were induced by continuous subcutaneous injection of CClHepatic tissue was taken and fixed in 10% formalin and embedded in paraffin. The paraffin-embedded tissue was sectioned at 5 μm and then placed on slides, deparaffinized in xylene, hydrated in decreasing concentrations of ethanol, and washed in water. After hematoxylin-eosin staining, Masson’s trichrome staining, and Sirius red staining, the sections were examined under a microscope.Each dog’s peripheral blood samples were taken from the small saphenous vein of the hind leg for blood viscosity and liver function tests. The blood density test was performed by weighing 1 millilitre of blood using an electronic balance. The blood density measurements were repeated at least three times and then averaged.Each canine underwent an abdominal Doppler ultrasound scan after an overnight fast and a venous injection of pentobarbital sodium 30 mg/kg) in accordance with previously published methods [ mg/kg inEach dog was fixed in the supine position and underwent an abdominal contrast-enhanced CT after an overnight fast and a venous injection of pentobarbital sodium (30 mg/kg) in accordance with previously published methods , 32. A nEach canine’s FPP was measured after general anaesthesia. An abdominal midline incision was made, exposing the right gastroepiploic vein, and a pressure sensor-connected catheter was inserted into the portal vein through the right gastroepiploic vein. The FPP was recorded by a physiological signal acquisition system. The right atrium pressure was defined as the zero reference point.The simulation model of the canine portal venous system, which was created from canine CT images by the IQQA-Liver system version 2.0 , was imported into the Fluent software version 6.3 . The model was divided into different parts, with each inlet and outlet branch identified as a separate part. The model surface was then meshed into 0.2–1.0 mm triangular surface grids and the body meshes were created accordingly. The laminar viscous model was used. The material type was set to fluid, blood density and overall viscosity were used as the properties of the fluid. The pressure outlet boundary conditions module was used for the portal vein, with the following parameters: backflow reference frame: absolute; gauge pressure: 0; backflow direction specification method: normal to boundary; radial equilibrium pressure distribution: disabled; average pressure specification: disabled; target mass flow rate: disabled. The velocity inlet boundary conditions module was used for each inlet and outlet branch, with the following parameters: velocity specification method: magnitude, normal to boundary; reference frame: absolute; supersonic/initial gauge pressure: 0. The velocity magnitude value was set to the blood flow velocity at the boundaries of each branch, which was calculated according to the inner diameter, blood flow velocity and direction measured by Doppler ultrasound, the inner diameter at the boundaries obtained from the simulation model, and the principle of mass conservation. The equations are as follows:b: inner diameter at the boundaries; vb: velocity at the boundaries; dus: inner diameter measured by Doppler ultrasound; vus: velocity measured by Doppler ultrasound.Q: volume flow rate; A: cross-sectional area; v: velocity; dAccording to Doppler ultrasound images (one case is shown in Fig. The mass conservation equation:m: mass added to the continuous phase.ρ: density; t: time; SFor axisymmetric geometries, the mass conservation equation can be written as follows:x: axial velocity; vr: radial velocity.x: axial coordinate; r: radial coordinate; vThe momentum conservation equation:p: static pressure; μ: molecular viscosity; I: unit tensor; T: temperature.The energy conservation equation:eff: effective conductive coefficient; h: enthalpy; J: diffusion flux; Sh: volumetric heat sources.E: total energy of fluid; kE, the total energy of fluid, can be written as follows:The FLUENT software was used to solve the Navier-Stokes equations, simulate the blood flow within the portal venous system, and obtain the pressure on each volume grid. The vFPP equals the pressure at the centre of the portal vein.Continuous variables were checked for normal distribution and summarized by either mean ± standard deviation or median and inter-quartile range, as appropriate. Comparison of continuous variables were performed using Student’s t-test or analysis of variance for normally distributed variables and the Mann-Whitney U test or the Kruskal-Wallis test for non-normally distributed variables as appropriate. The numeric correlation between FPP and vFPP was analysed by Bland and Altman’s limits of agreement analysis . Bias wa


Less effective autoregulation in the first 24 h following the LSW time was associated with increased rates of parenchymal hematoma types 1 and 2 hemorrhagic transformations (PH1–PH2). These data suggest that patients with incomplete recanalization and poor autoregulation  may warrant closer blood pressure monitoring and control in the first few days post ictus.The development of the endovascular thrombectomy (EVT) technique has revolutionized acute stroke management for patients with large vessel occlusions (LVOs). The impact of successful recanalization using an EVT on autoregulatory profiles is unknown. A more complete understanding of cerebral autoregulation in the context of EVT may assist with post-procedure hemodynamic optimization to prevent complications. We examined cerebral autoregulation in 107 patients with an LVO in the anterior circulation  and internal cerebral artery (ICA) terminus) who had been treated using an EVT. Dynamic cerebral autoregulation was assessed at multiple time points, ranging from less than 24 h to 5 days following last seen well (LSW) time, using transcranial Doppler ultrasound recordings and transfer function analysis. Complete  3) recanalization was associated with a more favorable autoregulation profile compared with TICI 2b or poorer recanalization ( Acute stroke management has improved dramatically over the past few years, particularly with the development of the endovascular thrombectomy (EVT) technique for large vessel occlusion (LVO) strokes ,2,3,4,5.Cerebral autoregulation is the ability of cerebral vasculature to maintain stable cerebral blood flow despite fluctuations in the systemic blood pressure through modulation of the cerebrovascular tone ,9. This However, the effect of the recanalization of affected vessels with EVT on cerebral autoregulation remains unknown. Although clinical practice varies, many stroke and critical care neurologists aim for tighter blood pressure control in patients via successful recanalization using EVT compared to those who did not undergo EVT, with the assumption that all patients will have impaired autoregulation and therefore are at a high risk of reperfusion injury after recanalization . HoweverThe objective of this study was to assess the dynamic cerebral autoregulation in patients with LVO who underwent EVT and determine the relationship between the degree of recanalization and the cerebral autoregulatory profiles over the first 5 days following their LSW time using transcranial Doppler (TCD).Adult patients with a large vessel occlusion in the anterior circulation  and the internal cerebral artery (ICA) terminus), with a National Institutes of Health Stroke Scale (NIHSS) score ≥6 at any time within 72 h of the last seen well (LSW) time who underwent endovascular thrombectomy were eligible for the study. Patients were enrolled if the first TCD measurement could be performed within 120 h of the LSW time. The exclusion criteria included the inability to tolerate TCD measurements and inadequate temporal acoustic windows for TCD measurements. Patients were recruited from both the Brigham and Women’s Hospital in Boston, Massachusetts, and the Centro Hospitalar Universitário São João in Porto, Portugal, between December 2016 and January 2019. The institutional ethical standards committees at both hospitals approved this study, and written consent was obtained from each subject or healthcare proxy.Members of the stroke team found the NIHSS score at admission and discharge for each patient. The Thrombolysis in Cerebral Infarction (TICI) scores were found post thrombectomy  and incomplete (TICI 2a/2b)), with TICI 2a representing less than 50% reperfusion of the affected territory and TICI 2b representing greater than 50% reperfusion . The inf2) was continuously recorded using a nasal cannula attached to a capnograph .The TCD data were collected at multiple time points post-LSW time in each patient with data collected at <24 h (66 patients), 24–72 h (47 patients), 72–96 (27 patients), and/or >96 h (23 patients) after the LSW time. Bilateral 2 MHz probes were applied with a headset to insonate the bilateral proximal middle cerebral arteries (MCAs)for data acquisition. In situations in which flow velocities in the M1 segment of the MCA were not reliable due to insufficient recanalization, proximal M2 segments were insonated; if this was not possible, patients were excluded. Simultaneous blood pressure recordings were performed using either a noninvasive monitoring device  or an arterial line if clinically indicated, as appropriate. Prior work has demonstrated similar results in dynamic cerebral autoregulation parameters using blood pressures derived from Finapres and arterial line techniques . In the Transfer function analysis was used to determine the relationship between spontaneous fluctuations in the mean cerebral blood flow velocity (CBFV) and mean arterial pressure (MAP) . The traWe have relied on spontaneous, rather than induced, blood pressure and cerebral blood flow oscillations for assessing the autoregulation. While assessing cerebral autoregulation through induced blood pressure changes has recently been shown to be a more reliable metric , this teWe have previously shown that the coherence at the frequency bands used in this study is a relatively reliable measure of the integrity of autoregulation, although the gain and phase shift may be less reliable . By defip > 0.1 for all). Thus, the cerebral blood flow measurements of each hemisphere were used as repeated measures. The two frequency band ranges (<0.03 Hz and 0.03–0.07 Hz) were considered separately.Our initial analysis provided evidence of bilateral impairments in autoregulation; there were no significant hemispheric differences in the estimated transfer function  between contralateral and ipsilateral sides within each frequency region and across all measurements (ANOVA We used linear mixed-effects models with the group (complete (TICI 3) vs. incomplete (TICI 2a/b) recanalization) and time point  as the fixed effects, and the measurement side and time point nested within each patient as random effects. This allowed us to reliably explore the differences in cerebral autoregulation while explicitly accounting for the repeated measurements and the missing data and/or time points. Whenever a significant effect was evident, we used appropriate post-hoc analyses to identify the differences across time points.p < 0.05).A total of 136 subjects with large vessel occlusions were enrolled, of which, 107 subjects had useable data. Patients were excluded due to atrial fibrillation, a high burden of premature ventricular contractions (PVCs), and a poor signal-to-noise ratio in the recorded data. This relatively high proportion of patients with non-utilizable data was possibly reflective of the critical care population with a higher incidence of cardiac dysrhythmias and PVCs; patient agitation may have also been contributory. Of the 107 subjects, 39 showed “incomplete” recanalization (TICI 2a or 2b), and 68 showed “complete” recanalization (TICI 3) . Of notep < 0.01) compared with patients with complete (TICI 3) recanalization (p < 0.01 for coherence and p = 0.01 for gain) and LF bands (time × infarct size effect p = 0.01 for coherence)  recanalization had significantly higher infarct volumes at 24 h and lower early neurologic recovery , and then gradually return to the <24 h values, while the gain peaked at 72–96 h . Incomplete recanalization (TICI 2a or 2b) was associated with a higher coherence and a higher gain, i.e., worse autoregulation (significant differences were observed in the VLF band and a trend that did not achieve significance was observed in the LF band) . Given that the infarct volume was significantly higher in patients with incomplete recanalization and the potential effects of the infarct volume on cerebral autoregulation, this effect was accounted for in our analysis (discussed further in the Methods section). Moreover, the end-tidal CO2 levels tended to be higher in larger strokes .Time-dependent impairments in cerebral autoregulation were observed in both groups. Cerebral autoregulation was observed to initially worsen and gradually recover approximately 72 h after an ischemic stroke, the effects of which were significantly more pronounced in patients with incomplete recanalization . Coherenp = 0.63, occlusion side and hemorrhage × occlusion interaction p < 0.01; LF: hemorrhage type p = 0.73, occlusion side p < 0.01, and interaction p = 0.01). There were no significant differences in the gain  or the phase  in the <24 h after the LSW time period. There were no statistically significant differences in any of the transfer function parameters relative to the hemorrhage during any of the other time points.Impairment in the cerebral autoregulation within the first 24 h after a stroke onset was also associated with a hemorrhagic transformation . Among p2 levels were shown to demonstrate a temporal trend with higher levels in patients with incomplete recanalization (TICI 2b or less) compared with TICI 3. This was statistically significant after 96 h, p = 0.03  recanalization after the thrombectomy had less severe impairments in their autoregulation than patients with incomplete recanalization (TICI 2a or 2b). Impairments in autoregulation were primarily observed 24 to 96 h after the LSW time and were bilateral, affecting both the ipsilateral and contralateral hemispheres, supporting prior work demonstrating the presence of global impairments in autoregulation after an ischemic stroke ,13,37. HTo our knowledge, this is the first study to examine the effects of the degree of recanalization post thrombectomy on cerebral autoregulation. These findings have important implications for patient management. First, the observation that incomplete recanalization may place patients at risk for less efficient autoregulation provides additional support for technique optimization aimed at achieving complete (TICI 3) recanalization, particularly given prior data showing that impairments in autoregulation correlate with larger infarct sizes and worse long-term outcomes ,13. Seco2 demonstrated in this study highlight the importance of monitoring this variable in large vessel occlusion ischemic stroke patients, especially in the immediate peri-procedural and post-procedural period, given its known effect on cerebral blood flow [2 levels in patients with incomplete recanalization, especially at later time points, is intriguing and may reflect higher infarct volumes, which this variable  was shown to be associated with. However, this finding is not sufficient to account for all the between-group differences noted in the cerebral autoregulation, which were demonstrated early, while the end-tidal CO2 differences were more obvious at time points beyond 96 h. The temporal changes in the end-tidal COood flow ,19. The Notably, the hemorrhagic transformation (PH1–PH2)  was primThere are inherent limitations of the TCD for continuous blood flow monitoring. TCD provides a measure of the blood flow velocity but not the flow rate. However, the former is an adequate surrogate for the latter as long as the diameter of the insonated artery remains constant. Given that we acquired data in the semi-supine position and relied on spontaneous measurements, we did not anticipate any changes in the observed artery diameter. We also note that autoregulation in the examined vascular territories  may not be reflective of autoregulation in other vascular territories. Second, the requirement of adequate acoustic windows to obtain data and difficulties with identifying completely occluded versus partially occluded vessels in the absence of transcranial color-coded duplex sonography can lead to increases in interobserver variability. We attempted to minimize the interobserver variability by ensuring all our TCDs were performed by three professional sonographers . Third, we used conventional frequency ranges to assess cerebral autoregulation. However, as noted before ,28, thesDespite its limitations, our results suggest that dynamic cerebral autoregulation was impaired in a time-dependent manner after an LVO stroke and an EVT, and complete recanalization (TICI 3) was associated with an improved autoregulatory profile compared to an EVT with incomplete recanalization. These results strongly suggest that patients with incomplete recanalization may require closer hemodynamic monitoring up to 4 days post thrombectomy.


A Mobil-O-Graph monitor was used for measuring hemodynamic parameters. Only 6.2% of patients were professionally active, 19% used a wheelchair for transport, and 16% used crutches. More than half (51%) were independent in everyday activities reaching 80–100 points on Bi. The rest, with Bi < 80, were considered as dependent. The most common causes of disability were CV complications. The independent group (80–100 points) was characterized by significantly lower pulse wave velocity (PWV) and lower QRISK®3 compared to dependent patients. The degree of disability negatively correlated with age, PWV, and QRISK®3. Multivariate logistic regression revealed that disability (Bi < 80) was independently associated with CV events in the past adjusted odds ratio (adj.OR) 4.83 : 1.74–13.41) and higher PWV adj.OR 1.45 (95% CI: 1.15–1.82). Our results indicate that CV diseases are the most important cause of functional impairment.The number of elderly hemodialysis patients is constantly increasing worldwide. This population has a high burden of comorbid conditions, which impair daily activities. The aim of the study was to analyze problems of disability in hemodialysis patients in the context of cardiovascular (CV) complications and vascular condition. In this cross-sectional study, 129 patients (mean age 64.5) were enrolled. The degree of disability in Barthel index (Bi) and 10-year cardiovascular risk (QRISK Patients aged 75 years or older represent the fastest growing segment of the subjects starting dialysis . This poThe aim of the study was to analyze the problems of FD in HD patients in the context of cardiovascular complications and vascular condition.The potential participants were identified through a review of all patients undergoing hemodialysis who were recruited from two dialysis stations.The inclusion criteria for hemodialysis patients were as follows: (1) age 18 years and over, (2) received regular dialysis for at least 6 months, and (3) were able to provide informed consent. The exclusion criteria included the following: (1) currently enrolled in another study or (2) receiving emergency in-patient care within four weeks. Written informed consent was received from each patient entering the study. Of the 139 eligible participants, 10 did not agree to take part in the study. Patients who were not recruited were similar in age and gender to those participating in the study. ®3 online calculator).One hundred twenty-nine patients  were enrolled in this cross-sectional study. Demographic and comorbidity data were collected from medical records and from a direct interview. This information allowed us to assess their degree of disability (Barthel index) and a 10-year cardiovascular risk (QRISKCardiovascular (CV) diseases included diseases of the heart, vascular diseases of the brain, and diseases of blood vessels  particulCoronary heart disease was defined as self-reported or on the basis of a history of myocardial infarction, coronary angioplasty, or bay-pass grafting. Stroke included a history of transient ischemic attack in the past or an ischemic/hemorrhagic event with neurological consequences. Peripheral arterial disease was defined as self-reported or medical report history of lower extremity angioplasty or significant vessel stenoses in imagine tests, amputation due to ischemia. In most of patients , two or more disorders were found, which may have a negative impact on performing ADLs. In such cases, an algorithm of choosing the leading disorder, responsible for disability, relies on determining which disorder was the most important in ADLs disability. Weakness associated with dialysis, as a leading disorder of disability, was found as self-reported when severely limiting the mobility and after excluding other potential factors of low muscle strength. Joint and skeletal system manifestation encompassed disorders typical for aging, i.e., degenerative joint diseases, but also disorders related to dialysis, such as following: Chronic Kidney Disease–Mineral and Bone Disorder (CKD-MBD), renal osteodystrophy due to secondary hyperparathyroidism, and dialysis-related amyloidosis.The Barthel index is a 10-item instrument, measuring functional independence, in personal activities of daily living (ADLs) and the need for supervision or support. It is composed of 10 categories and includes the following items: feeding, bathing, grooming, dressing, bowel control, bladder control, toilet use, and transfers (bed to chair and back) ,8. The s®3 score is an online tool evaluating a 10-year risk of cardiovascular accident and it was validated for different ethnicities and CKD patients [QRISKpatients . It takeIn addition, ambulatory measurements of hemodynamic parameters with Mobil-O-Graph monitor (Industrielle Entwicklung Medizintechnik und Vertriebsgesellschaft GmbH (IEM), Stolberg, Germany), which records oscillometric arm blood pressure: systolic and diastolic blood pressure (SBP and DBP), central systolic and diastolic blood pressure (cSBP and cDBP), pulse pressure (pPP), ejection fraction (EF), cardiac output (CO), and pulse waves. It calculates the augmentation index normalized to the heart rate (Aix@75) as a measure of wave reflections, and pulse wave velocity (PWV) as a measure of arterial stiffness. All tests were performed before the start of the one-day hemodialysis sessions.t-test was used to compare the means of two continuous variables and the chi-square test for categorical variables. The relationship between two continuous variables was evaluated using the Pearson correlation. The unadjusted and adjusted multivariate Cox regression analysis was presented as an odds ratio ). A p-value < 0.05 was considered significant.Statistical analysis was performed using standard software ). Data for continuous variables were expressed as means and standard deviations. Paired independent sample Ethics approval was granted by the Ethics Board of Wroclaw Medical University No KB 587/2018.The baseline demographic and blood chemistry characteristic are displayed in ®3, and fewer CV events in the past compared to the dependent group (p > 0.05). The degree of disability according to Barthel index was negatively correlated with age, PWV, and QRISK®3  was characterized by a significantly lower PWV, QRISKnt group . In the  QRISK®3 .Development and results of logistic regression model.®3, age, higher PWW, lower diastolic pressure (DBP and cDBP), higher central pulse pressure (cpPP). No significant relationship with disability was observed for Aix@75, BMI, dialysis vintage SBP and MBP, and parameters of heart function .Crude odd ratios (ORs) for all predictors are shown in Based on a correlation analysis between each predictor, the groups of strongly associated predictors were extracted and finally one representative was chosen to avoid collinearity. All the remaining predictors were entered into a multivariable logistic regression model to obtain adjusted estimates. CV events in the past and higher PWV were the strongest, independent predictors for ADL disability with adjusted ORs 4.83 (95% CI: 1.74–13.41) and OR 1.45 (95% CI: 1.15–1.82), respectively .Disability is defined as difficulty or dependency in carrying out activities that are essential to independent living. The Barthel index encompasses 10 activities of daily living (ADLs): feeding, bathing, grooming, dressing, using a toilet, bowels and bladder incontinence, transfers, mobility, and use of stairs. The inability to perform such activities engages family members or other informal caregivers. In addition, ADLs disability may strongly predict morbidity, mortality, and hospitalization in dialysis adult [The results of our recent study reflect three important findings regarding ADLs disability. The first was that disability is common in the end-stage renal disease (ESRD) population. Half of the studied population (48% of patients) was functionally dependent and their Barthel index was lower than <80 points, which means that they need support in at least one ADL. Previous studies reported the approximate rates of functional impairment in ADLs (29–52%) ,12. The The second discovery was that cardiovascular (CV) complications are the leading cause of disability. The history of CV event was observed in 66% of study subjects and more frequently in the group of dependent patients . The group of dependent patients is characterized by significantly increased arterial stiffness expressed by pulse wave velocity PWV; . Lower dData from the Dialysis Outcomes and Practice Patterns Study (DOPPS study) confirm that there is an independent relationship between functional impairment and adverse health outcomes . The accNaturally, cardiovascular diseases are not a separate culprit of impaired functioning. In 22% and 14% of participants, fatigue/weakness associated with dialysis and skeletal system manifestations were the leading cause of FD, respectively. This issue should be discussed in connection, as both include non-atherosclerosis disorders frequently limiting functional independence. Sarcopenia is a common disturbance in the dialysis population and is associated with physical disability and mortality ,30. The In our analysis, the duration of renal replacement therapy has no impact on functional impairment. Due to the cross-sectional character of the study, this finding should be regarded with caution, as from clinical practice functional decline is usually observed in most patients after years of dialysis. In a large study from Taiwan, using the Barthel index for a longitudinal evaluation of functional dependence, in follow-up time of 13 years, the authors found that patients who started dialysis at an age above 35 years experienced approximately 3 years of disability; however, with age increases the proportion of functional disabilities and care needs . It shouIdentification of a functional decline in the HD population may be clinically important, because early intervention may diminish the degree of disability. Some evidence suggests that multidisciplinary rehabilitation programs may improve the ability to perform different tasks of daily living. These programs should encompass counselling with a specialized team, including a physiotherapist, psychiatrist, behavioral specialist, geriatrist, or others when appropriate. Individualized, supervised, or grouped exercise training may significantly improve muscle strength and performing ADLs even in low functioning patients ,43. SomeA few limitations should be underlined when assessing our findings. Precise data indicate that except stiffness of large and small arteries, many factors may influence hemodynamic parameters of pulse wave analysis including cardiac output, existence of arteriovenous fistula, and hydration status of the individual patients . Owing tTo our knowledge, this is first study evaluating functional disability (FD) in hemodialysis (HD) patients in the context of vascular conditions. Our results indicate that half of HD patients show some degree of FD, with considerable consequences on their autonomy. Functional independence in the HD population appears to be the exception rather than the rule. Cardiovascular (CV) events are the most important cause of functional decline. The group of patients with a higher degree of disability is usually older and characterized by a high burden of CV complications. Additionally, more advanced changes in the arteries might be the reason for the higher risk of CV incidents in the future.


Increased urinary albumin excretion (UAE) in diabetes is a sensitive marker of microvascular injury and a reliable predictor of cardiovascular outcomes. Hypertension-induced hemodynamic pressure load, diabetes-related metabolic processes and large artery stiffening have all been implicated in the development of microalbuminuria. We investigated whether hyperglycemia per se, or rather increased blood pressure (BP) and macrovascular dysfunction, is a stronger predictor of UAE at the earliest stages of diabetes.Consecutive newly diagnosed patients with diabetes type 2, who were normoglycemic within a year’s time prior to diagnosis, were enrolled. UAE was estimated in 24-h urine samples. Both office and 24-h ambulatory BP was recorded. Arterial stiffness was evaluated by measurement of carotid-femoral pulse wave velocity (PWV) with applanation tonometry.p = 0.049).Among 71 newly diagnosed patients with median diabetes duration of just 1 month, 15.5% presented microalbuminuria. UAE did not differ between hypertensive and normotensive diabetics; however, newly diagnosed patients for both hypertension and diabetes exhibited significantly higher levels of UAE, compared to diabetic patients with long-standing hypertension. UAE strongly and significantly correlated with office systolic BP, HbA1c, PWV and estimated glomerular filtration rate. However, in the multivariate analysis adjusting for these factors, only HbA1c was independently associated with UAE (beta = 0.278, Hyperglycemic state emerges as a powerful predictor of increased UAE even at the earliest stages of diabetes. The relative contribution of hypertension and macrovascular dysfunction to the development of microalbuminuria seems to be obscured by hyperglycemia, even in patients whose diabetes onset does not exceed a few months’ time. Microalbuminuria, typically defined as urinary albumin excretion (UAE) of 30–300 mg in a 24-h urine sample, corresponds to a subclinical microvascular derangement in the glomerular filtration barrier that precedes overt diabetic nephropathy . It has Apart from diabetes, hypertension represents a major risk factor for increased UAE. When both diseases coincide in the same individual, which is typically the case for the vast majority of patients with diabetes mellitus type II (DMII), the risk of developing microalbuminuria is substantially aggravated . AnotherAltogether, it remains unclear as to which extent hyperglycemia, increased blood pressure (BP) and macrovascular dysfunction, contribute to microalbuminuria in the very early stages of DMII, long before the establishment of the disease-related cardiovascular complications. Hence, the aim of our study was to investigate the association of increased UAE with high BP, hyperglycemia and arterial stiffness in a meticulously selected population of newly-diagnosed patients with DMII.We enrolled consecutive patients recently diagnosed with Diabetes Mellitus type II (less than 6 months from diagnosis). We excluded patients with cardiovascular disease or stroke, chronic kidney disease [glomerular filtration rate (GFR) ≤45 ml/min/m2], inflammatory diseases, and pregnancy, as well as patients that had or were receiving antidiabetic treatment were excluded, with the only exception of Metformin. DMII diagnosis was documented two impaired glucose tests in separate days [fasting blood glucose (FBG) ≥ 126 mg/dl and/or 2-h post-load glucose ≥200 mg/dl in oral glucose tolerance test ] , 10. We 2. Office systolic/diastolic BP (SBP/DBP) was measured with a validated oscillometric device  in the sitting position according to the guidelines , patients who were simultaneously diagnosed with both hypertension and DMII exhibited significantly higher levels of UAE, compared to diabetics who presented long-standing hypertension .Results of univariate correlation analysis of UAE with demographic, metabolic and blood pressure parameters are depicted in Table p = 0.013). Finally, increasing UAE was associated with renal function, reflected in GFR , in our population of newly diagnosed patients with DMII . These results imply that neither the concomitant diagnosis nor the long-standing history of hypertension can overcome the detrimental effect of hyperglycemia even at the very early stages of DMII. Importantly, only patients who were normoglycemic within a year’s time prior to the diagnosis were included, in order to verify the recent onset of DMII. Even though the rate of DMII-related microvascular complications increases with the duration of disease , 8 the pThe observed associations of UAE with BP and arterial stiffness merit further attention. Both were strongly and positively associated with UAE in the univariate analysis. However, the strength of these associations was attenuated and they were subsequently rendered non-significant after adjustment for HbA1c Table . ConsideLikewise, the association between arterial stiffness and UAE no longer remained significant after adjustment for HbA1c. Increased arterial stiffness has been proposed as an additional mechanism triggering microalbuminuria in patients with DMII, through increased intrarenal pulsatile stress and enhanced hemodynamic load in the renal tubules and glomeruli induced by large artery stiffening. This concept has been reinforced by several cross-sectional studies demonstrating an independent association between microalbuminuria and arterial stiffness in patients with DMII –16. HoweMechanisms responsible for microalbuminuria in hyperglycemic state include endothelial dysfunction and chronic inflammation triggered by oxidative stress, inflammatory cytokines and growth factors . GlycatiThe strengths of our study include our meticulously selected population of patients with very short duration of DMII, which is extremely difficult to find in the available literature, and the use of the gold-standard methods for the assessment of UAE and arterial stiffness. Presence of hypertension was not based on conventional office BP measurements, but was verified with 24-h ABPM recordings. Our study is limited by its cross-sectional design and the relatively small sample size. Consequently no conclusions can be deduced from the present study regarding potential associations between UAE and medication. Hence, our study might be considered rather as a pilot study, and further studies with a larger number of participants need to confirm our results. However, the difficulty of identifying patients with such short duration of DMII, who are free from significant comorbidities, needs to be acknowledged.In conclusion, our study identified increased HbA1c as the major mediator of renal microvascular impairment at the earliest stages of DMII. In patients with disease onset that does not exceed a few months’ time, hyperglycemia seems to obscure the observed associations of UAE with BP, renal function and arterial stiffness. These results stress out the need for early implementation of effective interventions targeting at this powerful modifiable predictor of microalbuminuria.


All testing sessions commenced at 8:00 a.m. each day and dCA parameters were quantified across the cardiac cycle  using transcranial Doppler ultrasound to insonate cerebral blood velocity within the middle and posterior cerebral arteries . No cardiac cycle alternations were seen spontaneous  while a trend was noted in some driven  dCA metrics. Driven dCA produced much lower coefficient of variances  compared with spontaneous . Moreover, no sex differences were found within driven metrics . Between vessels, PCA absolute gain was reduced within all spontaneous and driven measures  whereas coherence, phase, and normalized gain were unchanged . There appears to be little influence of diurnal variation on dCA measures across the day (8:00 a.m. to 6:00 p.m.). Absolute gain was blunted in the PCA relative to the MCA and consistent with previous literature, driven methods demonstrated vastly improved reproducibility metrics compared to spontaneous methods. Finally, no dCA differences were found between biological sexes, demonstrating that males and females regulate in a harmonious manner, when females are tested within the early follicular phase of the menstrual cycle.Presently, the literature describing the influence of diurnal variation on dynamic cerebral autoregulation (dCA) metrics is sparse. Additionally, there is little data with respect to dCA comparisons between anterior/posterior circulation beds and biological sexes using squat‐stand maneuvers. Eight male and eight female participants  metrics elicited more robust measures compared to spontaneous metrics across the day (8:00–18:00). Additionally, both the middle and posterior cerebral arteries regulated similarly across the day, as well did both males and female participants. Therefore, in the future when feasible, squat‐stand maneuvers should be used to assess dCA in participants, which can be performed in both vessels, across the cardiac cycle and in both biological sexes, as there is minimal influence of diurnal variation across the day within these measures. All participants were in good health with no history of neurological, cerebrovascular, cardiorespiratory, or musculoskeletal complications. Participants performed the standing (spontaneous) and squat‐stand (driven) protocol at seven time points throughout the day. To ensure the comparison between individuals were similar, all testing was initiated at 8:00 a.m. each day, and successive protocols were executed at 9:00 a.m., 10:00 a.m., 11:00 a.m., 1:00 p.m., 3:00 p.m., and 5:00 p.m. All participants remained within the testing location to ensure they remained at rest and were instructed to sit quietly for 5 min before each testing session, to minimize the likelihood any covariates  played a significant role in influencing the data . Eight females and eight males (This study was a subsection of a larger study examining the postexercise effects moderate‐intensity continuous training (MICT) and high‐intensity interval training (HIIT) have on cardiovascular (cardiac baroreceptor sensitivity and heart rate variability) and cerebrovascular function  was measured with an online gas analyzer  and was calibrated with known gas concentrations prior to data collection. Data were sampled at a frequency of 1,000 Hz  time‐locked, and stored for offline analysis with commercially available software .Heart rate was obtained through the use of a three‐lead electrocardiogram (ECG). Transcranial Doppler ultrasound was employed to insonate and quantify the right MCA blood velocity and the left PCA blood velocity in real‐time by placing 2‐MHz ultrasound probes (Spencer Technologies) over the temporal acoustic windows. Once vessels were insonated and identified, they were confirmed with a visual task and a carotid artery compression challenge  which adheres to the standards and rigors established in the Cerebral Autoregulation Research Network (CARNet) white paper , which congruently compared spontaneous to driven dCA methodology at two time points rather than seven  by seven  within‐subjects repeated‐measures ANOVA were performed for each TFA measure of interest . A priori Bonferroni post hoc corrected comparisons for simple effects were performed between the follow‐up time points to establish if any time point was different from the others. Data are presented as mean ± 2.5.3t tests were run for all dCA metrics  to determine if any measures were different between biological sexes or vessels. Each individual's data were collapsed across the seven time points in order to provide an averaged within‐subject estimate of dCA. Bonferroni corrections were applied for comparisons performed across the cardiac cycle . Data are presented as mean ± SD. Significance was set a priori at p < .05.Independent 33.12, resting standing blood pressure of 92 ± 6 mmHg, and resting standing heart rate of 85 ± 6 bpm  of 22 ± 2 kg/cm3.2ETCO2: all p > .565; MCA blood velocity: all p > .520; PCA blood velocity: all p > .111; mean arterial pressure: all p > .544; heart rate: all p > .229; Table ETCO2: all p > .140; MCA blood velocity: all p > .358; PCA blood velocity: all p > .186; mean arterial pressure: all p > .166; heart rate: all p > .334; Table At all seven time points across the day, all cardio‐ and cerebrovascular parameters were consistent during the 0.05 Hz squat‐stand maneuvers (P3.3p > .148) and spontaneous  or between the vasculature . Furthermore, at 0.05Hz, the blood pressure power spectrum density was congruent between biological sexes at diastole , mean , and systole . Likewise, at 0.10 Hz, the blood pressure power spectrum density was similar between biological sexes at diastole , mean , and systole .Between spontaneous and squat‐stand maneuvers at 0.05 Hz, blood pressure power spectrum density was increased an average of 78‐fold in diastole, 86‐fold in mean, and 96‐fold in systole, whereas at 0.10 Hz, it was augmented an average of 58‐fold at diastole, 69‐fold at mean, and 46‐fold at systole. The MCA power spectrum density was enhanced an average of 49‐fold in diastole, 47 in mean, and 46 in systole at 0.05 Hz and 46‐fold in diastole, 41‐fold in mean, and 11‐fold in systole at 0.10 Hz. At 0.05 Hz, the average PCA power spectrum density elevated 31‐fold in diastole, 45‐fold in mean, and 52‐fold in systole, whereas at 0.10Hz, it increased 43‐fold in diastole, 42‐fold in mean, and 11‐fold in systole. These did not differ between sexes in both driven , phase , absolute gain , or normalized gain  between any time points, in both the MCA and PCA across the cardiac cycle , phase , or normalized gain  while there was a trend for alterations in absolute gain  across the cardiac cycle in both the MCA and PCA for driven measures at 0.05 and 0.10 Hz ; however, no other VLF or LF spontaneous metric  differed between sexes  and driven measures  and driven metrics  Driven dCA measures demonstrated reduced levels of variation and greater reproducibility as demonstrated by the augmented coherence and minimal within‐subject CoV. (b) There was minimal variation present across the day due to diurnal factors, as noted in the driven oscillations across the cardiac cycle, whereas greater variation was observed within spontaneous measures. (c) The main conduit vessels within the cerebrovasculature (MCA and PCA) were regulated similarly within the squat‐stand protocols aside from the absolute gain metric. (d) No differences emerged between sexes in driven measures. Collectively, these results demonstrate driven dCA measures through squat‐stand maneuvers enable more robust interpretations to be drawn in anterior and posterior cerebral circulations across the typical workday (8:00–18:00) at all three phases of the cardiac cycle in both biological sexes. Furthermore, these results highlight the importance of normalizing the TFA gain value, as it is highly dependent upon the amount of blood pressure driving cerebral blood flow to the cerebrovascular region of interest.4.1Birch et al. 1995) were the first to propose squat‐stand maneuvers as a way to assess dCA; however, Claassen et al.,  were the were theMoreover, prior to this study, there have been no studies that have examined the effect diurnal variation on driven dCA measures across the workday. The current findings demonstrate that driven TFA coherence, phase, absolute gain, and normalized gain were consistent at both frequencies within both conduit vessels Figure  and were4.2There is substantial literature describing the circadian variation in CBV  investigated by Deegan et al., (p > .504) within all driven measures in the current investigation. Second, this may be attributable to the notion dCA metrics were collapsed across seven time points for each participant, thus increasing the accuracy of each estimate. Third, several research groups have noted that cardiorespiratory fitness levels may play a factor in influencing dCA metrics  found that the autoregulation index did not differ within the MCA and the basilar artery in young healthy participants , which is similar to the age range in this study . Similarly, Tontisirin et al.  found th4.5From this investigation, several implications can be drawn, which are imperative for future studies examining dCA metrics. The results within this study are in agreement with previous research .4.6ETCO2 levels . Additionally, both MCA and PCA regulated similarly across the day, as well did both males and female participants. Therefore, in the future when feasible, squat‐stand maneuvers should be used to assess dCA in participants, which can be performed in both vessels, across the cardiac cycle and in both biological sexes, as there is minimal influence of diurnal variation across the day within these measures. However, as mentioned, in some clinical populations this technique may not be possible, and thus other driven techniques should be used over spontaneous measures. Finally, future studies assessing dCA using repeated spontaneous measures should use caution when interpreting the results, as this study demonstrated TFA variables to vary substantially across the day.The authors declare they have no conflicts of interest.J.S.B. and J.D.S. designed the study. J.S.B., P.C., A.M., O.M., and J.D.S. performed data collection. J.S.B. and J.D.S. performed statistical analysis and interpreted the data. J.S.B., P.C., A.M., O.M., and J.D.S. contributed to writing and proofing the final version of the manuscript.


While certain adverse events for example, diabetic ketoacidosis and genital mycotic infections are reproducibly increased by SGLT2i, the absolute increase in the risk of these complications is smaller than the absolute risk reductions conferred by SGLT2i. Other complications such as amputations, fractures and urinary tract infections are increased to a lesser degree, or not at all . Overall, SGLT2is appear to have a favorable safety profile and thus should be used by cardiologists, nephrologists, endocrinologists, primary care physicians when managing the cardiorenal risk of their patients.Sodium glucose contrasporter 2 inhibitors (SGLT2i) were initially introduced as a novel class of modestly effective antiglycemics. Over the last 5 years, multiple members of this class have been examined for their cardiovascular safety, effects on heart failure with reduced ejection fraction (HFrEF) and chronic kidney disease (CKD) in diverse populations with or without diabetes type 2. The plethora of studies and outcomes examined make it difficult for the practitioner to track the entirety of the evidence. SGLT2i improve cardiorenal outcomes and have a beneficial risk benefit ratio across populations with cardiovascular disease, HFrEF and kidney disease. In this quantitative review, we synthesize the data from the large outcomes trials about the benefits and risks of SGLT2i. SGLT2i reduce all cause, cardiovascular mortality, heart failure hospitalizations, need for dialysis and acute kidney injury as a  While CREDENCE recruited patients with type 2 diabetes, DAPA‐CKD also included patients without T2D. These CKD trials not only demonstrated that the drugs reduced a composite that involved worsening kidney function, the need for dialysis, and reduced cardiovascular outcomes.DAPA‐HFThe rapidly expanding landscape of the SGLT2i trials can be rather daunting to follow, given the variable study designs, populations, and the sequential testing strategy employed by the study authors. There remains understandable confusion about the relative merits of one SGLT2i versus another since individual study results tend to be presented as “significant” or “nonsignificant” without consideration of the totality of evidence across trials. In the present meta‐analysis we will synthesize the primary outcomes and the high‐profile adverse events, which to the authors' opinion seem to act as a barrier against the wider adoption of the SGLT2i.22.1We included all randomized, placebo‐controlled studies involving SGLT2i that included cardiovascular endpoints, such as cardiovascular (CV) death, MACE‐3 and its components, HHF, or composite renal end‐points of the four commercially available selective SGLT2i in the United States . Other prospective and nonrandomized studies were all excluded.2.2https://medlinetranspose.github.io/). Using this query string , which was calculated by REstricted Maximum Likelihood (REML). The p‐value of the Q test was used to test for the statistical significance of the observed heterogeneity. To explore replicability of these findings we calculated the prediction intervalhttps://bitbucket.org/chrisarg/sglt2imetanalysis.Information about trial characteristics, primary and secondary outcomes efficacy measures  were extracted from the source publications and converted to log‐HR and standard errors by standard formulas. For the analysis of adverse events, the number of events in the SGLT2i and placebo arms in each trial, were analyzed via a logistic regression and the log‐odds (log‐OR) ratio and standard error were extracted from the logistic model output. Log‐HRs and log‐ORs were synthesized via fixed (FE) and random effects (RE) meta‐analysis, to provide an overall Treatment Effect. The fixed effects model assumes that the treatment effect will be the same across all trials, while the random effects model assumes that the treatment effect in each of the trials, are similar but not identical. Statistical heterogeneity among the trials synthesized was quantified by the I3The initial quantitative synthesisp = .0006) and 15% (p < .0001) across populations of high cardiovascular risk as a result of diabetes Type 2, HFrEF and CKD (with or without diabetes) with little evidence of heterogeneity by drug . One may be tempted to assign the suggestion of heterogeneity to the numerically smaller risk reduction seen in the VERTIS‐CV trial, but it Is in line with the heterogeneity seen in both empagliflozin  and dapagliflozin . For example: the risk of death was reduced to a greater degree in the CVOT of empagliflozin compared to its HFrEF trial, but this pattern was reversed with dapagliflozin.SGLT2i reduce cardiovascular Figure  and all‐p < .0001 for both) without any evidence of heterogeneity by study drug  and nonfatal MI by a similar amount , they had no effect on stroke. SGLT2i reduced worsening kidney function or ESKD by 39% (p < .0001). The beneficial effect on MACE‐3/MI and kidney outcomes were observed irrespective of the study drug, and trial type. Examination of the prediction intervals, shows that the effects on MACE‐3 and kidney function are very likely to be recapitulated in future SGLT2i trials, while some uncertainty exists about the replication of the effect on MI.We also examined the effects of SGLT2i on MACE‐3 Figure , Nonfatap = .35), but are associated with reproducible increases in the rate of diabetic ketoacidosis . Whereas the rate of amputations appears to be increased in participants receiving SGLT2i, the magnitude of the effect appears to be small (OR 1.22), the statistical significance of the association dependent on the statistical model used , and considerable uncertainty remains about the observed effect in future trials. Similarly, SGLT2i are associated with small increase in fractures, that is, OR of 1.13  and considerable uncertainty of the rate in future trials.SGLT2i are unlikely to cause hypoglycemia , but acute kidney injury (AKI) was reduced by 25% , with the latter effect expected to be highly reproducible given the narrow width of the prediction interval. Mycotic infections were increased to a large extent by SGLT2i , but urinary tract infections (UTI) to small degree .Volume depletion was increased to a small extent by SGLT2i renal benefits in patients with diabetes at risk for cardiovascular disease, cardiovascular benefit in patients with diabetic or non‐diabetic kidney disease, and heart failure benefit in patients with known HFrEF or CKD with or without diabetes. In this meta‐analysis we provide a quantitative summary of the effects of SGLT2i, by integrating the efficacy and safety findings from the large outcome trials.SGLT2i reduce all cause and cardiovascular mortality, the 3 point MACE, HHF, MI, while also stabilizing kidney function, reducing the risk of dialysis and the odds of AKI in a dose independent manner. Out of these findings, the ones most likely to replicate in future clinical trials are the MACE‐3, HHF and kidney specific effects. The current evidence points to a neutral effect on stroke. The price to pay for these benefits are higher rates of genital infections and DKA, and to a much smaller and less reproducible extent, UTIs, fractures and amputations. Benefits and harms are consistently observed across trial populations, with little if any evidence of heterogeneity by study drug, i.e. these appear consistent with class rather than drug specific effects. Similar to anti‐hypertensive in‐class differences, the challenge in gaining stronger evidence of in‐class differences is the extremely large sample size that would be required for the expected small differences.While the benefits of SGLT2i are large, clinically meaningful, and robust, they come with certain side effects that appear to be rather unpalatable e.g. mycotic infections, or serious, disfiguring, or even potential lethal e.g. amputations, fractures or DKA. Providers may thus hesitate to prescribe SGLT2i, and patients resistant to take them. However, any apprehension about SGLT2is disappears once the frequency of these side effects is contrasted to the benefits. This is best understood via specific examples. In EMPEROR‐Reduced, 24.7% versus 19.3% individuals experienced the primary outcome of HHF or cardiovascular death in the placebo and SGLT2i arms. On the other hand, the impressive OR of 3.9 for mycotic infections translates to an absolute increase in the probability of this event from 0.6% to 1.7%. A patient or a provider may value one death/HHF event averted, to be almost five times (since [24.7–19.3]/[1.7–0.6]~5) less valuable than one additional mycotic infection for them not to use SGLT2i. Similarly, the absolute increase in the rate of diabetic ketoacidosis and amputations in the canagliflozin arm of CREDENCE over placebo was 2.0 and 1.1 episodes per 1000 patient years. However, use of canagliflozin also resulted in absolute rate reductions of cardiovascular mortality and ESKD by 5.4 and 13.4 events per 1000 patient years, while reducing the rate of HHF by 9.6 events per 1000 patient years. For most patients, the small absolute increase in side effects would represent a highly acceptable trade‐off to avoid (cardiovascular) death or dialysis.Several meta‐analyses about the effects of SGLT2i were published in late 2019 and early 2020 2 drop in eGFR after initiationreduced rates of AKI, an effect seen in both the large trials and multiple observational cohorts.Given the favorable risk benefit ratio, how do we get SGLT2i to be used more widely? We hope that by synthesizing the data, our meta‐analysis will inform the practice of the “four” key specialties . When using these drugs, a few commonsense rules should be employed to reduce risk of adverse events. Providers should consider temporarily discontinuing SGLT2i in clinical situations that predispose to ketoacidosis, for example, prolonged fasting, post‐surgery or an acute illness, a strategy known as the “sick day rule.” Peripheral arterial disease (PAD) is a major risk factor for atherosclerotic cardiovascular disease, and nearly 20%–25% of participants in these trials had PAD. Given the results of CANVAS, there has been concern about using SGLT2i in individuals with PAD. However, withholding SGLT2i from patients with PAD does not seem wise given the known benefits and the relative risk of amputations in other trials (including canagliflozin's CREDENCE). Such considerations led the FDA to remove the black box warning of amputations in August 2020. Nevertheless, it is reasonable to avoid SGLT2i in patients with active PAD  and discuss the potential for this complication in all other patients initiated on SGLT2i, while following them clinically for signs of incident or worsening PAD. Understanding the effects of these drugs on kidney function would also seem important; nearly all SGLT2i still carry warnings about AKI because of a major misunderstanding about the effects of these drugs on the eGFR during their launch as antiglycemics. All SGLT2i will cause an immediate and reversible 4–6 ml/min/1.73mArmed with the knowledge of benefits, risks, and some clinical sense about risk reduction, the four key specialties should no longer hesitate to discuss SGLT2i for cardiorenal protection with their patients.5class effect across a broad range of populations with diabetes Type 2 at risk for cardiovascular disease, patients with HFrEF or CKD with or without diabetes. Overall, SGLT2is appear to have a favorable safety profile and thus should be used by the four “key specialties”  first and foremost as agents that reduce cardiorenal and heart failure risk and only secondarily as antiglycemics.SGLT2i reduce all cause, cardiovascular mortality, heart failure hospitalizations, need for dialysis and acute kidney injury as a Michael E Johansen has nothing to disclose. Christos Argyropoulos has received consulting fees from Bayer, Baxter Healthcare, Health Services Advisory Group and research support from Dialysis Clinic, Inc.Appendix S1: Supporting InformationClick here for additional data file.


Thyroid hormones play an important role in growth, development, and physiology of the kidney. The kidney plays a key role in the metabolism, degradation, and excretion of thyroid hormones and its metabolites. The aim of this study is to investigate the prevalence of disease states of thyroid-kidney organs and detecting the correlation between thyroid and kidney function abnormalities. t-test were used for statistical analyses. The correlation between variables was assessed by Pearson's, Spearman's correlation tests and regression analyses.  In this retrospective study, a total of forty-five patients with thyroid and kidney dysfunction were investigated. Clinical features, laboratory data at initial presentation, management, and outcomes were collected. The paper has been written based on searching PubMed and Google Scholar to identify potentially relevant articles or abstracts. Median, percentage, mean ± standard deviation (SD), and the two-tailed  The mean ± SD of age of study patients was 48.2 ± 22.93 years (ranging from 1 to 90 years). There was no correlation between serum thyroid-stimulating hormone, free thyroxine levels with estimated glomerular filtration rate, and proteinuria. No association between antimicrosomal antibodies with estimated glomerular filtration rate was seen. Cardiovascular disease was the most common complication of overt hypothyroidism in kidney dysfunction patients.  The present study showed more prevalence of primary hypothyroidism in comparison with other thyroid dysfunctions in patients with kidney dysfunction. Reduced mean values of thyroid function profiles after treatment suggest that this thyroid disease should be considered and ameliorated with thyroid hormone replacement therapy in patients with kidney disease. Thyroid hormones are necessary for the growth and development of the kidney and for the maintenance of water and electrolyte homeostasis. On the other hand, kidneys are involved in the metabolism and elimination of thyroid hormones. Thyroid dysfunction is common in patients with chronic kidney disease . DocumenNormal thyroid function test Hypothyroid state Hyperthyroid state Normal values for thyroid-stimulating hormones (TSH) and free thyroid hormone levels (fT4 and fT3) are as follows:Euthyroidism Overt hypothyroidism (high TSH and low fT4)Subclinical hypothyroidism Overt hyperthyroidism (low TSH and high fT4)Subclinical hyperthyroidism Nonthyroidal illness Patients have been classified asAcute kidney injury (AKI), acute kidney disease (AKD), and CKD can form a continuum of disease, whereby initial kidney injury can lead to persistent injury eventually leading to CKD. AKI is defined as an abrupt decrease in kidney function occurring over 7 days or less, whereas CKD is defined by the persistent of kidney disease for a period of >90 days. AKD is defined as acute or subacute damage and/or loss of kidney function for the duration of 7 days and 90 days after exposure to an AKI initiating event. Recovery from AKI within 48 h of the initiating event typically heralds rapid reversal of AKI (16th ADQI consensus report of 2017). CKD is classified into zero to seven stages  according to estimated glomerular filtration rate (eGFR) and kidney damage such as proteinuria (>200 mg/day or protein to creatinine ratio >200 mg/g creatinine) or albuminuria .There are many uncertainties about thyroid abnormalities in kidney diseases and vice versa in literature review that can expressed as questions in this study. Furthermore, the aim of this study is to investigate the prevalence of disease states of thyroid-kidney organs and detecting the correlation between thyroid and kidney function abnormalities. The questions which are suggested are as follows:Thyroid functional disease is a risk factor for kidney disease, and some analyses suggest that even high-normal TSH levels may be a risk factor for kidney function. It has been suggested that hypothyroidism leads to kidney dysfunction via decreased cardiac output, altered intrarenal hemodynamics, reduced renin-angiotensin-aldosterone production and activation, and increased tubuloglomerular feedback in chloride channel and expression. Conversely, patients with CKD may be at higher risk for thyroid dysfunction via several pathways. Amelioration of risk factors prevents kidney disease progression, cardiovascular disease, and mortality. Therefore, more studies for evaluating the clinical and biochemical association are needed to better understand the causal implications of this disorder in kidney disease.Because clinical studies in patients with the dysfunctional thyroid state is low and not much data are available on how thyroid dysfunction influences renal function in human beings, this study has been planned. Furthermore, this study has been performed in these patients to investigate the alterations in kidney function in the dysfunctional thyroid state and to correlate these values with thyroid profiles of patients.All case reports were obtained via electronic search in PubMed and Google Scholar databases.Patients with thyroid dysfunction and kidney disorders in all ages and both male and female were considered in this study. They were assessed for cardiovascular endpoints and mortality dependent on the available data.Primary Outcomes. Development or progression of kidney disease, elevated serum creatinine (SCr), decrease of eGFR, and development or progression of thyroid dysfunction were primary endpoints in this study.(1) Secondary Outcomes. Cardiovascular events, dyslipidemia, progression of subclinical hypothyroidism to primary hypothyroidism, and mortality were secondary endpoints in this study.(2) The paper has been written based on advanced searching via PubMed and Google Scholar databases to identify articles that were published since inception to January 2020. The mentioned search included the following search terms: chronic kidney disease and thyroid dysfunction, thyroid and kidney disease, and thyroid and chronic kidney disease.The author reviewed references of all included articles and performed handsearching of related journals to identify the additional relevant studies.The search strategy was used to obtain titles and abstracts of studies that might be relevant to the review. The titles and abstracts were screened by the author who discarded studies that were not applicable; however, studies and reviews that might include relevant data or information on studies were retained initially. The author independently assessed retrieved abstracts and, if necessary, the full text of these studies to determine which studies satisfied the inclusion criteria.Data extraction was carried out by the author, and studies reported in non-English language journals were to be translated before assessment. Where more than one publication of one study existed, reports were grouped together, and the publication with the most complete data was included.All patients of thyroid dysfunction with renal disorders and patients of renal dysfunction with thyroid disorders were investigated. Clinical features such as age, sex, different symptoms, and physical signs were extracted from this study. Furthermore, biochemical variables of TSH, fT4, fT3, SCr, eGFR, serum total creatine phosphokinase (CPK), serum total cholesterol, serum triglyceride, hemoglobin (Hb), urine protein, antithyroid autoantibodies at initial presentation, imaging, management, and outcomes were collected.Case reports were analyzed using criteria developed by the Joanna Briggs Institute critical appraisal tool for case reports that have different assessment tools for each study design in question. The evaluation tool has 8 items for case reports.N) and percentage (%). The continuous variables were determined as to whether they were normally distributed using the Kolmogorov–Smirnov test. Continuous variables with normal distribution are reported as mean ± standard deviation (SD). Nonparametric variables are expressed as median and interquartile range . Comparisons between continuous variables with normally distributed (ND) data were assessed by the Wilcoxon-matched pairs test, and variables with nonnormally distributed (NND) data were assessed by the two-tailed one-sample t-test analysis. The correlation between continuous variables with normal distributed data was analyzed using product moment correlation (Pearson's correlation coefficient test) (r) and with nonnormally distributed data assessed with Spearman's rank correlation coefficient (rσ). When one variable was nonnormally distributed (X) and another was normally distributed data (Y), regression analyses were used. Significance was assessed with the p value of <0.05.Data were entered in Microsoft Excel 2010 software. Categorical variables are recorded as frequency  were included, and fifteen studies were discarded due to nonoriginal investigation . 1. Incl  Nonrandomized data of randomized trials were planned with systematic review design in this retrospective study.Study design  Sample sizes ranged from 45 to 59 patients in this study and fourteen patients were excluded from this study.Sample sizes  Most patients in this study were referred to single centers but several reports indicated multicenter follow-up.Setting  All patients are included in this study if they had thyroid function test abnormality and kidney failure including acute kidney injury, chronic kidney disease, glomerular disease, nephrotic syndrome, and tubular disease.ParticipantsPatients were excluded from the study if they had renal or thyroid carcinoma in initial presentation.Assessment of risk of bias and quality in included articles performed using Joanna Briggs Institute critical appraisal tools for case reports. Based on these criteria, three patients presented with eight score , thirty-three patients with seven score , five patients with six score , and four patients with five score  , as the most common symptom, fatique and generalized edema (11.1%), weight gain and lethargy (8.8%), tiredness and generalized weakness (6.6%), and dyspnea and poor appetite (4.4%) in the present study. Patients with primary hyperthyroidism presented with fatique and dyspnea (4.4%) and tiredness and increased appetite (2.2%). Patients with subclinical hypothyroidism presented with fatique and generalized weakness (2.2%) and patients with subclinical hyperthyroidism presented with fatique and muscle pain (2.2%) in this research. Patients with euthyroidism presented with dyspnea (2.2%) in the present study. Dry skin without edema has been seen in 12/30 (40%) patients as the most common sign in physical examination in the present study. Other signs in primary hypothyroidism include pallor and bilateral lower extremity edema (15.5%), periorbital edema (13.3%), overweight state (11.1%), enlarged palpable thyroid (8.8%), and inspiratory crackles (6.6%). Patients with primary hyperthyroidism presented with dry skin without edema (6.6%), enlarged palpable thyroid and inspiratory crackles (4.4%), and periorbital edema (2.2%). Patients with subclinical hypothyroidism presented with periorbital edema and bilateral lower extremity edema in 2.2%, and patients with subclinical hyperthyroidism presented with enlarged palpable thyroid and dry skin without edema in 2.2% cases (Supplementary X or insulin resistant syndrome in 2/30 (6.6%) of patients with overt hypothyroidism as the most common thyroid dysfunction in the present study. Prevalence of any risk factor of metabolic syndrome has been described in the present study , overt hyperthyroidism , subclinical hyperthyroidism , and subclinical hypothyroidism, euthyroidism, and not determined . Common causes of thyroid dysfunction in the present study consisted Hashimotoʼs thyroiditis in 6.6% of patients (3/45), and its other causes are described in nt study  , and mean value for elevated TSH was 156.51 ± 252.82 mIU/ml. Serum fT4 values decreased in 26 patients , and mean value of decreased fT4 levels was 0.5 ± 0.5 ng/dl. There was decreased fT3 in nine patients , and mean ± SD of this hormone was 1.93 ± 1.54 pg/ml  . There was hypercreatininemia in twenty-two patients  of primary hypothyroidism with a mean value of 1.67 ± 0.27 mg/dl, and there was no correlation between serum TSH and fT4 levels and serum creatinine in this study. Furthermore, the impact of kidney dysfunction on thyroid function abnormalities has been assessed, and there was no correlation between serum creatinine and serum TSH and fT4 levels in accordance to statistical analyses , and really there was no significant relationship between proteinuria and primary hypothyroidism  54 pg/ml . There w54 pg/ml . There w54 pg/ml . There wof 0.69) . Moreoveanalyses . There wanalyses . Moreoveanalyses  , and mean ± SD value of the decreased TSH level was 0.01 ± 0.004 mIU/ml. There was high fT4 in seven patients , and mean value for these amounts was 6.28 ± 4.66 ng/dl. Furthermore, there was high fT3 in four patients , and the mean ± SD value of these amounts was 30.82 ± 24.05 pg/ml.(2) Subclinical Hyperthyroidism. There was subclinical hypothyroidism in three patients  that included normal fT4, fT3, and low serum TSH in three patients. The mean ± SD value of low serum TSH levels was 0.03 ± 0.02 mIU/ml. There was metabolic syndrome in one patient of subclinical hypothyroidism in the current study.(3) Subclinical Hypothyroidism. There was subclinical hypothyroidism in one patient  that consisted high serum TSH levels of 11.89 mIU/ml.(4) Nonthyroidal Illness (Former Euthyroid Sick Syndrome or Sick Euthyroid Syndrome). This state is defined as variable serum TSH and fT4 levels, normal or decreased serum T4 levels, and low serum total or fT3 levels. Low fT3 levels have been reported in nine patients  in the present study.(5) Euthyroidism. There were euthyroidism in two patients , and mean ± SD values for serum TSH, fT4, and fT3 levels were 1.44 ± 0.64 mIU/ml, 1.16 ± 0.16 ng/dl, and 2.5 ± 0.33 pg/ml, respectively.(6) Chronic Kidney Disease. There was decreased eGFR in 1/45 (2.2%) of patients with primary hypothyroidism in CKD stages of 2, 3a, 3b, 4, and normal eGFR in 1/45 (2.2%) of patients with primary hyperthyroidism. Furthermore, there was stages 3a of CKD in 1/45 (2.2%) patients with euthyroidism (Supplementary (7) In this study, chest X-ray showed abnormal and normal results in two patients . Thyroid sonography performed in 19 patients resulted abnormal findings in 12 patients . Of these patients, six patients showed normal results  and one patient had borderline result . Abdominal sonography including kidney sonography was abnormal in five patients , and eleven patients had normal results . Thyroid radioscintigraphy was performed in four patients and had abnormal results in two patients . Renal nuclear scan was performed in one patient and showed abnormal result    in 34 patients , steroids in ten patients , antithyroid drugs including methimazole (MMI) and propylthiouracil (PTU) in nine patients , saturated solution of potassium iodide (SSKI) in four patients , angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin-receptor blockers (ARBs) in seven patients , beta-blockers, calcium channel blockers (CCBs), and kidney failure with replacement therapy (KFRT) in six patients , and statins, diuretics, multivitamin/minerals, and immunosuppressive drugs in five patients . Before treatment, median and IQR values of TSH in hypothyroid states contained 100 and 170.7 mIU/ml (Q3–Q1: 211.2–40.5), respectively. Median and IQR values of serum TSH after THRT resulted in 10.8 and 31.16 mIU/ml (Q3–Q1: 33.6–2.44), respectively. There was a statistical significance for serum TSH levels before and after treatment with THRT (lue = 0)  (Supplemlue = 0) .In this study, serum TSH has been assessed in nineteen patients  after treatment. Median time of blood sampling for initial normal serum TSH after drug treatment in these patients has been calculated 4 months with an IQR of 5 months (Q3–Q1 = 6–1), minimum (Min) of 0.5 mo, maximum (Max) of 24 mo, midrange of 23.5 mo, and mean of 5.96 mo. Outcomes of thyroid dysfunction in renal disease include cardiovascular disease, dyslipidemia, progression of subclinical hypothyroidism to primary hypothyroidism, and death  Figure  Supplem.P < 0.001) between normal and abnormal values of TSH, T3, and T4 [μmol/l (laboratory tests at the time of death). Hypothyroidism may induce de novo AKI or CKD progression due to the hypodynamic circulatory state that was created by thyroid hormone deficiency. Moreover, paralyticus ileus due to autonomic neuropathy  can be caused by urinary retention. Therefore, clinicians must be alert from rare manifestations or complications of hypothyroidism such as acute kidney injury and paralyticus ileus due to untreated hypothyroidism as if mostly thyroxine deficiency may be missed and treatment can reverse the complications [Thyroid and kidney functions are known to interact, and thyroid dysfunction is known to cause significant changes in kidney function, especially to affect GFR. Thyroid hormones are involved in the growth, development, and physiology of the kidney. Decreased or elevated thyroid hormones affect glomerular filtration rate, renal blood flow, tubular function, water-electrolyte balance, and kidney structure . Thyroid, and T4 . Prevale, and T4 . Further, and T4 . As we k, and T4 , but it , and T4 , while i, and T4 . Another, and T4 . The pre, and T4 . While oications . Consistications . There aications . Moreoveications . To end,The interplay between the thyroid and kidney in each other's function is known for many years. Thyroid function affects renal physiology and development, whereas kidney failure could result in thyroid dysfunction. The present study demonstrated that the prevalence of primary hypothyroidism was high in patients with kidney dysfunction. Prevalence of hypothyroidism, elevated CPK, hypercholesterolemia, and raised serum creatinine levels was high in stage 3b CKD patients. Moreover, prevalence of elevated TSH and low fT3 levels was high in stage 3b CKD, and low fT4 levels was higher in stage IV CKD. There was no correlation between thyroid function tests (serum TSH and serum thyroxine levels) and decreased eGFR, hypercholesterolemia, and proteinuria in the present study. The findings of the present study have a lot of clinical relevance, since a multisystem approach to treat patients with diseases affecting either of these organs (the thyroid or kidney) would prove vitality to avoid missing subtle but clinically relevant abnormalities.


Stress exposure is linked to elevated blood pressure, which increases risk for cardiovascular disease . Stress exposure may be especially harmful when concentrated in one particular domain  . Using a diversity index, we test whether high stressor exposure and low stressor diversity is associated with high resting blood pressure. Participants  completed four days of hourly self-report of stressful experiences , with clinic blood pressure separately assessed. Linear regression results indicate older adults experienced lower stressor diversity . Further, higher stressor exposure with lower stressor diversity related to higher diastolic blood pressure . Experiencing high stress concentrated in one domain may increase risk of high blood pressure. We discuss how low stressor diversity may help explain age-related risk of cardiovascular disease.