Diabetes is the leading cause of chronic kidney disease. African Americans are disproportionately burdened by diabetic kidney disease (DKD) and end stage renal disease (ESRD). Disparities in DKD have genetic and socioeconomic components, yet its prevalence in African Americans is not adequately studied. The current study used multiple biomarkers of DKD to evaluate undiagnosed DKD in uninsured and underinsured African American men in Greensboro, North Carolina. Participants consisted of three groups: nondiabetic controls, diabetic patients without known kidney disease, and diabetic patients with diagnosed DKD. Our data reveal undiagnosed kidney injury in a significant proportion of the diabetic patients, based on levels of both plasma and urinary biomarkers of kidney injury, namely, urinary albumin to creatinine ratio, kidney injury molecule-1, cystatin C, and neutrophil gelatinase-associated lipocalin. We also found that the urinary levels of meprin A, meprin B, and two kidney meprin targets (nidogen-1 and monocytes chemoattractant protein-1) increased with severity of kidney injury, suggesting a potential role for meprin metalloproteases in the pathophysiology of DKD in this subpopulation. The study also demonstrates a need for more aggressive tests to assess kidney injury in uninsured diabetic patients to facilitate early diagnosis and targeted interventions that could slow progression to ESRD. Diabetic kidney disease (DKD) is the leading cause of end stage renal disease (ESRD). Minority ethnic groups in the United States  are disproportionately affected by DKD. A 2008 US Renal Data Systems survey showed that ESRD rates associated with diabetes are three times higher in African Americans than in their Caucasian counterparts, with the percentage of new cases of kidney disease attributed to diabetes among young African Americans currently standing at 43%. The prevalence of type 2 diabetes is related to nutrition and sedentary lifestyles , which pα and β, encoded by distinct genes on chromosomes 6 and 18, respectively, in humans [α-α or α-β) and meprin B (β-β). Meprin β gene polymorphisms were associated with DKD in the Pima Indians, an ethnic group in the United States with an extremely high incidence of type 2 diabetes and subsequent ESRD [While susceptibility genes are known to contribute to the disparities in DKD, the cellular and molecular mechanisms involved in its progression are not fully understood. Such knowledge is important for the development of therapies and diagnostic tools that are efficacious for people from diverse ethnic backgrounds. Recently, several protein biomarkers have been developed that may offer insights into the molecular mechanisms of disease pathology. These include the type I transmembrane glycoprotein, kidney injury marker-1 (KIM-1), the cysteine-protease inhibitor, cystatin C, and the ubiquitous lipocalin family member, neutrophil gelatinase-associated lipocalin (NGAL) –9. Meprin humans , 14, andn humans . Oligomeent ESRD . Interesent ESRD . αβ double knockout mice exhibit more severe kidney injury upon streptozotocin-induced type 1 diabetes [ In vitro and in vivo studies have identified several kidney meprin targets that play a role in renal fibrosis. For example, meprins are capable of cleaving and/or degrading several extracellular matrix (ECM) proteins, such as procollagen III, collagen IV, laminin, fibronectin, and nidogen-1 [β (IL-1β) [β4 [Consistent with how decreased meprin activity relates to kidney injury, we recently showed that meprindiabetes . In vitridogen-1 –22. Sincidogen-1 –26 due tidogen-1 . Such mo (IL-1β) , IL-6 [2 (IL-1β) , 30, IL- (IL-1β) ) and mon (IL-1β) ) as well-1β) [β4 . The objn = 76); (ii) diabetic patients with diagnosed kidney disease (n = 21); and (iii) age-matched nondiabetic controls (n = 75). Surveys were administered to establish patient profiles and family medical history. Medical information was provided by participants through surveys and verified using medical records. Patients with ESRD and other chronic disease conditions were excluded. All patient data were deidentified prior to analysis.Diabetic African American men aged 18–65 years were recruited through the Cone Health Community Health and Wellness Center in Greensboro, North Carolina, a facility that primarily serves uninsured and underinsured patients. This study was approved by the North Carolina A&T State University and Cone Health Institutional Review Boards (IRB). Written informed consent was obtained from each study participant. Age-matched, nondiabetic controls were also recruited through the Community Health and Wellness Center and local faith-based organizations. Three groups were included: (i) diabetic patients without known kidney disease . Blood samples were obtained by trained phlebotomists via intravenous route, collected into heparin tubes, and stored on ice for an average of one hour before being processed to obtain plasma. To obtain plasma, the blood samples were centrifuged at 2,750 ×g for 15 minutes at 4°C using an Allegra X-14R centrifuge . The plasma was then aliquoted into microfuge tubes and stored at −80°C until proteomic analysis. Urine samples were also held on ice before being aliquoted and stored at −80°C until analysis.For biochemical assessment of kidney injury, we performed assays for traditional biomarkers of kidney injury, namely, urinary albumin and creatinine, which were then used to calculate the urinary albumin to creatinine ratio (UACR). The UACR is the current gold standard for clinical diagnosis of DKD. Albumin assays utilized Albuwell® ELISA kits from Exocell  while creatinine was measured using a calorimetric assay kit from Diazyme Laboratories . We also determined the levels of three recently developed protein markers of kidney injury, namely, KIM-1, cystatin C, and NGAL using enzyme-linked immunosorbent assay (ELISA) . All of the assays were performed according to the manufacturers' instructions with absorbance being read at 450 nm using a F500 Pro multimode microplate reader . Standard curves for all biomarkers except albumin were generated using four parameter logistic (4-PL) curve fits (GraphPad Prism software). Standard curves for albumin were generated using log-log regression, according to the manufacturer's instructions. The urinary levels of each kidney injury marker were normalized to the urinary creatinine levels.μl of the urine samples were combined with SDS loading buffer supplemented with β-mercaptoethanol and heated at 80°C for 5 minutes. Three or four representative samples from each group were then resolved on the same 8% polyacrylamide gel under denaturing conditions. Following electrophoresis, the proteins were transferred to a nitrocellulose membrane, blocked in blocking buffer ), and then probed with primary antibodies for meprin A , meprin B , or nidogen-1 . The HMC14 and HMC77 antibodies were a gift from Dr. Judith Bond . Following incubation with the primary antibody solution, membranes were washed three times in TBS-T for 15 min each and then incubated with corresponding secondary antibodies conjugated to horse radish peroxidase . Finally, membranes were washed three times in TBS-T for 15 min each before the addition of chemiluminescence substrate . Protein bands were detected by exposure to X-ray film or by exposure of the membrane to Amersham Imager 600 . The Western blots were repeated for a total of 9 or 12 samples from each subcategory. We first grouped samples based on self-reported and diagnosed diabetes status, with 4 representative samples from each group  included in each gel. Subsequent blots grouped the samples from diabetic patients without diagnosed kidney disease based on their UACR levels, with 3 samples from each group included in each gel, that is, (i) nondiabetic, (ii) normoalbuminuria (UACR < 30 mg/g), (iii) microalbuminuria (30 mg/g ≤ UACR ≤ 300 mg/g), and (iv) macroalbuminuria (UACR > 300 mg/g).Western blot analysis was used to determine the urinary levels of meprin A, meprin B, and nidogen-1, according to previously described protocols –36. BrieWe performed assays for a second meprin target, monocyte chemoattractant protein 1 (MCP-1), using ELISA kits (R&D Systems) according to the manufacturer's instructions. Standard curves generated using 4-PL curve fits (GraphPad Prism) were used to determine the MCP-1 concentrations. Urinary MCP-1 levels were normalized to the urine creatinine levels in each sample.The data were analyzed by one-way ANOVA and Tukey's honest significant difference test (GraphPad Prism Software). Logarithmic transformation was conducted for the kidney injury biomarker values  and MCP-1 before statistical analysis. To identify the diabetic subjects with high risk for kidney injury, the mean, standard deviation, upper quartile (Q3), and interquartile range (IQR) from the nondiabetic group were calculated. Diabetic subjects with values greater than mean + 2SD and Q3 + 1.5IQR of the nondiabetic group were considered to be at high risk for DKD.Since the metabolic syndrome is often associated with diabetes mellitus, we first assessed various measures of obesity and cardiovascular health among members of each group. Based on BMI measurements, the majority of the participants in our study were either overweight (25.0 ≤ BMI ≤ 29.9) or obese (BMI ≥ 30), with no significant differences between nondiabetic and diabetic participants . On the p = 0.01 after transformation). Interestingly, there was a large degree of variation in UACRs among the diabetic patients, suggesting that members of this group may exhibit varying degrees of kidney injury (p < 0.0001) than nondiabetic controls  compared to all the other groups except for the macroalbuminuria subgroup.The current study reveals undiagnosed kidney injury in a significant proportion of uninsured and underinsured diabetic African American men in Greensboro, NC . Importaprotease . The curprotease , 54. In protease , 56. In protease , 57. In β gene were associated with diabetic kidney injury among the Pima Indians, a US ethnic group with extremely high incidence of type 2 diabetes and diabetic nephropathy [This study also suggests that the meprin metalloproteases, meprin A and meprin B, and two kidney meprin targets, nidogen-1 and MCP-1, may play a role in the pathology of DKD in African American men. Previous studies have implicated meprins in the pathophysiology of acute and chronic kidney injury in humans and rodent models of DKD , 17. Forhropathy . Consisthropathy , 17. In hropathy , 58. It hropathy . The fachropathy , 60. Furhropathy . In vitro studies have shown that both meprin A and meprin B proteolytically process and cause inactivation of MCP-1 [Knowledge about potential mechanisms by which meprins modulate the pathology of kidney disease is growing. Several studies have identified meprin targets in the kidney, which release proteolytic products into urine. Urinary meprins have previously been proposed as biomarkers of DKD . The curof MCP-1 . The curof MCP-1 , 65. Uriof MCP-1 .Together, these studies suggest that meprins and several meprin targets could serve as diagnostic tools for the identification of kidney injury in African American men. However, additional large-scale studies are needed to determine the efficacy of these proteins as biomarkers of DKD in this population. Likewise, the utility of meprins and their proteolytic products as diagnostic biomarkers of DKD in other ethnic groups has yet to be explored. Indeed, due to genetic factors contributing to disparities in DKD, new biomarkers are needed for early identification of patients who are prone to the development of DKD. In the age of precision medicine, the development of such biomarkers would facilitate early interventions and thus slow progression to ESRD. Importantly, participants for this study were recruited from a community health and wellness clinic run by Cone Health, the largest healthcare provider in the city of Greensboro, NC. Community clinics play a large role in providing healthcare for uninsured and underinsured patients. The outcomes from this study will enable us to plan community outreach programs that are relevant to African American men in North Carolina.


Diabetes mellitus (DM) is a hypercoagulable state and is associated with highly increased risk of vascular complications. In the theory of traditional Chinese medicine (TCM), these vascular complications are classified as blood stasis. Diagnosis of the tongue plays an important role in TCM; a bluish tongue, petechiae, and engorged sublingual collateral vessels are manifestations of blood stasis. This study aimed to characterize the tongue manifestations of blood stasis and derive a relationship between blood stasis and vascular disorders in patients with type 2 DM.We conducted a cross-sectional study of 140 patients with type 2 DM, and compared demography, laboratory, physical examination, ankle brachial index(ABI), brachial-ankle pulse wave velocity (ba-PWV), and tongue manifestation datas. An automatic tongue diagnosis system was used to capture tongue images and characterize clinical tongue manifestations.p = 0.02; R:1937.28 ± 405.55 v.s.1741.99 ± 325.82, p = 0.03).A bluish or petechiae tongue was assoicated with a significant decrease in high-density lipoprotein level, and bluish tongue was associated with significant increase in blood triglyceride in patients with type 2 DM. On assessing arterial stiffness, patients with a petechiae tongue had a higher ba-PWV for both sides (L:1938.41 ± 469.54 cm/sec v.s.1723.99 ± 302.16, Blood stasis, particularly a tongue with petechiae, may be associated with arterial stiffness in patients with type 2 DM. Furthermore, tongue diagnosis could detect blood stasis relevant to DM and could serve as a feasible predictor for DM. As the global population increases and ages, diabetes mellitus (DM) has become a major public health concern worldwide –3. DM inBlood stasis is one of the most important pathological concepts in traditional Chinese medicine (TCM) . Blood sTongue diagnosis is important in TCM . The tonHowever, to the best of our knowledge, no study has focused on tongue diagnosis in patients with type 2 DM, despite the theoretical and clinical applications. This study aimed to investigate the tongue characteristics of and relationship between blood stasis and vascular disorders in patients with type 2 DM.We conducted across-sectional study and recruited patients with type 2 DM from the Department of Chinese Medicine, Changhua Christian Hospital, between January 2012 and December 2013. We excluded patients with type 1 DM or type 2 DM who had cancer. One hundred and forty eligible patients with type 2 DM were enrolled. The purpose, procedures, potential risks, and benefits of the study were thoroughly explained to the patients. The personal details and photographs of the patients were kept confidential, and all participants signed consent for publication. This study was approved by the Institutional Review Board of Changhua Christian Hospital (IRB#:111106).Patient metadata were collected . Physical examinations included blood pressure, body mass index(BMI), waistline, hipline, foot examination, ankle brachial index (ABI), and brachial-ankle pulse wave velocity (ba-PWV). Ba-PWV is a direct measurement of aortic stiffness and is the gold standard of arterial stiffness measurements . ABI is An automatic tongue diagnosis system was developed to capture tongue images. The consistency and stability of image capturing relies on the brightness and color calibration to compensate for variations, such as intensity and color temperature of light source as well as imaging hardware , 16. Anat tests were used to determine differences between continuous variables. Regression models were used to analyze the relationship between the change in ba-PWV and patients possessing tongue manifestations of blood stasis. A p-value less than 0.05 was considered statistically significant.The statistical analysis of datawas performed with IBM SPSS Statistics 19 . After determining if that data was normal (Kolmogorov-Smirnov test), Student’s 2 , and mean HbA1C was 7.03 ± 1.08 %  and 60 % females (84 patients), the average age was 62.95 ± 11.10 years old (range of 33 to 87 years); the mean BMI was 25.94 ± 3.93 kg/mn = 123, 87.9 %), enlarged , and small  , red , or pale . Other characteristics observed on the tongue surface included teeth-marks , fissures , spots  and petechiae . A bluish toned tongue may indicate a problem with blood circulation . The classifications of fur color and thickness were white  or yellow  and thin fur , thick fur , or peeled fur , respectively. The amount of saliva observed was normal , dry , or wet . There were 99 patients (73.3 %) with engorged sublingual collateral vessels.Tongue inspection refers to the visual examination of tongue body shape, tongue color, fur color, and fur thickness, as well as other characteristics. The tongue body shape was classified as median n = 13, 87.9 %p = 0.03) and a significant increase in TG (p = 0.04) in the lipid profile  were significantly higher in patients with a petechiae tongue than in patients with type 2 DM.According to the TCM theory, a bluish tongue, petechiae, and engorged sublingual collateral vessels are potential manifestations of blood stasis Fig. . TherefoThe core of assessment in Chinese medicine is “pattern identification/syndrome differentiation and treatment” based on inspection, listening and smelling examinations, inquiry, and palpation. Inspection is the most important of the four assessments, and tongue assessment is a crucial part of observation. Tongue appearance is a crucial indicator of physiological and pathological changes to the internal organs . StudiesTo the best of our knowledge, this is the first attempt to apply TCM tongue diagnosis to the survey of patients with type 2 DM. Tongue inspection refers to the shape, color, and fur color, and fur thickness, as well as other characteristics . In patiPulse wave velocity (PWV) is a noninvasive clinical index of arterial stiffness. Arterial pulse wave velocity reflects the stiffness of arteries, and serves as an indicator of atherosclerosis , 28. Artp = 0.037). This suggests that patients with type 2 DM have increased blood stasis tongue manifestations that are correlated with severe arterial stiffness.Tongue manifestations are important features for detecting blood stasis . Our stuThere were several limitations of our study. First, the sample size was relatively small. Second, we did not enroll healthy controls or patients with type 1 DM; this is because most patients with type 1 DM only use conventional medicine  and do not utilized TCM as a complementary therapy. Therefore, further studies with larger sample sizes, including healthy subjects as well as type 1 and type 2 DM groups, are required to determine the relationship between tongue manifestations and disease. This proposed study can provide a rationale for a wider use of tongue diagnosis in clinical practice.Blood stasis of the tongue, particularly petechiae tongue, is associated with arterial stiffness in patients with type 2 DM. Tongue diagnosis is helpful for detecting blood stasis and could serve as a feasible predictor of DM.


Aims: Although evidence has accumulated that white matter hyperintensity (WMH) is associated with the deterioration of cognitive function and impairment of activities of daily living (ADL), the clinical relevance of WMH in elderly patients with diabetes mellitus (DM) is not still clear. The aim of this study was to examine whether WMH volume is associated with ADL and cognitive function and whether glucose control and glucose variability can affect WMH volume in these patients.Methods: This cross-sectional study investigated the associations of WMH with cognitive function and instrumental ADL (IADL), as well as metabolic and vascular risk factors in a total of 178 elderly patients with diabetes. The study assessed WMH volumes and the functional status of cognition and IADL. WMH volumes were evaluated by obtaining axial T2-weighted and fluid-attenuated inversion recovery sequence images on brain magnetic resonance imaging and assessing the images using Software for Neuro-Image Processing in Experimental Research.Results: We found a significant association between WMH volumes and Mini-Mental State Examination (MMSE) scores (p = 0.039) and between WMH and IADL status (p = 0.006). Furthermore, we found significant relations of large WMH volumes with a high glycoalbumin/glycohemoglobin ratio (GA/HbA1c) (p < 0.001). Large WMH volumes were also found to be associated with a low body mass index (p = 0.014) and a low diastolic blood pressure (p = 0.024), but not with HbA1c. Multiple regression analysis showed that high GA/HbA1c, which reflects high glucose variability, was a significant determining factor for large WMH volumes. We also found that GA/HbA1c was negatively associated with both MMSE (p = 0.036) and IADL (p < 0.001).Conclusion: GA/HbA1c, which is a marker of glucose variability, was independently associated with WMH volumes, which could lead to the decline of cognition and IADL in elderly patients with DM. White matter hyperintensity (WMH) is a type of lesion in white matter that is detected with magnetic resonance imaging (MRI), showing high intensity in both T2-weighted and fluid-attenuated inversion recovery (FLAIR) sequence images . The patRecently, WMH has been demonstrated to be associated with cognitive dysfunction and impairment of activities of daily living (ADL) , which aWe hypothesized that WMH is associated with cognitive impairment and ADL dysfunction in elderly patients with DM similar to that in the general population. In the assessment of factors affecting WMH volumes in DM patients, we especially focused on glucose variability. Glucose variability is known to induce oxidative stress and endothelial dysfunction , and it To test our two hypotheses, we performed a cross-sectional study in 178 elderly patients with DM and investigated the relations between WMH and cognitive function, instrumental ADL (IADL), GA/HbA1c, and other clinical factors.Elderly (≥65 years of age) patients with DM who presented between October 2013 and June 2016 were included in this study. DM was diagnosed based on the following criteria: highest value of recorded HbA1c ≥ 6.5% or a history of taking antidiabetic medications. Patients with any history of symptomatic stroke or severe diseases were excluded. This study was carried out in accordance with the recommendations of the ethics committee of Tokyo Metropolitan Geriatric Hospital with written informed consent from all subjects. All subjects gave written informed consent in accordance with the Declaration of Helsinki.Blood samples were extracted ad lib. HbA1c  was measured using high-performance liquid chromatography, and GA was measured using an enzymatic method.Magnetic resonance imaging images were obtained using 1.5-T MR scanners and included T2-weighted and axial FLAIR sequence images. The images were obtained using GE Signa HDxt . The slice settings were as follows: 20–22 slices with 5-mm thickness and an interslice gap of 2 mm were obtained in parallel with the anterior commissure–posterior commissure line, covering a maximum of 154 mm and ranging from the vertex down to the lower end of the pons. Eight-channel head coils were used for MR signal acquisition and transmission. The parameters of the T2-weighted sequence were as follows: repetition time (TR), 4300 ms; effective echo time (TEef), 90 ms; echo train length (ETL), 16; field of view (FOV), 220 mm; acquisition matrix, 256 × 288; number of acquisitions (NA), 2. The parameters of the FLAIR sequence were as follows: TR, 10,000 ms; TEef, 100 ms; inversion time (TI), 2500 ms; ETL, 16; FOV, 220 mm; acquisition matrix, 192 × 288; NA, 1.White matter hyperintensity volumes were evaluated using Software for Neuro-Image Processing in Experimental Research (SNIPER), as previously described . WMH volCognitive function was tested using the Mini-Mental State Examination (MMSE). IADL was evaluated using the IADL subscaleof the Tokyo Metropolitan Institute of Gerontology Index of Competence, as shown previously . This ist-test and analysis of variance, with Tukey’s test as a post hoc analysis, respectively. As GA/HbA1c was not normally distributed, we used the Mann–Whitney and Kruskal–Wallis analyses to evaluate GA/HbA1c between MMSE and IADL categories, respectively. Correlations of two continuous variables were analyzed using Spearman’s rank correlation. In multiple regression analysis to identify the determining factor for WMH, we defined WMH/IC as the outcome value, and age, sex, body mass index (BMI), GA/HbA1c, and diastolic pressure as the independent values. Further, to identify the determining factor for MMSE and IADL decline, binomial logistic regression analyses were performed. In these analyses, MMSE and IADL categories were defined as outcome values. IADL scores were divided in two categories (4–5 and 0–3 points), and age, sex, and common logarithms of WMH/IC and GA/HbA1c were substituted as independent values. All statistical analyses were performed using the SPSS Statistics 20 software package . In all comparisons, the significance level was set at p < 0.05.Mini-Mental State Examination scores were divided into the following two categories: normal (27–30 points) and cognitive impairment (≤26). IADL scores were divided into the following three categories: 5, 4, and 0–3 points. Common logarithms of WMH/IC and PVH/IC were compared between MMSE and IADL categories using the unpaired Table 1. The median age was 77 years, and the median HbA1c and disease duration were 7.5% and 15 years, respectively. The median BMI and systolic and diastolic blood pressures were 23.8 kg/m2 and 131 mmHg and 70 mmHg, respectively. The median GA value was 21.5%, and the median GA/HbA1c was 2.85. The rates of patients taking antidiabetic and antihypertensive medications were 92.1 and 64.6%, respectively. In our study population, over 130 patients participated in an interview and in MMSE and ADL testing.The baseline profiles of the patients are shown in p = 0.039 for total WMH/IC and p = 0.029 for PVH/IC; Figure 1). However, there were no significant correlations between DWMH/IC and MMSE (data not shown). Similarly, we found significant negative correlations of WMH/IC and PVH/IC with the IADL categories . However, DWMH/IC was not related to IADL (data not shown).We found a significant difference in WMH volumes between the MMSE categories  and between GA and WMH/IC . However, GA/HbA1c was significantly and positively associated with both the total WMH/IC and PVH/IC  but not with DWMH/IC (data not shown).We found no significant association between HbA1c and WMH/IC  but not with DWMH/IC (data not shown).Body mass index was negatively associated with both the total WMH/IC and PVH/IC . Of note, however, diastolic pressure was significantly and negatively correlated with both the total WMH/IC and PVH/IC . No significant correlations were found between DWMH/IC and blood pressure (data not shown).Plots between WMH and diastolic blood pressure are shown in Table 2. WMH/IC was significantly and negatively correlated with GA/HbA1c, even after adjustment for age, sex, BMI, and diastolic pressure .The results of the multiple regression analysis are shown in p = 0.036; Figure 6). However, HbA1c (p = 0.944) and GA (p = 0.085) were not associated with MMSE (data not shown). Similarly, GA/HbA1c was significantly and negatively associated with the IADL categories . Additionally, there was a significant difference in GA (p = 0.038), but no difference was found in HbA1c .We found a significant difference in GA/HbA1c among the MMSE categories (p = 0.012) and male sex (p = 0.023) were identified as significant risk factors for low MMSE values, whereas neither the common logarithm of WMH/IC nor GA/HbA1c was a significant determining factor. On the other hand, in the analysis with IADL categories as the outcome variable, GA/HbA1c (p = 0.006) was identified as the most significant risk factor for low IADL, and its significance was greater than that of age (p = 0.056) and the common logarithm of WMH/IC (p = 0.051).In the analysis with MMSE categories as the outcome variable, age , BMI, and diastolic pressure. Among the factors studied, GA/HbA1c was a stronger determinant for WMH volume than BMI or diastolic pressure. Furthermore, we found that GA/HbA1c was negatively associated with both MMSE and IADL.10 (WMH/IC) corresponding to 1, 2, and 3 on the Fazekas scale are approximately -0.5, 0.1, and 0.5, respectively, calculated from the values in our previous report . From these results, we speculate that WMH could influence IADL impairment in the very early phase. Although we could not convert the 1-point loss in our IADL scale to indices of frailty, such as the Clinical Frailty Scale , it is sRecently, it has been shown that large glucose variability could induce oxidative stress and could be a risk factor for the progression of diabetic complications. Considering that increased glucose variability is negatively correlated with endothelial function  and that2, which is considered to indicate malnourishment. Recently, the harmful effects of low BMI in the elderly have been reported. For example, Interestingly, we found a negative correlation between WMH volume and BMI, which is contradictory to the results of previous reports . One of We found an inverse correlation between diastolic pressure and WMH volume. High blood pressure has been identified as a major risk factor for the progression of WMH. As for diastolic blood pressure, Although we found positive correlations between WMH and both MMSE and IADL, and between GA/HbA1c and WMH, glucose variability itself could be a risk factor for cognitive dysfunction and IADL decline. Indeed, in a cross-sectional study, it was shown that glucose variability was negatively correlated with MMSE scores . In thisp-value of WMH was small, and it is possible that glucose variability and WMH partly have direct effects on low ADL, independent of each other. A further longitudinal study is needed to clarify the roles of WMH and glucose variability on the progression of MCI, dementia, frailty, and ADL dysfunction in these populations.In binomial logistic regression analyses, we could not find greater significant effects of WMH and GA/HbA1c on low MMSE compared with the effects of age and male sex; however, this negative result might be attributed to the ambiguity of MMSE scoring as described above. On the other hand, it is worthy to note that GA/HbA1c had a significant association with low IADL even after adjustments with age, sex, and WMH. This result indicates that GA/HbA1c is a more influential factor than WMH. However, although there was no statistical significance, the The present study has several limitations. First, because this was a cross-sectional study, the long-term influence of WMH on cognitive decline and ADL dysfunction were unknown. The results of a longitudinal study are highly awaited. Additionally, the causal relationship between WMH and BMI, glucose variability, or diastolic blood pressure has not been fully elucidated. Whether these factors could actually affect the progression of WMH should be clarified in further longitudinal observational studies. Second, the meaning of the categorizations of PVH and DWMH is unclear. In this study, we observed associations of WMH with IADL, GA/HbA1c, BMI, and diastolic pressure in total WMH and PVH but not in DWMH. However, the automatic segmentation program of SNIPER recognized the majority of WMH volumes as PVH, and the relative volumes of DWMH were negligible. Moreover, We found a significant negative association between WMH and cognitive function and between WMH and IADL status in a group of elderly patients with DM. Furthermore, we found a significant association of WMH with GA/HbA1c, BMI, and diastolic blood pressure. Glucose variability is the most influential factor, and the avoidance of glucose fluctuations may be a key strategy to prevent WMH and the further progression of cognitive impairment and IADL decline in elderly patients with DM.This study was carried out in accordance with the recommendations of Ethical Guidelines for Medical and Health Research Involving Human Subjects, Ministry of Education, Culture, Sports, Science and Technology and Ministry of Health, Labour and Welfare, Japan, with written informed consent from all subjects. All subjects gave written informed consent in accordance with the Declaration of Helsinki. The protocol was approved by the ethical committee of Tokyo Metropolitan Geriatric Hospital.YoT, TS, and AA designed the study, analyzed data, and wrote the draft of the manuscript. YK, TY, KS, YuT, RK, YC, and SM contributed to data collection, analysis and interpretation of data. YF, AT, and HI contributed to data interpretation, and critically reviewed the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Median of frequency of urinary tract infections (fUTI): 1.2 episodes/year. In 24 children: low-pressure, in 30 children: high-pressure bladder was noted. Vesicouretral reflux (VUR) was noted in 23 children (42.6%). fUTI were more common in high-grade VUR group. High-grade VURs were more common in group of patients with severe renal damage. At the end of the survey 11.1% children were qualified to higher stages of chronic kidney disease. Renal parenchyma damage progression in RS was noted in 22.2% children. Positive VUR history, febrile recurrent UTIs, bladder wall trabeculation, and older age of the patients constitute risk factors of abnormal renal scans. More than 2.0 febrile, symptomatic UTIs annually increase by 5.6-fold the risk of severe renal parenchyma damage after five years.Myelomeningocele (MMC) results from a failure of normal neural tube fusion in early fetal development. Retrospective, observational study of medical data of 54 children treated in Pediatric Nephrology and Urology Clinics for five years was performed. The following data were analyzed: serum creatinine, eGFR, urine analysis, renal scintigraphy (RS), renal ultrasound, and urodynamics. Mean age of studied population: 12.3 years, median of eGFR at the beginning and at the end of survey was 110.25 and 116.5 mL/min/1.73 m Myelomeningocele (MMC) results from a failure of normal neural tube fusion in early fetal development. Including spina bifida (SB), it is one of the most common non-chromosomal birth defects, resulting in a severe damage of numerous organs. In the general population, the incidence of MMC ranges from 0.3 to 4.5/1000 births [The abnormal innervation of the bladder detrusor and sphincter is called a neurogenic bladder (NB). In children with MMC, it causes problems in the bladder storage and emptying functions, which may lead to high intravesical pressures and recurrent urinary tract infections (rUTIs) that, in time, will produce renal scarring and progressive deterioration of the upper urinary tract (UUT) . These pChildren with MMC are generally born with normal UUT, but are at a high risk of CKD secondary to poor bladder dynamics . CKD in The aim of the study was the evaluation of the occurrence of renal parenchymal damage in RS and US examinations, as well as assessment of the renal function in children with NB secondary to MMC during a five-year survey. The secondary objective was to identify the clinical risk factors affecting those outcomes. Sixty-five children treated in our center in the years 2007–2013 were initially selected to participate in the retrospective, observational study. However, 11 of them did not meet the criteria of the number and type of the required examinations. Ultimately, a detailed analysis included comprehensive medical records of 54 children followed up at the Pediatric Nephrology and Urology Clinics, Jagiellonian University Medical College, for five years. Children that, at the time of inclusion into the study, were already at the ESKD stage were excluded from the analysis. All of the included children were followed up at the above clinics for a minimum of 12 months and were treated in keeping with procedures in force and current medical knowledge. The study group included children above two years of age, since all of the available pediatric formulas for eGFR calculations were developed for older patients and, thus, there are no accurate eGFR formulas for children less than two years [The study consisted of the analysis of the below listed procedures, routinely performed in our center: lab tests including determination of SCr concentration, eGFR calculation based on the one-marker equation developed by Schwartz et al. , generalClinical data were entered retrospectively on a regular basis on standardized medical hospital record sheets at the time of each clinic visit. The information was then extracted between January 2007 and December 2013 for the purpose of this study.The eGFR value was calculated based on the one-marker equation developed by Schwartz et al. . eGRF caRenal 99mTc ethylenedicysteine scintigraphy (EC RS) is a safe, reliable, and objective method of assessing both kidney parenchymal damage, and at the same time marker stasis and secretion within the pyelocalyceal system (PCS). According to the literature, 99mTc EC RS as compared to 99mTc DMSA (dimercaptosuccinic acid) RS is an excellent single-modality comprehensive investigational agent for renal morphology, function and outflow tract evaluation with the added advantages of lower cost, convenience and low radiation exposure to the patient . The anaUrinary tract and kidney ultrasound (US) is a safe, inexpensive, widely available, and convenient method of evaluating kidney and urinary tract morphology, although it is not an objective way of assessing an organ. For this reason, in the present study, US images were interpreted by two appropriately trained and dedicated staff members. The analysis included interpretation of US examinations performed in the first and last year of the follow-up. The following parameters were evaluated: kidney parenchymal echogenicity , corticomedullary differentiation , PCS stasis: stasis at the renal pelvis  and the calyces level . Thus, a semi-quantitative analysis of the degree of kidney damage in US was performed. The parameters were evaluated separately for each kidney and subsequently added. In further analysis, the following abbreviations were employed: US1: no signs of kidney parenchymal damage in US; US2: moderate kidney parenchymal damage in US; US3: severe kidney parenchymal damage in US.2O and LPP < 40 cm H2O, respectively). The study included children in whom urodynamics was performed at least twice in the first or second and fourth or fifth year of the survey. While analyzing its results, attention was mainly focused on intravesical pressure, dividing the bladders into high-pressure and low-pressure (LPP ≥ 40 cm HAll of the children included in the study were prescribed low dose chemiprophylaxis (LDCP) and clean intermittent catheterization (CIC) to be performed 2–6 times per day for a minimum of three years of the follow-up, with 21 patients employing a catheter during the night (for a minimum of two years during the follow-up). Retrograde voiding cystoureterography (RVC) was performed as clinically indicated. All the analyzed children were subjected to at least one such examination. Low-grade vesicoureteral reflux (VUR) was termed 1–3 grade VUR, while high-grade VUR was marked as 4–5 grade VUR.t-test, for data described by mean and SD, or with the Wilcoxon rank-sum test, for data summarized with the median and IQR. All of the data describing the frequency of occurrence were compared with the use of the chi-square test with Yates correction. In the comparative tests, the indication of significant difference was assumed for p-values below 0.05. The linear regression model comprising the relationship between the patient age and the eGFR value was built based on the McPearson correlation coefficient with a relevant p-value. For selected data, the receiver operating characteristic (ROC curve) analysis was performed with the smoothed curve obtained after Gaussian modelling. The STATISTICA  and MATLAB  packages were used for all computations.According to the most commonly used parametric description of the study group, to allow for performing a comparative study, the mean and unbiased standard deviation (SD) estimators were used to characterize experimental distribution of the data related to age, height, and weight. While height and weight proved to be Gaussian, according to the Kolmogorow-Smirnov test (threshold 0.1), the age turned out to be non-Gaussian (threshold 0.05). The test also indicated non-Gaussian distribution of percentile values for body mass and body height. Thus, for age and specified percentiles we also provided median and interquartile ranges (IQR), i.e., the range between percentiles 25% and 75%. As some of the investigated numerical data exhibited non-Gaussian distribution, for the sake of uniformity, all such sets of data were parameterized with the use of the median and IQR. The differences between distributions were tested with either the Student’s The detailed characteristics of the studied population are included in As it follows from the data in r = −0.444; p = 0.008)  (RS1 vs. 3); 140.8 vs. 183.8 (months) (RS1 + 2 vs. 3)). Moreover, a negative, average, significant correlation was noted between the age of the patients expressed in months and kidney function expressed as the eGFR value (= 0.008) . No corrAdditionally, high VUR values in RS assessment of kidney parenchyma function was significantly more common in the group with severe damage as compared to children without or with moderate damage (10% vs. 66.7% (RS1 vs. 3); 12% vs. 66.7% (RS2 vs. 3); 11.1% vs. 66.7% (RS1 + 2 vs. 3)). In case of US assessment, significance was noted solely between the group without signs of damage and children with severe damage. On the other hand, bladder wall trabeculation was significantly more common in the group with a severe or moderate degree of renal parenchymal damage as compared to patients without such damage (25% vs. 78% (RS1 vs. 3); 25% vs. 61.8% (RS1 vs. RS2 + 3)).However, no significant differences were noted in both RS and US imaging in the percentage of high-pressure bladders, frequency of CIC employment (≥ or <4 times a day), or type of used pharmacotherapy affecting the bladder motility.As it follows from the analysis of the ROC curve for fUTI after five years of the follow-up, with a cut-off value of fUTI of 2.0 annually , the risk of severe kidney damage in RS (RS3) increased 5.6-fold .At the end of follow-up, deterioration of eGFR values was noted in 11 (30.4%) patients, of whom six (11.1%) children were qualified to higher CKD stages. Progression of renal parenchymal damage in RS imaging was seen in 12 (22.2%) children ; while US demonstrated such a progression in 25 (46.3%) children . The correlation between the degree of kidney damage in RS and US imaging at the beginning and end of the follow-up was 76% and 74.1%, respectively.As it follows from the above analysis, in the studied population, severe kidney damage was predominantly affected by an older age of the patient , higher fUTI frequency , high VUR values and the presence of bladder trabeculation indicating long-term bladder outlet obstruction. No effect on the degree of kidney damage assessed in RS or US imaging was observed in case of CIC frequency, employment of alpha-lytic and cholinergic medications, and type of neurogenic bladder.p = 0.043). A significantly lower fUTI frequency was also demonstrated in the group without VUR as compared to patients with any degree of VUR  and in the groups employing CIC <4 times vs. ≥4 times/day (median: 0.8 vs. 1.2). Thus, no effect was observed of the type of neurogenic bladder and CIC frequency on the frequency of symptomatic fUTI.Significant bacteriuria was noted in each child at least once at any time of the follow-up. However, only 33.3% cases of such significant bacteriuria were qualified as symptomatic UTI and required treatment with antibiotics or full-dose chemotherapeutic agents. Frequency of particular etiological agents of UTIs are presented in Escherichia coli vaccine in three (2.4%) children. One type of treatment during 5 years of the follow-up was employed in 15 (27.8%) children; two types of medications in 21 (38.9%); three types in 11 (20.4%); four types in four (7.4%); and five types in three (5.5%) patients. Low dose chemiprophylaxis (LDCP) was employed in all of the children. In total, 121 treatment courses were used, including furazidin therapy in 52 (43%), trimethoprim and sulfamethoxazole in 33 (27.3%), herbal preparations in 16 (13.2%), bladder lavage (1% neomycin/gentamycin) in 10 (8.3%), fluoroquinolones (cipro-/norfloxacin) in seven (5.8%), and oral Symptomatic UTI was most commonly treated with cefuroxime (29.3%), ceftazidime (23.3%), amoxicillin with clavulanic acid (10.3%), and ciprofloxacin (9.5%). Full doses of furazidin (4.3%), meropenem (3.4%), full doses of trimethoprim and sulfamethoxazole (2.6%), piperacillin with tazobactam (2.6%), and vancomycin (2.6%) were employed more rarely. Symptomatic UTI of fungal etiology was most frequently treated with azoles  and caspofungin (1.8%).At birth, most newborns with MMC have a normal UUT. However, the majority will develop deterioration of renal function and bladder wall changes, which start within the first six months of life . Two maiThe incidence of renal scarring in RS in the current study was 16.7%, which is quite coherent with numbers found in the literature in similar groups of patients, as several reports described scarring rates of 12.8%–28.6% ,11. DisoEC RS is a useful tool in determining the loss of renal parenchyma in MMC children with febrile, rUTIs and high-grade VUR. However, in case of the impossibility of performing RS, US imaging as cheap, fast, and easily accessible is also acceptable for first-line renal parenchyma assessment since, in the present investigation, the correlation between RS and US at the beginning and the end of the study was as high as 76% and 74.1%, respectively.UTIs are a common source of morbidity among children with MMC; however, they persist as one of the most difficult complications to diagnose, treat, and prevent in those patients. Appropriate specimen collection is of a paramount importance and UTI cannot be diagnosed based on a culture and urinalysis alone in the absence of clinical symptoms. Hence, in the literature, the reported incidence of UTI in MMC patients is variable. It is estimated that the overall rate of UTI in patients with NB is 0.3 to 2.5 episodes per patient per year . In the Febrile, symptomatic UTIs and VURs are closely linked with each other and are strong risk factors of renal scarring and CKD progression. In the current study, VUR was noted in 42% of the patients and the percentage is quite comparable to the values reported in the literature on the subject. In the present study, the median of fUTI was statistically significantly higher in the high-grade VUR group vs. the group without VUR or with low-grade VUR, and in the patients with VUR of any grade vs. the children without this complication. The incidence of VUR in the MMC populations reported in particular studies ranges from 26.8%–50% . The autAccording to the literature, asymptomatic bacteriuria not requiring any treatment is noted in 60%–85% of MMC patients, whereas only 21%–35% of them become symptomatic and receive pharmacological treatment ,20. In tThe main goal of CIC is the protection of renal parenchyma by decreasing the intravesical pressure and preventing VUR. CIC, along with anticholinergics and α1-selective blockers, are commonly used treatment modalities in MMC populations worldwide. The percentage of CIC in the literature is quite variable and—to quote various authors—its number varies from 63.9%–100% of patients , whereasIn a European survey, 85% of centers rarely prescribed LDCP to MMC children when not on CIC, but prescribed it in nearly 50% of children on CIC . In the Despite a great progress in nephro-urological management of MMC patients, renal failure still remains life-threatening in this population. Renal function deterioration at various time frames of a long-term surveillance reported in the literature was noted, being in the ranges from 10.7%–18% ,10 of paThe authors are aware of the limitations of this study. It was a retrospective, observational, single-center study, wherein all the patients were taking LDCP. Notwithstanding, during the five-year study, all the essential data were minutely collected on a current basis and the entire patient management proceeded as clinically indicated. We also realize that eGFR values calculated according to the Schwartz et al.  equationThe objective of the present study was increasing our understanding of risk factors involved in renal deterioration in MMC patients. It was found that preventing febrile UTI, high-grade VUR, and bladder wall trabeculation by ensuring free urine outflow may reduce the risk of renal parenchymal damage.To prevent renal damage, nephro-urological highly specialized management of NB should start right in the neonatal period. For optimal treatment results, a multidisciplinary approach is needed, with collaboration of members from numerous medical specialties. Compliance with long-term, wearisome treatment is suggested to be another important factor constituting a challenge for the patients and caregivers.In MMC patients, the presence of high-grade VUR is correlated with febrile UTIs. In turn, a positive VUR history, febrile rUTIs, bladder wall trabeculation and older patient age constitute risk factors of abnormal renal scans at the end of a 5 year survey in this population. More than 2.0 febrile, symptomatic UTIs annually increase by 5.6-fold the risk of severe renal parenchymal damage assessed in RS at the end of five-year follow-up. Due to the lack of reliability of SCr in MMC patients, repeated EC or DMSA RS for early detection of renal scarring are strongly recommended. However, the US imaging technique is also acceptable for general renal parenchyma assessment. To answer the question formulated in title of this paper, firstly: the administration of LDCP might be limited only to children with a high risk of renal cortical scarring in RS; secondly: it might be considered that renal function in this population would be assessed by the Cystatin C and iohexol method.


Estimates of glomerular filtration rate (eGFR) should provide accurate measure of an individual’s kidney function because important clinical decisions such as timing of renal replacement therapy and drug dosing may be dependent on eGFR. Formulae from which eGFR is derived are generally based on serum creatinine measurement, such as Cockcroft–Gault, MDRD and CKD-EPI. More recently, calculation of eGFR using other laboratory biomarkers such as cystatin C has emerged with apparent greater accuracy. In old people, there is age-related physiological change in the kidney, which could lead to reduced GFR. Likewise, physiological changes in body composition that occur with the ageing process impede the use of a single creatinine-based calculation of eGFR across all adult age groups. Studies have shown differences in the prevalence of CKD based on the type of equation used to estimate GFR. This review discusses the evolution of eGFR calculations and the relative accuracy of such equations in older population. Dialysis usually begins when patients become symptomatic with an eGFR of <15 ml/min/1.73 m2.Accurate measure of renal function is a vital part of day-to-day safe medical care. For example, overestimation of glomerular filtration rate (GFR) may lead to drug toxicity, and underestimation of GFR may lead to sub-therapeutic drug levels. Potentially, life-changing clinical decisions such as when to start dialysis are also partly based on GFR measurement. Some guidelines recommended that planning for patients’ future dialysis should begin when their estimated GFR (eGFR) is <30 ml/min/1.73 m2.GFR calculated by measuring the clearance of inulin by the kidney is considered “Gold standard”; precise measurement of GFR is possible but expensive, time-consuming and impractical. For this reason, there has been a constant strive to develop an equation which can estimate GFR reliably from blood and urine biochemical markers such as creatinine. These are rapid and cost-effective. However, with age there is a change in both renal physiology and muscle mass, both of which may affect eGFR calculation , 2. This2 and therefore no CKD when using the four-variable MDRD equation [Similarly, the described incident rate and prevalence of chronic kidney disease (CKD) can also vary with the method of estimation of GFR. In a cross-sectional study of 9931 institutionalised individuals aged >65 years, Garg et al.  compared51Cr) EDTA and contrast media [The clearance of inulin by the kidney is considered a gold standard method to calculate GFR because inulin is a physiologically inert substance, i.e. it is freely filtered by the kidneys without any absorption or secretion by the tubules . In clinst media , to measst media .p < 0.001) when iohexol was compared with 51Cr EDTA to measure GFR. In another study comparing iohexol with inulin clearance, there was a similarly high correlation  [More recently iohexol, a non-ionic contrast agent, has been used to measure GFR via a single intravenous bolus followed by blood sampling 2–10 h afterwards. A study by Krutzén et al. [125I-iothalamate, which showed that CG equation overestimated GFR by 16% [Historically, serum creatinine has been used as a surrogate of GFR based on the assumption that it is produced, filtered and secreted in a steady state. The Cockcroft–Gault (CG) equation was then developed to estimate creatinine clearance, on the presumption that creatinine clearance was a direct measure of GFR, which it is not. CG uses serum creatinine adjusted for age, weight, serum creatinine and gender to derive creatinine clearance. CG was the most widely used index of renal function  from itsR by 16% .The reason for this and the key limitations of using creatinine clearance and serum creatinine as estimates of GFR are that there are actually many factors which can affect the metabolism of creatinine from creatine in the muscles and the rate of secretion of creatinine in the tubules. Most clearly, creatinine is affected by muscle mass, which in turn changes with older age, and also between genders and ethnic groups. Other factors which can affect the production and secretion of creatinine and which can also differ in older versus younger patients include dietary protein intake, malnutrition and prescribed medication. Studies have also shown that creatinine clearance overestimates GFR due to the secretion of creatinine from the tubules in normal individuals. In patients with CKD, there is increased extra-renal and decreased urinary elimination of creatinine leading to overestimation of GFR from serum creatinine.A further complicating factor in using serum creatinine alone is the nonlinear relationship between creatinine and GFR . HistoriR2 (percentage of variability in the log GFR explained by the regression model) of 90.3% on internal validation and was considered the most accurate equation to estimate GFR. Subsequently, a four-variable MDRD equation  was introduced to simplify the estimation of GFR [125I-iothalomate). The MDRD equation can easily calculate eGFR using simple demographic data and a readily available laboratory biomarker. This inclusion of ethnicity and exclusion of weight in estimating renal function were a significant departure from historical equations including CG. A summary of current and historical equations and the variables they use is found in Table The most widely used equation for eGFR is the four-variable abbreviated MDRD equation . This was adopted by the Kidney Disease Outcomes Quality Initiative (KDOQI) Clinical Practice Guidelines for Chronic Kidney Disease (CKD) . The MDRn of GFR , and in n of GFR . As wellThere are, however, several limitations to the MDRD equation as it was developed and internally validated in a limited CKD population . Primari30). The overall P30 was 83%, and for stages 3, 4 and 5 CKD this was 84, 81, and 72%, respectively , the P30 was 84%. In the subgroup of patients aged >65 years, the P30 for eGFR<60 ml/min/1.73 m2 was 82%, and for eGFR >60 mL/min/1.73 m2 it was 88%. Perhaps surprisingly, by this measure MDRD performed best in older patients with preserved renal function, a subgroup specifically excluded from the original MDRD cohort.The performance of the MDRD equation has subsequently been externally evaluated in a diverse population of 5504 subjects from pooled data of 10 different studies . In thisA more recent and more accurate creatinine-based method of estimating eGFR using the same four variables as MDRD has been developed, the CKD-EPI equation (Chronic Kidney Disease Epidemiology Collaboration) . This ha2, the bias compared to mGFR for CKD-EPI and MDRD was similar, 1.9 and 2.0, respectively. However, the bias was better with CKD-EPI for eGFR levels above this .The performance of CKD-EPI and MDRD was then compared using this external validation cohort . In this2, the bias was comparable between equations (1.3 and 0.9). However, CKD-EPI performed better in patients aged >65 years with an eGFR between 60 and 89 ml/min/1.73 m2 (0.7 vs. 4.5).In patients aged >65 years, the overall bias was 1.3 and 1.4 for the CKD-EPI and MDRD equations, respectively. In patients aged >65 years and with eGFR <60 ml/min/1.73 mIn an independent evaluation of the performance of CKD-EPI and MDRD in older patients with CKD, old people again being defined as those aged >65 years, Kilbride et al.  comparedHowever, one of the limitations of these analyses is the definition of old people, as, for example, patients aged between 65 and 70 years are likely to have significantly different physiology to those aged over 80 years. Hence, an equation aimed at estimating GFR more accurately specifically in older people has been produced by the Berlin Initiative Study (BIS) . Here, a30 values were 71, 78 and 95%. A number of other studies have also compared bias and P30 between MDRD, CKD-EPI and BIS1 in older patients. Lopes et al. [30 was 80, 75 and 70%, respectively, for these equations. In a slightly younger population (mean age of 75 years), Koppe et al. [30 of 76, 72 and 71%, respectively. Liu et al. [99mTc-DTPA. In this study, the bias was again small , but the P30 was very low compared to the studies listed above . Pottel et al. developed an eGFR equation for people of all ages (FAS). This used serum creatinine derived from the healthy population, adjusted for age and sex. The performance of this equation was validated using a pooled data set of 6870 subjects of various age groups . The mGFR was calculated using various methods of clearance: inulin, iohexol and iothalamate. In the age group ≥70 years, the FAS equation performance was superior to CKD-EPI with a bias of 1.1 and −5.6, respectively, and a P30 of 86.1 and 77.6, respectively [In this study, iohexol was used to assess measured GFR. The BIS investigators compared the bias of BIS1 with MDRD and CKD-EPI equations. All overestimated mGFR but with BIS1 performing markedly better. The bias for MDRD, CKD-EPI and BIS1 was −11.2, −9.7 and −0.8, respectively. The Ps et al.  comparede et al.  comparedu et al.  also comectively . These sectively , 27, arep = 0.90). Despite the identical creatinine, mGFR was modestly but statistically significantly lower in the older group . The mean serum cystatin C was significantly higher in the older age group . There was better correlation between serum cystatin C and inulin clearance  than serum creatinine and plasma inulin clearance  This suggests that cystatin C is superior to creatinine for estimating GFR in the elderly [The limitations of creatinine discussed above have also led to the development of eGFR equations based on other serum biomarkers. One such biomarker which has now making its way into routine clinical care is cystatin C. Cystatin C is a protease inhibitor that is freely filtered through the glomeruli, reabsorbed and degraded by the proximal tubules . The CAPA equation had negligible bias (0.1) and CKD-EPIcystatin, and the Japanese equation both modestly underestimated mGFR  and Japanese study groups. In a comparison of performance against mGFR in 805 older patients with a mean age of 80 years, the P2). The respective P30 values were 75, 65 and 85%. The respective bias values were −1.7, 7.4 and 4.0 [As a development from equations using creatinine or cystatin C alone, many of the study groups listed above have derived eGFR equations using both creatinine and cystatin C in the same model. Such models appear to be more accurate than using either biomarker alone. For example, one study has compared CKD-EPI equations using creatinine alone, cystatin C alone, and both in 95 patients aged 85 ± 4 years  increase;Stage 22.0–2.9 times baseline;Stage 3≥3.0 times baseline OR serum creatinine >350 µmol/L (3.95 mg/dL) or dialysis.The current KDIGO guidelines define AKI as any of the following : an incr2 with no other evidence of CKD [The 2012 KDIGO clinical practice guidelines have recommended the use of the creatinine-derived CKD-EPI equation for the estimation of eGFR in routine practice. This is because cystatin C is not yet available for daily use in all centres. The guidelines suggest that cystatin C-based equations be limited to use in individuals with eGFR between 45 and 59 ml/min/1.73 me of CKD  to verifChanging the recommended equation for calculation of eGFR has a consequent impact on the reported prevalence of CKD. For example, the prevalence of CKD in 754 subjects with a mean age of 61 years was 17.2% based on the four-variable MDRD equation that was recommended for use until 2012, whereas with an equation based on both creatinine and cystatin C the prevalence is as low as 5.8% .n = 8). The GFR measurements (mean ± standard deviation) for each were 1381 ± 264, 1373 ± 182 and 1212 ± 274 µL/min/100 g body weight, respectively [The conventional measurement of GFR involves the measurement of a biomarker in either urine or blood. This is invasive and time-consuming and provides no longitudinal data unless repeated. The use of transcutaneous measurement of GFR in rat models has evolved significantly. This method of GFR is non-invasive and can measure real-time GFR. Several methods of transcutaneous measurement of GFR are described and are based on the elimination kinetics of fluorescent exogenous biomarker like flourescein isothiocyanate (FITC)-sinistrin –41. Receectively . Such noThe estimation of GFR in older patients is based on equations largely derived in younger populations despite physiological changes with age that may affect metabolism of biomarkers. Despite this, the performance of eGFR equations is becoming more robust for the older population group. In particular, the use of cystatin C has the potential to improve CKD diagnosis and epidemiology, as its physiological behaviour is different to creatinine. Current guidelines do not specify the use of cystatin C-based equations as first line for calculating eGFR, but this reflects its often-limited availability rather than poor performance. Indeed, if there is any clinical suspicion that a patient’s clinical status and calculated eGFR do not match, then a combined cystatin C/creatinine equation (CKD-EPI or BIS2) is a useful next step before one needs to consider isotope GFR studies for mGFR (see also Table


Obstructive sleep apnea (OSA) is a prevalent sleep disorder as is hypertension (HTN) in the 21st century with the rising incidence of obesity. Numerous studies have shown a strong association of OSA with cardiovascular morbidity and mortality. There is overwhelming evidence supporting the relationship between OSA and hypertension (HTN). The pathophysiology of HTN in OSA is complex and dependent on various factors such as sympathetic tone, renin-angiotensin-aldosterone system, endothelial dysfunction, and altered baroreceptor reflexes. The treatment of OSA is multifactorial ranging from CPAP to oral appliances to lifestyle modifications to antihypertensive drugs. OSA and HTN both need prompt diagnosis and treatment to help address the growing cardiovascular morbidity and mortality due to these two entities. Obstructive sleep apnea (OSA) is a highly prevalent sleep disorder that affects 15 to 24% of all adults [The major risk factors for OSA are obesity, male sex, and advancing age . Since tNumerous studies have shown the relation between elevated blood pressure and increased cardiovascular morbidity and mortality. However recent studies have implicated a stronger correlation of cardiovascular events with elevated ambulatory blood pressure monitor (ABPM) readings due to the elevated nocturnal readings and nondipping blood pressure patterns. Elevated nocturnal blood pressure as is noted with nocturnal catecholamine surges in patients with OSAS adds to poor outcomes. Findings from the MAPEC (Monitorizacion Ambulatoria para Prediccion de Eventos Cardiovasculares) study suggest that bedtime chronotherapy with ≥1 conventional hypertension medication to target sleep blood pressure significantly reduces cardiovascular disease risk . The maiThe prevalence of OSA continues to increase in developed countries in conjunction with the rise in obesity. Although its prevalence may vary across different populations and age groups, OSA has been ascertained to affect 24% to 26% of men and 17% to 28% of women between 30 and 70 years of age , 16. HypThere is overwhelming epidemiologic evidence supporting the nexus between OSA and chronic hypertension which suggests a causal, bidirectional relationship between the two entities. Not only does OSA predispose patients to developing HTN, but also there is a greater incidence of OSA in hypertensive patients –20. The Over the years, numerous cross-sectional studies have established an association between OSA and hypertension, independently of age, weight, and other confounding factors –30, as aThe WSCS found a dose-response relationship with increasing OSAS severity and incidence of HTN, independent of confounding risk factors such as age, sex, BMI, and initial BP. Those with AHI > 15 were reported to have a 3.2-fold greater odds of incident hypertension  and 4 ti2 in VSC); more hypertensive at baseline (51% versus 28% in WSCS and 24% in VSC); and more racially diverse than the other two. The WSCS cohort was also more obese (BMI = 29) with a higher male preponderance (56% men versus 48% in the VSC) and hailed from a working population instead of the general population. While the VSC and SHHS used unattended at-home polysomnography to diagnose SDB, the WSCS employed in-laboratory polysomnography. The WSCS used an AHI of 0 as their reference point, whereas SHHS used a range of 0–4.9. The VSC used 0–2.9th quartile for Respiratory Disturbance Index (RDI) as their reference range owing to the fact that very few patients truly have an AHI of 0.Similarly, the Vitoria Sleep Cohort (VSC)  that obsIn addition, a cross-sectional study in Canada demonstrated that an increase in the AHI by one event/h was associated with a 1% risk of having hypertension . Data frPopulation based studies employing 24 h ambulatory BP monitoring (ABPM) have demonstrated that participants with a drop in BP of <10% during the night (nondippers) and those who mount an increase in BP at night (risers) demonstrate a greater degree of end organ damage , higher Sex appears to influence the prevalence of OSAS, which affects males 8–10 times more commonly than females –50 in clThe pathophysiology of hypertension in OSA is complex and is dependent on various factors such as sympathetic tone, peripheral vasoconstriction, increased renin-angiotensin-aldosterone activity, and altered baroreceptor reflexes . The intTamisier et al.  in theirIn addition to the increased sympathetic response to hypoxia, there is also a simultaneous reflex stimulation of the respiratory centers causing increased depth and frequency of breathing. Lung inflation reflexively stimulates the vagal stretch receptors, mitigating the increased sympathetic activity, hence maintaining autonomic homeostasis –67. In tOSAS causes intermittent negative intrathoracic pressure, which, coupled with transient nocturnal catecholamine surges, exerts profound mechanical stress on the heart, gradually causing left ventricular hypertrophy and atrial remodeling, thereby increasing the risk of heart failure and arrhythmias such as atrial fibrillation , even inDecreased sympathetic and increased parasympathetic activity during NREM sleep, which comprises the majority of sleep time, contributes to the normal circadian variation of blood pressure, causing “dipping” of both systolic and diastolic BP at night, approximately by 10–15% , 78. NRERecurrent nocturnal hypoxemia with subsequent reoxygenation increases oxidative stress to the body, much like ischemia reperfusion injury, inducing release of reactive oxygen species, inflammatory cytokines, and vasoactive substances, thereby mediating endothelial damage –82. OSASEndothelin levels have been shown to increase in hypoxia in in vitro studies . OSAS paP = 0.003) and obstructive sleep apnea severity .Obesity is rampant in OSAS patients and is a well-known independent risk factor for glucose intolerance. Other mechanisms responsible for insulin resistance include enhanced resting sympathetic tone causing reduced levels of adiponectin , recurreAnother mechanism which potentially contributes to HTN in OSAS is increased activity of the renin-angiotensin-aldosterone system (RAAS). Periodic hypoxia has been shown to boost angiotensin I expression and angiotensin II receptor stimulation in the carotid body , 109 as The nexus between OSA and HTN appears to be bidirectional according to epidemiological studies , 129. ThWhile CPAP remains the mainstay therapy for OSAS, its effect on blood pressure reduction has been variable, most likely owing to the multifactorial nature of hypertension. CPAP therapy has been observed to attenuate the nocturnal sympathetic surge and mediate acute reduction in nocturnal BP in OSAS patients , 135–138P < 0.001; I2, 58%) and −4.99  observed in SBP and DBP, respectively, according to a meta-analysis [P = 0.02). The BP lowering effect was also more pronounced in patients who used CPAP for at least 4 hours per night, with a drop of 1.3 mm Hg in BP detected per hour of CPAP therapy used.The generalizability of the results of these trials however is limited owing to variability in factors affecting both the study population  and methodology . The magnitude of the drop in BP is subject to various factors such as CPAP compliance , 151, duanalysis . In nondanalysis  which heanalysis , 164. Th2O (between 6 to 12 cm H2O). In the subtherapeutic treatment group, pressure was left unchanged at the lowest possible value for the CPAP device used (3 or 4 cm H2O). After an average treatment of 9 weeks, far substantial reductions in mean BP (9.9 ± 11.4 mm Hg) and both nocturnal and daytime systolic and diastolic BP (10 mm Hg approximately) were noted in the therapeutic CPAP group, most likely owing to the length of the trial and treatment pressure used . The fact that, despite causing 50% reduction in AHI, subtherapeutic CPAP was not effective enough to cause any relevant change in BP (P = 0.01) further highlights the significance of highly effective therapy. Since OSA-mediated hypertension has a chronic etiology involving endothelial dysfunction and cardiovascular remodeling, it is very possible that short-term controlled studies may not entirely reveal the actual potentially far reaching consequences of scrupulous long-term CPAP therapy on hypertension and its cardiovascular sequelae.A randomized controlled trial  was condNotwithstanding increased benefits of CPAP therapy in those patients who demonstrated more than 50% reduction in AHI following CPAP , this efCPAP mediated BP reduction is also contingent on the presence of daytime somnolence, with far lower efficacy observed in patients who did not report EDS, despite having severe OSA with AHI > 30/h , 167. EvSince obesity is the single most important risk factor for OSA, even modest reductions in weight help attenuate the severity of both OSA and OSA induced hypertension. In a study  that exaSince both OSA and obesity have an independent causal relationship with hypertension, an integrated approach that includes lifestyle modifications such as weight loss should be recommended in OSA patients receiving treatment with CPAP and antihypertensives. In a randomized control trial  assessinP = 0.04), −2.7 mm Hg , and −2.40 mm Hg , respectively. Since most of the studies in this meta-analysis were also observational, the true effect of oral appliances on BP reduction in OSA remains nebulous. Andren et al. [Oral appliances are a recommended alternative treatment to CPAP in patients with mild to moderate OSA. There have been only limited clinical studies on this intervention, most of which were observational with small sample sizes and short durations. A meta-analysis of seven studies involving 399 OSAS patients  found a n et al.  in theirn et al.  althoughn et al. .P = 0.18) and morning SBP , SBP index , and DBP .Surgical options such as tonsillectomy and uvulopalatopharyngoplasty (UPPP) have also been looked at for impact of blood pressure in patients with OSAS. The SKUP3 randomized controlled trial by Di Munro et al.  showed tn = 16) or valsartan (n = 15). While both the drugs effectively reduced both systolic and diastolic BP, nebivolol had a significantly more marked impact on the decrease of heart rate compared to valsartan (P < 0.001), which may help in patients with nocturnal tachycardia. In a study by Kraiczi et al. [Hypertensive patients with mild to moderate OSA who do not need CPAP are ideal candidates for hypertensive therapy, as are those with severe OSA who do not tolerate or are not compliant with CPAP. Due to lack of adequate evidence, there are no specific guidelines as to which class of antihypertensive medications should be used to treat hypertension in OSA patients. Hypothetically, however, owing to the pathophysiological mechanisms causing and maintaining HTN in OSA such as the sympathetic and RAAS overactivity, antihypertensive drugs that modulate the activity of these systems such as B-blockers and aldosterone antagonists may be the best treatment options for hypertension in OSA patients. Aldosterone levels are generally normal in OSA except in patients with treatment resistant hypertension or severe OSA . The aldi et al. , B-blockAccording to most studies, antihypertensive drug mediated nocturnal blood pressure reduction has not been found to be associated with any significant decrease in the severity of sleep disordered breathing as measured by AHI, suggesting nocturnal high BP contributes only minimally to apneic events and OSA severity. The results have been observed across all the commonly used classes of antihypertensive drugs including B-blockers, calcium channel blockers, angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), hydrochlorothiazide, methyldopa, and clonidine –181. HowHowever, most of these studies had extremely limited samples (12–24 patients), variable populations, short duration of treatment and follow-ups, and lack of placebo effect and used noninvasive methods to measure BP. Since BP varies greatly during apneic cycles (between 150 and 300 mm Hg), invasive BP measurement is the most accurate technique to evaluate the mean nocturnal BP in patients with sleep disordered breathing. Hence there exists a lack of definitive recommendations regarding the use of antihypertensive agents for OSA treatment.P = 0.005) and an 8% decrease in sleep efficiency (P = 0.004). On the other hand, no other antihypertensive drug, such as diuretics and beta-blockers, was found to have an adverse impact on sleep duration. Notwithstanding these results, it is worth mentioning that most of these adverse effects need a long time before they can be discernable. Hence, the limited duration of these studies is not adequate to assess the true impact that these medications have on OSA severity. Walia et al. [Conversely, there has been some incriminating evidence advising against the use of ACE inhibitors in hypertensive OSA patients. According to Cicolin et al. , enalapra et al.  analyzedThere are numerous mechanisms that can potentiate the development of hypertension in OSA, with wide variation in individual susceptibility. These include increased sympathetic tone, inflammation, endothelial dysfunction, peripheral vasoconstriction, increased RAAS, heightened chemoreflex, and blunted baroreflex sensitivity. Conversely, acute rise in BP may cause an inhibition of the upper airway muscles. This, coupled with volume overload due to increased activity of the RAAS and rostral fluid displacement during sleep, can cause pharyngeal edema and subsequent airway obstruction, thus causing OSA in hypertensive patients. Treatment options for OSA range from surgical options such as tonsillectomy and adenoidectomy in children to modified UPPP in adults, to noninvasive measures such as CPAP therapy, oral appliances, and lifestyle modifications to address obesity; and lastly use of antihypertensive drugs has been investigated. These measures help address the issues of resistant hypertension that are frequently found in patients with OSAS which is linked with cardiovascular morbidity and mortality. Hence OSA and HTN both need prompt diagnosis and treatment to help address the growing cardiovascular morbidity and mortality due to these two entities. Continued advancements in the field of medicine may lead to newer treatment modalities in the future.


An increasing number of patients require precise intraoperative hemodynamic monitoring due to aging and comorbidities. To prevent undesirable outcomes from intraoperative hypotension or hypoperfusion, appropriate threshold settings are required. These setting can vary widely from patient to patient. Goal-directed therapy techniques allow for flow monitoring as the standard for perioperative fluid management. Based on the concept of personalized medicine, individual assessment and treatment are more advantageous than conventional or uniform interventions. The recent development of minimally and noninvasive monitoring devices make it possible to apply detailed control, tracking, and observation of broad patient populations, all while reducing adverse complications. In this manuscript, we review the monitoring features of each device, together with possible advantages and disadvantages of their use in optimizing patient hemodynamic management. While medicine is moving toward standardized care, the 2015 Precision Medicine Initiative aimed to understand how a person's genetics, environment, and lifestyle can help determine the best approach to prevent or treat disease. It is now possible to improve patient outcomes by setting individualized hemodynamic parameters according to specific and customized comorbidities or current pathologies. Enhanced Recovery After Surgery (ERAS) protocols recommend individualized intraoperative fluid optimization through integrated hemodynamic monitoring  is one of the most important vital signs monitored. The recent development of monitoring technologies allows clinicians to obtain both minimally invasive and continuously non-invasive BP. Hemodynamics describes a patients' BP, cardiac output (CO), and systemic vascular resistance (SVR). Appropriate and precise evaluations of these parameters make it possible to evaluate tissue perfusion. Although the optimal hemodynamic parameters for each patient are undefined, patient outcomes can potentially be improved by applying therapeutic strategies based on hemodynamic information . Poor peThe goal of this review is to describe the existing scientific scholarship on perioperative hemodynamic monitoring techniques and patient outcomes. We will describe different monitoring techniques as well as the advantages and disadvantages of each device. By using tailored monitoring tools, it is possible to adjust therapeutic decisions for each patient individually and for specific situations.Blood circulation supplies the necessary nutrients and oxygen to each tissue and collects unnecessary or toxic substances. The proper maintenance of pressure is necessary to distribute enough blood so that the organism can adapt to vigorous activity. Normally, organisms maintain their circulation homeostasis adequately, but surgery, anesthesia, and/or critical illness may disturb this homeostasis. Accurate hemodynamic monitoring is mandatory in these situations, most particularly with vulnerable patients who might not be able to adequately adapt to these unique conditions. Accurate monitoring provides necessary and invaluable information to launch appropriate interventions.Circulatory systems are often compared to electric circuits and are explained by Ohm's law. Ohm's law relates pressure, flow, and resistance by a simple mathematical expression that can be applied to the human circulatory system. In the human body, the amount of electrical current is translated to CO. Electrical resistance correlates to vascular resistance Figures . ConsideThe most popular, noninvasive continuous BP monitor uses finger cuff. Small cuff(s) with photoplethysmogram (PPG) are applied to the fingers. The cuff inflates to cancel out changes in the PPG. The balanced pressure represents the patients' blood pressure at the cuff site. The equipment reconstructs brachial arterial pressure from the finger BP waveform's transformation. It calculates arterial BP using estimated arterial resistance based on the patients' physical characteristics. When a patients' vessel characteristics differ greatly from the installed software, the obtained value may differ greatly from the actual and real value. This technique is still subject to some controversy: while some studies report it as a reliable, others conclude it to be inaccurate. Table Applanation tonometory, on the radial artery, continuously measures the tone calibrated with a conventional arm cuff. Although the first machine was invented in 1963, a major disadvantage of this monitor has been the difficulty in sensor fitting . FrequenPulse wave transit time (PWTT) is recognized as a parameter related to hemodynamics, especially SV, BP, and vascular resistance. The device is comprised of a common basic sensor, such as an electrocardiogram and a pulse wave detector on finger (often a pulse oximeter), possibly adding a phonocardiograph. The use of a phonocardiograph can help to provide more precise measurements. In recent years, time resolution, analytical algorithm, and its speed were improved by computer performance and cuff-less BP measurements . PWTT isThis method measures the impedance or reactance between a pair of electrodes on the chest wall or on the tracheal tube while applying an imperceptible alternating current that estimates changes in blood volume present in the thorax, particularly in the aorta. Changes in impedance or reactance during one cardiac cycle is considered to reflect stroke volume. This method estimates the stroke volume based on an internal database according to the patients' physical characteristics. Deviation from the database may enhance measurement errors . While iThere are roughly two methods to measure flow rate using an ultrasound device: one obtains the SV as the difference of the left ventricular end diastolic volume and the end systolic volume, while the other calculates the SV from the product of a certain cross-sectional area and velocity time integral. Minimally invasive and noninvasive CO monitors are designed with the latter method, which is simple and can reduce operator-dependent discrepancies . A varieEmerging BP and CO monitoring devices using the relation of SV with PWTT are commercially available and tested . AlthougPulse contour analysis has been investigated and modified since it was first developed. Improved algorithms have been adopted by various commercial devices. Pulse contour analytic CO monitors calculate SV from arterial pressure waveform based on the Windkessel model Figure  and/or wAdditionally, counter analysis has developed some secondary parameters such as Pulse Pressure Variation (PPV) and Stroke Volume Variation (SVV). These dynamic parameters are used as an index for fluid responsiveness, allowing for appropriate fluid management. The risk of arterial catheter-related infection was reported 1.3% and comparable with 2.7% of central venous catheters .Blood temperature changes are detected by a special arterial cannula which has a thermistor on its tip. Cold fluid boluses are injected through a central venous catheter, which is then sensed in the thermistor tip. CO is calculated from the thermodilution curve according to the Stewart–Hamilton equation. Following this intermittent manual measurement, it continuously calibrates the pulse contour analysis and displays CO. Since calibration is carried out every time the thermodilution is performed, the value is fairly accurate . Unlike 2 production and blood CO2 tension, the indirect Fick method. A dedicated rebreathing loop is connected to the patients' breathing circuit and the system measures CO by calculating carbon dioxide metabolism with partial rebreathing technology. This technology is not affected by vessel anatomical abnormalities or peripheral circulatory insufficiency, as it only needs information from exchange gases. Several validation studies have been published, mainly in the ICU setting  and fingertip photometric sensors, which detect indocyanine green (non-invasive). The advantage of products using arterial catheters is that they continuously measure the pulse contour analysis. Repeated measurements with frequent indicator can lead to dye accumulation, resulting in measurement errors and adverse effects. Muscle relaxants  can disturb the lithium ion sensor and rare allergic reactions have been reported with indocyanine green.A summary of noninvasive and minimally invasive continuous cardiac output monitors available can be found in Table The appropriate BP values vary from patient to patient, and the “correct” BP may differ depending on the surgery requirements or current situation. A surgical insult may cause the rapid or abrupt change in hemodynamic parameters, making it imperative to continuously monitor BP or other hemodynamic parameters. While controversial, hypotensive anesthesia is practiced with the goal to reduce intraoperative blood loss. This technique requires careful monitoring to avoid dramatic and sudden changes. Patients that have known vascular pathology are also candidates for continuous BP measurement.Studies showed that sustained intraoperative hypotension is associated with adverse patient outcomes, including increased mortality and organ injury. The duration of hypotension is also an important contributing factor for poor outcomes. Table The perioperative hemodynamic management of surgical patients extends beyond cardiovascular complications. Delayed recovery of cognition, whether delirium , or the long-lasting phenotype termed postoperative cognitive decline (POCD), has been linked to intraoperative blood pressure fluctuations  or maintNumerical, target-oriented volume and inotropic management based on hemodynamic measurement is crucial for a rapid recovery. It is increasingly accepted that the traditional fixed volume therapy should be abandoned and the administration of fluids to achieve a certain volume  improves outcomes. In addition to pressure measurement, hemodynamic parameters such as SV need to be calculated  and miniThe International Guidelines for Management of Severe Sepsis and Septic Shock brought further attention to the need for hemodynamic assessment in critically ill patients . ManagemNo single monitor is able to comprehensively identify the spectrum of pathophysiologic changes for high risk patients, despite various commercially available devices with a range of differing measurement principles.Understanding the measurement principles behind minimally invasive and noninvasive techniques can facilitate accurate evaluation of patients' hemodynamic status, even taking into consideration a possible measurement mismatch. When choosing and applying these monitors, it is important to clarify the purpose for monitoring and how to correctly employ the obtained parameters. The development of minimally invasive and noninvasive devices derives from the need to reduce complications from invasive tools. The application of two complementary devices, with different background principles, might even be an alternative to an invasive technology.N = 40), SVVs assessed using the FloTrac/Vigileo and the PiCCOplus systems performed similarly in predicting fluid responsiveness (In order to improve patient outcomes, monitoring itself should not be the goal. Monitoring principles need to be understood to guide therapy and decision making. New techniques have led to the development of new hemodynamic parameters. Dynamic parameters such as SVV and PPV are now widely recognized as important signs that can be used to guide fluid management. SVV has been shown to be a valid measure of fluid responsiveness , 39 and siveness . Today msiveness , the pulsiveness  and respsiveness . This insiveness , and cansiveness , 49–52. siveness , 53. PVIsiveness . PVI hassiveness . Today, The assessment of hemodynamics allow for a customized approach to patient management, one in which treatment decisions are being guided by more precise, multimodal and technologically sophisticated monitoring of physiological variables. Monitoring equipment that can provide precise hemodynamic information without the complications and complexity of invasive techniques can facilitate individualized hemodynamic management and lead to improved outcomes and many other positive contributions to the field.TY, SV, and MC are responsible for manuscript research, writing, editing, and review. YG is responsible for manuscript review.MC is a founder of Sironis and holds a patent on closed-loop hemodynamic optimization licensed to Edwards Lifesciences. The other authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.