To evaluate whether the decrease in blood pressure caused by the increase in the positive end-expiratory pressure corresponds to the pulse pressure variation as an indicator of fluid responsiveness.2O (positive end-expiratory pressure level 1), from 10 to 15cmH2O (positive end-expiratory pressure level 2), and from 15 to 20cmH2O (positive end-expiratory pressure level 3). Changes in systolic blood pressure, mean arterial pressure, and pulse pressure variation were evaluated during the three maneuvers. The patients were classified as responsive (pulse pressure variation ≥ 12%) or unresponsive to volume replacement (pulse pressure variation < 12%).This exploratory study prospectively included 24 patients with septic shock who were mechanically ventilated and subjected to three stages of elevation of the positive end-expiratory pressure: from 5 to 10cmHkappa = 0.42; 95%CI: 0.19 - 0.56). The systolic blood pressure was < 90mmHg at positive end-expiratory pressure level 2 in 29.2% of cases and at positive end-expiratory pressure level 3 in 41.63% of cases.The best performance at identifying patients with pulse pressure variation ≥ 12% was observed at the positive end-expiratory pressure level 2: -9% systolic blood pressure variation , with a sensitivity of 63% and specificity of 80%. Concordance was low between the variable with the best performance (variation in systolic blood pressure) and pulse pressure variation ≥ 12% (Variations in blood pressure in response to the increase in positive end-expiratory pressure do not reliably reflect the behavior of the pulse pressure as a measure to identify the fluid responsiveness status. More recently, it was observed that the drop in mean arterial pressure (MAP) caused by the increase in PEEP allows the identification of responsive patients. However, the application of high PEEP levels may result in severe hypotension or hypoxemia, especially in more hypovolemic patients..7 Considering that the use of lower levels of PEEP is safer, it was hypothesized that the generation of a gradient of 10cmH2O aimed at lower levels of final PEEP can help in the evaluation of fluid responsiveness.In 1999, Michard et al. observed that PPV could be used to monitor the hemodynamic effects of the application of PEEP, such as decreased cardiac output (CO) and blood pressure.The objective of this study was to evaluate whether the decrease in blood pressure caused by increased PEEP corresponds to PPV as an indicator of fluid responsiveness.Hospital Municipal São José and the Centro Hospitalar Unimed in Joinville (SC), Brazil, from January to October 2018.This is a prospective exploratory study conducted in the adult ICUs of the Patients older than 18 years diagnosed with septic shock, admitted to the ICU for up to 24 hours, under mechanical ventilation, and under the effect of analgesic and/or pharmacological muscle paralysis were considered eligible for the study and were included immediately after initial volume expansion.The exclusion criteria were confirmed or suspected intracranial hypertension, heart disease , pulmonary arterial hypertension, auto-PEEP or bronchospasm, abdominal compartment syndrome, and absence of invasive blood pressure monitoring.The diagnosis of septic shock was made based on the coexistence of an infectious focus and the need for infusion of vasoactive amine.2) that would maintain arterial oxygen saturation (SaO2) ≥ 92% and PEEP of 5cmH2O. The analgesic level and synchronization with mechanical ventilation were evaluated. If necessary, additional doses of analgesics, sedatives, or neuromuscular blockers were administered.Patients were ventilated with a ventilator  in controlled volume mode, with tidal volume (Vt) of 8mL/kg, 1:3 inspiration/expiration ratio, an inspired oxygen fraction (FiO2) and hemodynamic variables , including continuous electrocardiography, pulse oximetry, central venous pressure (CVP), and invasive blood pressure measurement. The pressure transducers were zeroed at the mid-axillary line. The infusion rate of vasoactive amines was kept constant throughout the intervention period. The monitored variables were divided into ventilatory  or potentially unresponsive to volume (PPV < 12%).The CO was not evaluated, and the fluid-responsiveness status was inferred from the continuous PPV measurement. Based on the findings of a recent meta-analysis, a cut-off point of 12% was adopted to infer volume responsiveness.1 (level 1), corresponding to a PEEP increase from 5 to 10cmH2O for 60 seconds; PEEP2 (level 2), which was an increase in PEEP from 10 to 15cmH2O for 60 seconds; and PEEP3 (level 3), which was the increase in PEEP from 15 to 20cmH2O, also for 60 seconds.After adjusting the ventilatory parameters, performing initial volume expansion with 30mL/kg of crystalloids, complementing muscle sedation and/or paralysis if necessary, and estimating the fluid responsiveness status from the PPV, the patients were subjected to three distinct stages of airway pressurization by increasing the PEEP to three different levels: PEEPThe variation in blood pressure was calculated for each of the three PEEP levels, and the percentage variations in MAP  and SBP  were determined after PEEP application according to 2 < 88%, and Ppl > 35cmH2O.The maneuvers were interrupted, and their values were recorded whenever any of the following situations were detected for more than 30 seconds: HR < 60bpm or > 150bpm, MAP < 65mmHg or SBP < 90mmHg, SaOAfter recording the monitored hemodynamic variables , all patients with PPV ≥ 12% and clinical and/or laboratory signs of hypoperfusion received 500mL of crystalloid over 15 minutes. Five minutes after the end of the infusion, the PEEP elevation maneuvers were repeated at three levels, as was the recording of hemodynamic variables.i, ΔMAP, PPV, and CVP) and ventilatory variables .The following variables were collected and recorded for analysis: sex, age, Simplified Acute Physiology Score (SAPS) version 3, type of shock, infectious site , hemodynamic variables  was used for statistical analysis. Continuous variables are expressed as median and interquartile range (IQR) and were compared with Student’s We constructed receiver operating characteristic (ROC) curves for ΔMAP and ΔSBP at each of the PEEP elevation levels to identify the best cutoff values that corresponded to 12% PPV, as well as the corresponding sensitivity and specificity. Areas under the ROC curve (AUC) of 0.70 to 0.79 indicate moderate discriminatory capacity, and AUC ≥ 0.80 indicates excellent discrimination.Hospital Municipal São José (CAAE: 88510818.1.0000.5362), and the Informed Consent Form was obtained from each patient or guardian family member.The study was approved by the Research Ethics Committee of the Twenty-four patients with septic shock were analyzed, whose clinical and demographic information is shown in 2, in which a ΔSBP of -9% was identified  0.49 - 0.79; sensitivity of 0.63, 95%CI 30.8 - 89.1; and specificity of 0.80, 95%CI 44.4 - 97.5). There was no association between ΔMAP and the estimate of fluid responsiveness by PPV at any of the PEEP levels tested.1 , PEEP2 , and PEEP3 . The correlation between ΔSBP and PPV according to the different PEEP levels was PEEP1: r = -0.60 ; PEEP2: r = -0.66 ; and PEEP3: r = -0.36 .The correlation coefficient between PPV and ΔMAP was determined at PEEPThe agreement between the best-performing variable (ΔSBP) and PPV ≥ 12% for identifying patients responsive to volume was moderate  .Among the 13 patients with PPV ≥ 12%, 12 (92.3%) showed a decrease in PPV after volume expansion, while six (40.0%) had a decrease in SBP and seven (46.7%) had a decrease in MAP. The median reduction in PPV went from 16% (14% to 21%) to 11% (9% to 13%), with p < 0.001. At the same time, ΔSBP ranged from -8% (-12% to -2%) to -4% (-8% to -2%), with p = 0.26, while ΔMAP ranged from -4% (-10% to -1%) to -5% (-9% to -2%), with p = 0.34 .2  and PEEP3 (p < 0.001). Seven (29.2%) patients had SBP < 90mmHg at PEEP2 and 10 (41.6%) had SBP < 90mmHg at PEEP3. Regarding MAP, five (20.8%) patients had values < 60mmHg at PEEP2 and seven (29.2%) had values < 60mmHg at PEEP3. The inspiratory pressures were higher starting at PEEP2, and the plateau pressure exceeded 30cmH2O at PEEP3.The present findings do not demonstrate a relationship between PPV and decreased blood pressure (ΔSBP or ΔMAP) caused by increased PEEP as an indicator of fluid responsiveness in patients with septic shock. Thus, the effects of increased PEEP on blood pressure to guide volume replacement should be further investigated. The limitations of this method have motivated the search for alternatives. The increase in PEEP displaces the cardiac function curve and reduces ventricular filling, CO and, consequently, blood pressure. These changes are more prominent in hypovolemic patients, who tend to have a greater need for fluids and vasopressors to restore hemodynamic stability. Thus, it is understood that the fluid status is the basis of hemodynamic tolerance to acute PEEP increases. Based on this physiological foundation, changes in PPV through the application of PEEP could be used to infer changes in CO and assist in the determination of fluid responsiveness status. Even so, PPV has limitations that should be considered. As an alternative that would help circumvent some of these shortcomings, a proposal was made to relate the reductions in MAP and PPV through the elevation of PEEP to identify the fluid responsiveness status, and it was concluded that an 8% MAP reduction by increasing the PEEP from 10 to 20cmH2O could discriminate between responsive and unresponsive patients.Pulse pressure variation is a widely known and reliable substitute marker for assessing volume responsiveness., on the contrary, found an AUROC of 0.91 (95%CI 0.77 - 1.00) for ΔMAP and 0.82 (95%CI 0.64 - 1.00) for ΔMAP, whereas the highest AUROC observed in this study was 0.73 (95%CI 0.49 - 0.79) for ΔSBP at the PEEP2 level, which demonstrated only a moderate ability to discriminate potentially responsive from unresponsive patients. The additional increase in PEEP to 20cmH2O did not increase the accuracy of the method.The decrease in blood pressure (both MAP and SBP) in the presence of progressive PEEP application did not safely differentiate patients with PPV ≥ 12% from patients with PPV < 12%, regardless of the PEEP level adopted. Wilkman et al. Thus, blood pressure may be of limited worth during hemodynamic evaluation in hypovolemic patients. This limitation is highlighted by the finding that there was no change in the ΔMAP (p = 0.18) or ΔSBP (p = 0.14) after volume expansion among the 13 patients with PPV ≥ 12%, at the same time that PPV decreased from 16% to 11% (p < 0.001). In addition, 12 of the 13 volume-responsive patients showed a reduction in PPV, while ΔMAP and ΔSBP varied in half of these responsive patients , which may signal the need for further studies.These results did not reproduce some previous findings,The decrease in blood pressure in response to the increase in positive end-expiratory pressure did not reliably reflect the behavior of pulse pressure respiratory variation in the effort to identify the fluid responsiveness status, in addition to causing hypotension in a considerable portion of the patients.


The presence of acute kidney injury in the setting of acute heart failure (AHF) or acute decompensated heart failure (ADHF) is a very common occurrence and was termed cardiorenal syndrome 1 (CRS1). Neutrophil gelatinase-associated lipocalin (NGAL) in the blood and urine is one of the earliest biomarkers of acute kidney injury due to ischemia or renal toxicity. This study was aimed to evaluate the diagnostic efficacy of plasma NGAL in the diagnosis of CRS1.  There were 139 patients with AHF or ADHF in the department of Cardiovascular Resuscitation and Interventional Cardiology at Ho Chi Minh City 115 People Hospital from September 2018 to March 2019. This was a prospective cohort study. p < 0.05. The optimal cutoff plasma NGAL for diagnosing CRS1 was >353.23 ng/ml, area under curve (AUC) 0.732 , sensitivity 74.47%, specificity 68.48%, positive predictive value 54.7%, and negative predictive value 84%. Multivariable logistic regression analysis eGFRCKDEPID1 remained the strongest independent predictor of CRS1. Building the optimal regression model (without eGFRCKDEPID1) by the BMA (Bayesian model average) method with two variables NGAL and Creatinine D1, we had the equation: odds ratio = ey while y = −2.39 + 0.0037 × NGAL + 0.17 × Creatinine D1. The nomogram (without eGFRCKDEPID1) was designed to predict the likelihood of CRS1 with AUC 0.79.  There were 48 cases (rate 34.5%) with CRS1, mean age was 66.12 ± 15.77 and men accounted for 50.4%. There were no significant differences of vital signs at admission, diagnosis, and EF-based heart failure between CRS1 and non-CRS1 groups. The urea, creatinine on first day (creatinine D1) and third day (creatinine D3), NT-proBNP, and NGAL levels were higher in the CRS1 group than the non-CRS1 group,  The combination of plasma NGAL and creatinine D1 on the first day at admission had a high accuracy of predictive model for CRS1. Acute kidney injury (AKI) in the setting of acute heart failure (AHF) or acute decompensated heart failure (ADHF) is a very common occurrence and was termed cardiorenal syndrome type 1 (CRS1) . It is eIn the CRS type 1, the diagnosis of acute kidney damage is often delayed because of the creatinine and urine output according to KDIGO . Neutrophil gelatinase-associated lipocalin (NGAL) in the blood and urine is one of the earliest indicators of acute kidney injury due to ischemia or nephrotoxicity. One study showed using NGAL in urine to diagnose acute kidney injury with 90% sensitivity and 99% specificity . NeutropWe aimed to evaluate the diagnostic efficacy of NGAL in diagnosis of CRS1 in AHF or ADHF patients.All patients with AHF or ADHF were admitted to the Cardiovascular Resuscitation and Interventional Cardiology Department of 115 People Hospital in Ho Chi Minh City from November 2018 to May 2019.Inclusion criteria for this study were adult inpatients (≥18 years old) with AHF or ADHF with or without CRS type 1.µ mol/l); or within 48 hours, there was a 50% increase in serum creatinine from the level on admission during hospitalization. Urine criteria (0.5 mL/kg per hour for 6 hours) were not utilized for AKI diagnosis because of the potential alterations in the urine volume induced by therapeutic medication.  Criteria for diagnosing AKI: according to the KDIGO clinical practice guideline for acute kidney injury 2012 , serum c  Criteria for diagnosing CRS type 1: patients who suffered from AHF or ADHF developed AKI within 48 hours .Criteria for diagnosing AHF or ADHF was used according to Canadian Cardiovascular Society guidelines for the management of heart failure 2017 .  CriterExclusion criteria were not agreeable to participation; hospitalization period <2 days; multiple organ failure or septic shock; AKI caused by contrast; renal dialysis; kidney transplant; progressive hepatitis; acute pancreatitis; long-term use of high dose steroids; cyclosporin; and malignancy.This was a prospective cohort study.nse estimated the sample size to estimate for sensitivity, nsp estimated the sample size to estimate for specificity, and Pse is the reference sensitivity according to the literature. For NGAL, this sensitivity is 100% . While systolic blood pressure was 120 [90–140] mmHg and diastolic blood pressure was 70 [60–80] mmHg. Percentage of patients diagnosed with acute pulmonary edema, ADHF, and cardiogenic shock were 43.2%, 38.8%, and 16.5%, respectively. There were 56 patients (40.9%) diagnosed with acute myocardial infarction. Only 5 patients  with acute myocardial infraction had percutaneous coronary intervention and all patients were tested NGAL, cystatin C, and NT-proBNP before percutaneous coronary intervention. There are similarities in vital signs at admission and diagnosis between two groups with CRS1 and non-CRS1. This was also explained by the fact that both groups were patients with AHF or ADHF.CKDEPID1, and eGFRCKDEPID3 in the CRS1 group were lower than the non-CRS 1 group, p < 0.05. Patients in the CRS1 group had considerably lower GFR and higher creatinine and NGAL at baseline. One possible explanation is the rate of history of chronic kidney disease in the CRS1 group being higher than the non-CRS1group, as NGAL and cystatin C have been shown to be elevated in patients with chronic kidney disease. Unfortunately, these findings made cutoff points for diagnosing CRS1 of NGAL which were higher than patients without history of chronic kidney disease, but this was unavoidable clinically because chronic kidney disease is a comorbidity in heart failure.The present study revealed a similarity in laboratory values at admission: left ventricular ejection fraction EF, neutrophil, and hemoglobin between the two groups CRS1 and non-CRS1. However, urea concentration, creatinine D1 and D3, NT-proBNP, and NGAL in the CRS1 group were higher than the non-CRS1 group. Conversely, sodium concentration, eGFRp < 0.001. The cutoff point was >353.23 ng/ml, AUC curve 0.732 , sensitivity 74.47%, specificity 68.48%, positive predictive value 54.7%, and negative predicted value 84%. The plasma NGAL concentration and cutoff point for the diagnosis of CRS1 in our study was higher than that of the author Margarida et al. [Neutrophil gelatinase-associated lipocalin (NGAL), a protein of the lipocalin superfamily, is synthesized abundantly in kidney tubules. Its expression is rapidly upregulated by ischemia-reperfusion injury in renal tubular epithelial cells, and NGAL is released via urine in an experimental model . In humaa et al. . This miCKDEPID1 remained the strongest independent predictor of CRS1. Plasma NGAL failed to predict the occurrence of early CRS1. In case of without eGFRCKDEPID1, there were two variables (creatinine D1 and NGAL) independently predicting CRS1.When entering the variables into a univariate logistic regression analysis, 6 variables predicted the occurrence of early CRS1. During multivariable regression analysis, eGFRey, where y = −2.39 + 0.0037 × NGAL + 0.17 × creatinine D1 and nomogram, as shown in We built a predictive model for CRS1 with two variables, plasma NGAL and creatinine D1, by the equation: Odds ratio Several reports evidenced the role of NGAL in the setting of heart failure, underlying the leading part of tubular damage independently from baseline renal dysfunction –19. DataThere are several limitations to the study. First, this study was conducted in a single center in Vietnam, limiting the external validity to other centers with different settings. Second, most patients are seriously ill so they have not been fully assessed for hospitalization because ADHF patients may not be admitted to the cardiac resuscitation department. Third, some kidney diseases (such as urinary tract infections or immune diseases) can also lead to an increase in NGAL levels. Although we had tried to eliminate these patients with a history and physical examination, they were still not completely controlled. Fourth, we did not measure hemodynamics or more accurate measurements of glomerular filtration rate to directly link the increased NGAL level to the compensatory kidney condition. Fifth, our sample size is still relatively small and there were some missing data. Sixth, we only evaluated for CRS1 within 48 hours, so we can skip cases with CRS1 after 48 hours to 7 days. Lastly, we only tested plasma NGAL once in the first day but did not test after 48 hours and before discharge to assess the variability of plasma NGAL concentration compared with creatinine concentration.p < 0.001), sensitivity 74.47%, specificity 68.48%, positive predictive value 54.7%, and negative predictive value 84%. The predictive model of CRS1, including 2 variables plasma NGAL and creatinine D1, had accuracy of 75.93%, sensitivity 76.74%, specificity 72.73%, positive predictive value 91.67%, and negative predictive value 44.44%.Plasma NGAL was valuable for the diagnosis of CRS1 with a cutoff point >353.23 ng/ml, the AUC curve was 0.732 (95% CI 0.65–0.80,


It has been shown that a value of WCN = 0.1 indicates the optimum state of arterial wave reflection in which left ventricle workload is minimized. The pressure wave, flow wave, and PWV are all required to compute WCN, which may limit the potential clinical utility of WCN. The aims of this study are as follows: (1) to assess the feasibility of approximating WCN from the pressure waveform alone (WCNPinf), and (2) to provide the proof-of-concept that WCNPinf can capture age related differences in arterial wave reflection among healthy women and men.The wave condition number (WCN) is a non-dimensional number that determines the state of arterial wave reflections. WCN is equal to HR × LPinf. The exact value of WCN was computed from PWV (measured by foot-to-foot method), HR, and Leff. A quarter wavelength relationship with minimum impedance modulus were used to compute Leff. WCNPinf was calculated using HR and the reflected wave arrival time. Previously published analyses from a healthy subset of the Anglo-Cardiff Collaborative Trial (ACCT) study population were used to investigate if non-invasive WCNPinf captures age related differences in arterial wave reflection among healthy women and men.Previously published retrospective data composed of seventeen patients  were used to assess the accuracy of WCNr = 0.83, p-value <0.0001) between WCNPinf and WCN was observed. The accuracy of WCNPinf was independent from relevant physiological parameters such as PWV, pulse pressure (PP), and HR. Similar changes in WCNPinf with advancing age were observed in both healthy men and healthy women. In young, healthy individuals (women and men) the WCNPinf was around 0.1 , and reduced with aging.A strong correlation (WCN can be approximated from a single pressure waveform and can capture age related arterial wave reflection alteration. These results are clinically significant since WCN can be extracted from a single non-invasive pressure waveform. Future studies will focus on investigating if WCN is associated with risk for onset of cardiovascular disease events. The cardiovascular system in mammals is based on various optimization criteria . Previouin vitro hemodynamic studies, published hemodynamics data on various mammalian species, and allometry analysis, they have shown that a value of WCN = 0.1 indicates the optimum state of arterial wave reflection in the mammalian systemic circulation. Furthermore, their analysis confirms that this optimum value of the WCN remains constant (0.1) at various levels of aortic stiffness, and is universal among all mammals regardless of size  workload is minimized in mammalian cardiovascular systems . Using a of size . Yigit a of size . Their w of size .It is well-known that various cardiovascular diseases (CVDs) alter arterial wave reflections . Therefodoes not imply that the aorta and its complex wave dynamics can be modeled as a straight tube with a single reflection site at the end.In any discipline of physics, wave dynamics in a medium are dominated by three factors: (1) material properties of the medium that define the wave speed, (2) fundamental frequencies of the waves, and (3) interfaces that create wave reflections. Although other wave characteristics such as dispersion or dissipation also contribute to overall wave dynamics, their effects are not dominant in general. Similarly, wave dynamics in the aorta and the arterial system are primarily controlled by (1) pulse wave velocity , (2) heart rate , and (3) reflection sites. The WCN number combines all reflection sites existent in various forms within the vascular network , and considers a hypothetical total reflection site from which the summated reflected waves appear to be reflected. Pahlevan and Gharib  used theLeff), PWV, and HR using the equation  and fZmin is the lowest frequency among all frequencies in which the amplitude of the impedance modulus is minimum. Mathematically speaking:Here fi is defined as:Where Z| is the amplitude of the impedance in the frequency domain, and is computed from pressure and flow harmonics as:Here |where:f, and P0, Q0 are the average of pressure and flow over the cardiac cycle, respectively.Here, tarr)  . AssuminSubstituting Eq. 8 into Eq. 1 gives:WCNPQ and WCNPinf.In Eq. 9, HR is expressed in beats-per-second. Pinf with respect to WCN computed from Eq. 1 by using the pressure and flow waves and the quarter-wavelength relationship (Eqs 2–7). Data from Pinf and aging among healthy individuals.Previously published retrospective data from The database published by In seven patients, the inflection point of the pressure waveform occurred before the peak systolic pressure with an augmentation index (AIx) greater than 12% [the so-called type A waveform ]. In sevPinf and investigate its relationship with age in both males and females among healthy populations. The data was a subset of the Anglo-Cardiff Collaborative Trial (ACCT) study population  on relevant physiological parameters such as PWV, pulse pressure (PP), and HR was investigated.Bland-Altman analysis  was usedPinf were approximated from the reported SDs of tarr and reported SD of the HR and their mean values for each age bracket range assuming that tarr and HR are independent from each other (The standard deviations (SD) of the non-invasive WCNch other .r = 0.83, p-value <0.0001) between WCNPinf  and WCNPQ calculated from Eq. 1 and, using the effective length computed from Eq. 2.The hemodynamics and the demographics of the study population are shown in Pinf error is independent from relevant physiological parameters such as PWV, PP, and HR. There was no significant correlation between WCNPinf error and PWV, PP, and HR with p-values of 0.76, 0.16, and 0.70, respectively.Pinf and age among healthy populations for both males (x = 35 indicates 30–40 years). The dashed bars are the standard deviation lines.The overall declining relationship between WCNth males  and femath males  is demonPinf in this manuscript) can capture age related differences in arterial wave reflection in a healthy population. The results also demonstrate that WCNPinf is approximately 0.1 , and thPinf moderately reduces in an aged population. However, the actual decline in the value of WCN among an elderly population is probably more significant since the true value of tarr in the elderly is over-estimated by the usage of the time of the inflection point. A recent study by tarr computed from the time of the inflection point over-estimates the true value of a tarr computed from a pressure-flow analysis. Although WCNPinf underestimates the impact of aging on WCN, it reveals the overall trends of aging on WCN among healthy populations. Perhaps WCN computed from other single waveform decomposition methods , in a large middle-aged population  indicate a decrease with age over two decades (35–56 years old) from 0.090 to 0.081 in men and from 0.081 to 0.73 in women. This behavior agree with the results presented in Pinf values and their variations with age are similar in both men and women; however, the average values of WCNPinf computed from the data reported by r = −0.57, p < 0.0001) drop in tarr with aging. Based on the results reported in tarr drops from 152 to 120 over 6 decades (20 to 80). Unfortunately, values of HR have not been reported by the authors. Using average HR values for healthy population reported by Pinf for the reported data from Pinf based on this data drops from 0.92 (20 years old) to 0.62 (80 years old) over six decades. These values are well within the results reported in os study  which inin vitro LV-arterial simulator  for pulmonary circulation. Although workload on the RV is much lower on than the LV, quantifying the optimum wave reflection can be helpful in patients with right heart failure or patients with pulmonary hypertension  events in large longitudinal cohorts. Such studies will reveal if WCN is a useful addition to standard risk assessment for one or more types of CVDs. Further research can also be focused on the pulmonary vasculature in order to evaluate optimum WCN for the minimization of the workload on the right ventricle (RV). The overall length of pulmonary networks is shorter than the overall length of systemic networks, and the nature of wave reflections at the end of pulmonary vasculature is different than the systemic vasculature . These trtension .Pinf did not include any patients older than 54 years. Future studies are needed to verify if the WCNPinf error remains within the same range indicated in this study. Another limitation related to the WCNPinf error is that the left ventricle (LV) ejection fraction (LVEF) values of the patients were not available. LVEF is one of the most relevant cardiovascular parameters that may affect the accuracy of WCNPinf. It is noteworthy that there are uncertainties in the assessment of WCN since the absolute accuracy of a WCN assessment depends on the flow and pressure measurement errors, the synchronization between pressure and flow measurements, as well as the sampling frequency of the measurements.One major limitation of this study is that the database for assessment of the accuracy of WCNWCN can be approximated from a single pressure waveform, independently from related hemodynamics indices such as PP, PWV, and HR. This study provides a proof-of-concept that non-invasive single-waveform WCN can capture age-related alterations of arterial wave reflections in a large healthy cohort. However, these changes in WCN with age are not as substantial in healthy populations, possibly limiting its usefulness for healthier individuals. These results are clinically significant since WCN can be extracted from a single non-invasive pressure waveform that is easily acquired using arterial applanation tonometry, a smartphone-based handheld device , or an uThe data used in this study for the analysis is uploaded as This study uses retrospective previously published data.NP contributed to the conceptualization, the analysis, the writing of the original draft, the revision, and the editing. SM  contributed to the statistical analysis, the revision, the discussion, and the editing.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.


Blood pressure (BP) variability has reportedly been a risk factor for various clinical events. To clarify the influence of BP visit‐to‐visit variability on adverse events in patients with nonvalvular atrial fibrillation, a post hoc analysis of the J‐RHYTHM Registry was performed.P=0.015 for thromboembolism; HR, 2.60, 95% CI, 1.36–4.97, P=0.004 for major hemorrhage; and HR, 1.85, 95% CI, 1.11–3.07, P=0.018 for all‐cause death) after adjusting for components of the CHA2DS2‐VASc score, warfarin and antiplatelet use, atrial fibrillation type, BP measurement times, and others. These findings were consistent when BP‐coefficient of variation was used instead of BP‐SD.Of 7406 outpatients with nonvalvular atrial fibrillation from 158 institutions, 7226 , in whom BP was measured 4 times or more (14.6±5.0 times) during the 2‐year follow‐up period or until occurrence of an event, constituted the study group. SD and coefficient of variation of BP values were calculated as BP variability. Thromboembolism, major hemorrhage, and all‐cause death occurred in 110 (1.5%), 121 (1.7%), and 168 (2.3%) patients, respectively. When patients were divided into quartiles of systolic BP‐SD , hazard ratios (HRs) for all adverse events were significantly high in the highest quartile compared with the lowest quartile (HR, 2.00, 95% CI, 1.15–3.49, Systolic BP visit‐to‐visit variability was significantly associated with all adverse events in patients with nonvalvular atrial fibrillation. Further studies are needed to clarify the causality between BP variability and adverse outcomes in patients with nonvalvular atrial fibrillation.https://www.umin.ac.jp/ctr/; Unique Identifier: UMIN000001569.URL:  AFFIRMAtrial Fibrillation Follow‐Up Investigation of Rhythm ManagementBP‐endblood pressure at the time closest to an event or at the end of follow‐upCrClcreatinine clearanceCVcoefficient of variationNVAFnonvalvular atrial fibrillationPT‐INRprothrombin time international normalized ratioTTRtime in therapeutic rangeSystolic blood pressure (BP) visit‐to‐visit variability was significantly associated with the increased risk of thromboembolism, major hemorrhage, and all‐cause death in patients with nonvalvular atrial fibrillation, independent of BP values at the closest time to an event and other conventional risk factors.Systolic BP visit‐to‐visit variability was superior to systolic BP values at the closest time to an event as a predictor of major hemorrhage and composite events.In Japanese patients receiving warfarin, BP variability was significantly correlated with time in therapeutic range in those aged ≥70 years and prothrombin time international normalized ratio variability.Systolic BP visit‐to‐visit variability is evidently important for the prevention of all adverse events in patients with nonvalvular atrial fibrillation as well as in patients without atrial fibrillation.BP visit‐to‐visit variability as well as anticoagulation quality (time in therapeutic range) and intensity  should be taken into account for the management of patients with nonvalvular atrial fibrillation.Hypertension is an established risk factor for several cardiovascular diseasesBP visit‐to‐visit variability, as an index of long‐term BP variability,The data that support the findings of this study are available from the corresponding author upon reasonable request from an appropriately qualified research group.The J‐RHYTHM Registry was conducted as a nationwide prospective observational study to investigate the status of anticoagulation therapy and the optimal anticoagulation therapy in Japanese patients with AF.Anticoagulation intensity was determined at the time of enrollment (baseline) and at each follow‐up visit using the prothrombin time international normalized ratio (PT‐INR) in patients receiving warfarin. Time in therapeutic range (TTR) was calculated by the Rosendaal methodPatients were followed up for 2 years or until an event, whichever occurred first. The primary end points were as follows: thromboembolism including symptomatic ischemic stroke, transient ischemic attack, and systemic embolic events; major hemorrhage including intracranial hemorrhage, gastrointestinal hemorrhage, and other hemorrhages requiring hospitalization; and all‐cause death. The composite of thromboembolism, major hemorrhage, and all‐cause death, whichever occurred first for each patient, was also evaluated. The diagnostic criteria for each event have been described elsewhere.According to a post hoc analysis of the AFFIRM  Study,2DS2‐VASc score ,P values of <0.05 were considered statistically significant. All statistical analyses were performed with SPSS software version 23.0  and R version 3.5.2 .Data are presented as mean±SD or number (percentage). For comparison of patient characteristics and 2‐year event rates among the quartiles, trend analysis was performed using Cochran‐Armitage test for categorical variables or Jonckheere‐Terpstra test for continuous variables, as appropriate. Relation between 2 parameters was assessed by Pearson’s correlation coefficient analysis. Kaplan‐Meier curves among the quartiles were compared with a log‐rank test. Univariable and multivariable analyses using Cox proportional hazards models were performed to investigate the influence of BP variability on adverse events. Cox proportional hazards assumption was verified by the log‐log survival curve in all of the study outcomes. Risks of BP variability for adverse events in each quartile were expressed as hazard ratios (HRs) and 95% CIs with the lowest quartile as a reference. Explanatory variables for multivariable analysis were adopted from well‐known risk factors used in our previous subanalysis for hypertension and BPOf the entire 7937 patients with AF enrolled in the J‐RHYTHM Registry,Clinical characteristics of 7226 patients are listed in Table Patient characteristics and medications in each systolic BP‐SD quartile are shown in Table During the 2‐year follow‐up period, thromboembolism, major hemorrhage, and all‐cause death occurred in 110 (1.5%), 121 (1.7%), and 168 (2.3%) patients, respectively. Corresponding incidence rates of these events were 0.8, 0.8, and 1.2/100‐person years, respectively, during the follow‐up period of 14 580 person‐years.P<0.001 for all, by log‐rank test) in the Kaplan–Meier curves with the worst event‐free survival rates in the highest quartile  of systolic BP‐SD for all events were significantly high in univariable and multivariable analysis Table ; whereasThe AUCs of BP‐SD for thromboembolism and all‐cause death were comparable with those of BP‐end, whereas the AUCs of BP‐SD for major hemorrhage and composite events were significantly larger than those of BP‐end Table .When BP‐CV was used instead of BP‐SD, similar results were obtained. Event rates showed significant trends across BP‐CV quartiles Table . HRs werWhen BP‐CV was analyzed as a continuous variable, HRs (/1% increase) of systolic BP‐CV were significantly high for all events in multivariable analysis as well as in unadjusted analysis Table , whereasThe AUCs of BP‐CV for thromboembolism and all‐cause death were comparable with those of BP‐end, whereas the AUCs of BP‐CV for major hemorrhage and composite events were significantly larger than those of BP‐end Table .The major findings of this study were as follows. First, age, BP, and prevalence of comorbidities showed significant trends across the quartiles of systolic BP variability. Second, the highest quartile of systolic BP‐SD of ≥13.20 mm Hg was independently associated with the increased incidence of all adverse events, but that of diastolic BP‐SD was not. Third, these findings were consistent when using BP‐CV instead of BP‐SD.In 1997, Grove et al.2DS2‐VASc score. Additionally, the third and highest quartiles of systolic BP‐SD were independently associated with a higher risk for stroke  as well as major hemorrhage . Patients in the highest quartile also had a higher risk for all‐cause death .There have been few studies on association of BP variability with clinical outcome in patients with NVAF. In 2017, Proietti et al.Our post hoc analysis showed results similar to those in the AFFIRM post hoc analysis.Since our previous report revealed that BP‐end, not BP at baseline, was independently associated with the incidence of both thromboembolism and major hemorrhage,As shown in Table Several mechanisms have been proposed for the association of increased BP variability with adverse cardiovascular events.In subanalysis of the AFFIRM Study,On the other hand, when evaluating separately in patients aged <70 years and ≥70 years since the Japanese guidelinesThis study had several limitations. First, it was a post hoc analysis of data from the J‐RHYTHM RegistrySystolic BP visit‐to‐visit variability was an independent risk for thromboembolism, major hemorrhage, and all‐cause death in patients with NVAF. Overall quality of anticoagulation control with warfarin was not associated with BP variability. Further studies are needed to clarify the causality between BP variability and adverse clinical outcomes in patients with NVAF.The following physicians participated in the J‐RHYTHM Registry: Executive Committee: H. Inoue, K. Okumura, H. Atarashi, and T. Yamashita. Local Executive Committee: M. Sakurai, Y. Kawamura (Hokkaido); K. Okumura, I. Kubota (Tohoku); Y. Kaneko, K. Matsumoto (North Kanto); S. Ogawa, H. Atarashi, T. Yamashita (South Kanto); H. Inoue, Y. Aizawa (Hokuetsu); I. Kodama, E. Watanabe (Chubu); Y. Koretsune, Y. Okuyama (Kansai); A. Shimizu, O. Igawa (Chugoku); S. Bando, M. Fukatani (Shikoku); T. Saikawa, A. Chishaki (Kyushu). Statistical Advisor: H. Origasa. Participating Investigators: N. Kato, K. Kanda, J. Kato, H. Obata, M. Aoki, H. Honda (Hokkaido); Y. Konta, T. Hatayama, Y. Abe, K. Terata, T. Yagi, A. Ishida, T. Komatsu, H. Tachibana, H. Suzuki, Y. Kamiyama, T. Watanabe, M. Oguma, M. Itoh, O. Hirono, Y. Tsunoda, K. Ikeda, T. Kanaya, K. Sakurai, H. Sukekawa, S. Nakada (Tohoku); T. Itoh, S. Tange, M. Manita, M. Ohta, H. Eguma, R. Kato, Y. Endo, T. Ogino, M. Yamazaki, H. Kanki, M. Uchida, S. Miyanaga, K. Shibayama, N. Toratani, T. Kojima, M. Ichikawa, M. Saito, Y. Umeda, T. Sawanobori, H. Sohara, S. Okubo, T. Okubo, T. Tokunaga, O. Kuboyama, H. Ito, Y. Kitahara (North Kanto); K. Sagara, T. Satoh, E. Kodani, K. Sugi, Y. Kobayashi, Y. Higashi, T. Katoh, Y. Hirayama, N. Matsumoto, M. Takano, T. Ikeda, S. Yusu, S. Niwano, Y. Nakazato, Y. Kawano, M. Sumiyoshi, N. Hagiwara, K. Murasaki, H. Mitamura, S. Nakagawa, K. Okishige, K. Azegami, H. Aoyagi, K. Sugiyama, M. Nishizaki, N. Yamawake, I. Watanabe, K. Ohkubo, H. Sakurada, S. Fukamizu, M. Suzuki, W. Nagahori, T. Nakamura, Y. Murakawa, N. Hayami, K. Yoshioka, M. Amino, K. Hirao, A. Yagishita, K. Ajiki, K. Fujiu, Y. Imai, A. Yamashina, T. Ishiyama (South Kanto); M. Sakabe, K. Nishida, H. Asanoi, H. Ueno, J. D. Lee, Y. Mitsuke, H. Furushima, K. Ebe, M. Tagawa, M. Sato, M. Morikawa (Hokuetsu); K. Yamashiro, K. Takami, T. Ozawa, M. Watarai, M. Yamauchi, H. Kamiya, H. Hirayama, Y. Yoshida, T. Murohara, Y. Inden, H. Osanai, N. Ohte, T. Goto, I. Morishima, T. Yamamoto, E. Fujii, M. Senga, H. Hayashi, T. Urushida, Y. Takada, R. Kato, N. Tsuboi, T. Noda, T. Hirose, T. Onodera, S. Kageyama, T. Osaka, T. Tomita, K. Shimada, M. Nomura, H. Izawa, A. Sugiura, T. Arakawa, K. Kimura (Chubu); T. Mine, T. Makita, H. Mizuno, A. Kobori, T. Haruna, M. Takagi, T. Watanabe, N. Tanaka, H. Shimizu, T. Kurita, K. Motoki, N. Takeda, Y. Kijima, M. Ito, A. Nakata, Y. Ueda, A. Hirata, S. Kamakura, K. Satomi, T. Noda, Y. Yamada (Kansai); Y. Yoshiga, H. Ogawa, M. Kimura, T. Hayano, T. Kinbara, H. Tatsuno, M. Harada, K. Kusano, M. Adachi, A. Yano, M. Sawaguchi, J. Yamasaki, T. Matsuura, Y. Tanaka, H. Moritani, T. Maki, S. Okada, M. Takechi, T. Hamada (Chugoku); A. Nishikado, Y. Takagi, I. Matsumoto, T. Yamamoto, T. Soeki, Y. Doi, M. Okawa, H. Seo, S. Kitamura, K. Yamamoto, M. Akizawa, N. Kaname (Shikoku); S. Ando, S. Narita, T. Nakamura, T. Inou, Y. Fukuizumi, K. Saku, M. Ogawa, Y. Urabe, M. Ikeuchi, S. Harada, H. Yamabe, Y. Imamura, Y. Yamanouchi, K. Sadamatsu, K. Yoshida, T. Kubota, N. Takahashi, N. Makino, Y. Higuchi, T. Ooie, T. Iwao, K. Kitamura, T. Imamura, K. Maemura, N. Komiya, M. Hayano, H. Yoshida, K. Yamashiro, K. Kumagai (Kyushu).The J‐RHYTHM Registry is registered at the University Hospital Medicine Information Network (UMIN) Clinical Trials Registry (UMIN000001569) and was supported by a grant from the Japan Heart Foundation (12080025). This research was partially supported by the Practical Research Project for Life‐Style related Diseases including Cardiovascular Diseases and Diabetes Mellitus from the Japan Agency for Medical Research and Development (AMED) (19ek0210082h0003).Dr. Kodani received remuneration from Daiichi‐Sankyo, Bristol‐Myers Squibb, and Ono Pharmaceutical; Dr. Inoue received remuneration from Daiichi‐Sankyo, Bayer Healthcare, Boehringer Ingelheim, and Bristol‐Myers Squibb; Dr. Atarashi received remuneration from Daiichi‐Sankyo; Dr. Okumura received research funding from Boehringer Ingelheim and Daiichi‐Sankyo and remuneration from Boehringer Ingelheim, Bayer Healthcare, Daiichi‐Sankyo, and Pfizer; Dr. Yamashita received research funding from Daiichi‐Sankyo, Bayer Healthcare, and Bristol‐Meyers Squibb and remuneration from Daiichi‐Sankyo, Pfizer, Bayer Healthcare, Bristol‐Myers Squibb, Toa Eiyo, and Ono Pharmaceutical; and Dr. Origasa received remuneration from Daiichi‐Sankyo and Bayer Healthcare.Tables S1–S10Click here for additional data file.


Chronic kidney disease (CKD) affects both brain structure and function. Patients with CKD have a higher risk of both ischemic and hemorrhagic strokes. Age, prior disease history, hypertension, diabetes, atrial fibrillation, smoking, diet, obesity, and sedimentary lifestyle are most common risk factors. Renal-specific pathophysiologic derangements, such as oxidative stress, chronic inflammation, endothelial dysfunction, vascular calcification, anemia, gut dysbiosis, and uremic toxins are important mediators. Dialysis initiation constitutes the highest stroke risk period. CKD significantly worsens stroke outcomes. It is essential to understand the risks and benefits of established stroke therapeutics in patients with CKD, especially in those on dialysis. Subclinical cerebrovascular disease, such as of silent brain infarction, white matter lesions, cerebral microbleeds, and cerebral atrophy are more prevalent with declining renal function. This may lead to functional brain damage manifesting as cognitive impairment. Cognitive dysfunction has been linked to poor compliance with medications, and is associated with greater morbidity and mortality. Thus, understanding the interaction between renal impairment and brain is important in to minimize the risk of neurologic injury in patients with CKD. This article reviews the link between chronic kidney disease and brain abnormalities associated with CKD in detail. Chronic kidney disease (CKD) is a type of kidney disease associated with gradual loss of kidney function, decreased glomerular filtration rate or increased albumin excretion in urine. CKD prevalence is estimated to be 8–16% worldwide . Kidney CKD in combination with other cardiovascular risk factors accelerates atherosclerosis and increases stroke risk in the predialysis stages. Medial calcifications occur frequently in patients with CKD, independent from the intima calcifications caused by atherosclerosis. Medial calcifications are associated with abnormal cushioning function of blood vessels and increased arterial stiffness. Intimal calcifications are mainly associated with ischemic stroke events, while media calcifications with high pulse pressure contribute to hemorrhagic stroke , 4. EndoOne of the hallmarks of CKD is proteinuria. Patients with proteinuria have a 71% greater risk of stroke compared to those without, as proteinuria is strongly associated with hypertension and other cardiovascular risk factors . However2 decrease in glomerular filtration rate, and the finding is consistent across major stroke subtypes  is another significant stroke risk factor common in CKD patients with an estimated prevalence ranging from 3.5 to 27% depending on AF type . CKD is Stroke is one of the most frequent neurological conditions and the leading cause of death. As patients with CKD have more risk factors for atherosclerosis, it is estimated that the risk for developing cardiovascular diseases, including stroke, is 5–30 times greater than in the general population . The preRecently mild cognitive impairment (MCI) has garnered a scientific interest in the nephrology community . CKD is Cognitive impairment affects quality of life . CognitiThe data supporting CKD-induced brain injury consist of epidemiological associations, expert opinion, and few studies. Brain lesions can be assessed either by radiological methods, which provide largely structural information, or validated neurocognitive tests with a functional information .The pathophysiology of cognitive dysfunction in CKD is very complex and encompasses endothelial dysfunction, vascular calcification and other vascular structural changes, impaired autoregulation, and various humoral factors specific to kidney disease. Possible mechanisms of brain injury in the setting of CKD are summarized in Various hypotheses have been proposed to explain kidney-brain interaction. “Vascular hypothesis” implies that impaired cerebral hemodynamics in CKD may lead to cognitive decline . Brain h“Neurodegenerative” hypothesis relates cerebrovascular injury in CKD to accumulating uremic toxins, disrupted blood-brain-barrier integrity (BBB), neurotransmitter derangement, and disturbed drug pharmacokinetics. The BBB and the blood-cerebrospinal fluid barrier (BCSFB) are paramount to keep central nervous system stable from fluctuating blood composition. These barriers consist of tightly connected cerebral endothelial cells, astrocytes and other components. This structure allows BBB and BCSFB to control transportation of various proteins and nutrients between central nervous system and the blood. Any BBB or BCSFB disorder or injury determines increased transportation of inflammatory cells and proteins into the brain tissue . BBB perThere are various other kidney-specific factors involved in pathophysiology of cognitive decline in patients with renal impairment. Secondary hyperparathyroidism can potentially interfere with neurotransmission by increasing calcium levels in the brain . Anemia The effect of various treatment strategies on cognitive function in CKD patients has been investigated. This includes more frequent or nocturnal dialysis and other . HoweverEffect of lower blood pressure levels on age-related cognitive decline in patients with and without CKD has been investigated in one large trial . Recently published SPRINT MIND study shows that intensive blood pressure control significantly reduces the risk of mild cognitive impairment  in whole cohort and in those with CKD  . The rolFurther research and intervention strategies are required to explore the cognitive decline in CKD.Cerebral microbleeds (CMBs) or microhemorrhages are 5–10 mm size round, homogenous, hypointense foci that can be visualized by magnetic resonance (MR) susceptibility-weighted (SW) imaging. Histopathologically, CMBs represent hemosiderin-laden macrophages, hemosiderin granules and different kinds of vascular damage  . In the p for trend = 0.003)  , 75. The= 0.003) .There are recent data on CMBs in patients on dialysis as well. Hemodialysis patients with no stroke history had been prospectively followed-up until they died or were transplanted. Study showed CMBs being a strong predictor for a future intracerebral hemorrhage, but not a cerebral ischemia , 78. TheFrom mechanistic perspective there are recent data pointing to the role of disruption of the blood–brain barrier in the genesis of CMBs in CKD . The papIn summary, different studies suggest that the decreased kidney function is a risk factor for CMBs, while the CMBs are considered to be an independent risk factor for overt cerebrovascular disease. Therefore, renal function can serve as a potential alternative predictor for cerebrovascular events. More studies are needed to determine if moderation of kidney disease can prevent the occurrence and progression of CMBs.Silent brain infarction (SBI) is a cerebral infarction that is visible on brain imaging but does not cause any clinical symptoms . SBI is Clinical studies suggest that SBI is a strong predictor for stroke , moreoveThere is a wide range of neurological pathologies which are related to CKD, including brain atrophy. Even in non-dialysis CKD patients, imaging studies consistently demonstrate a greater evidence of cerebral atrophy than in the general population.Mechanisms that connect brain atrophy and renal injury have not been fully explored, but several hypotheses might explain the association between both processes. Previous studies have shown that increasing small vessel disease is associated with cerebral atrophy . There aYakushiji et al. investigated the relationship between kidney function and subclinical age-specific cerebral atrophy in adults with no previous history of neurological disorders. They showed that decreased GFR is significantly associated with a substantial degree of cerebral atrophy . In one 2 was significantly linked to an increased volume of WMLs (β 0.322 [95% CI 0.080–0.564]) after adjusting for cardiovascular risk factors) (White matter lesions (WMLs) are areas of demyelinated cells found in the white matter of the brain. Moreover, WMLs are associated with increased risk of stroke, cognitive decline, and dementia. Recently, WMLs has been studied more, to clarify their link with CKD , becausefactors) . Thus, pUnderstanding the risks and benefits of established stroke prevention treatments is vital in patients with CKD, especially in those on dialysis. Especially, post-stroke management with anticoagulants, antiplatelet agents and lipid-lowering agents to prevent recurrent strokes presents the risk of undesirable side effects in CKD patients with reduced renal clearance.Stroke risk in CKD, similar to the general population, increases with higher systolic blood pressure (BP). Thus, blood pressure lowering is an attractive approach for both primary and secondary stroke prevention . HoweverP = 0.017]  study confirmed that hyperuricemia is associated with higher risk of ischemic stroke. Mediation analyses showed that indicators of hypertension severity are statistical mediators of the hyperuricemia-stroke association . The stu= 0.017] . Both fe= 0.017] . In addi= 0.017] .Sodium-dependent glucose transporters (SGLTs) proteins may be a viable therapeutic target in ischemic stroke in CKD patients. Interestingly, SGLTs are regionally increased in ischemic brain especially in the penumbral regions . Large cCKD is a coronary heart disease equivalent for future cardiovascular events, with risk exceeding that of diabetes mellitus . Thus, KTraditional anticoagulation guidelines with warfarin or novel oral anticoagulants (NOAC) for the general population for thromboembolic stroke prevention in AF may not be applied for advanced kidney disease or dialysis patients. Warfarin in patients with both ESRD and atrial fibrillation are associated with an increased risk for stroke, possibly due to accelerated vascular calcification occurring as a result of vitamin K antagonism . This riAccording to American Heart Society American College of Cardiology and American Heart Association 2019 atrial fibrillation guidelines NOACs are recommended over warfarin except in patients with moderate to severe mitral stenosis or a prosthetic heart valve, although kidney and liver function should be tested before initiation of NOAC and evaluated annually. For patients with AF and moderate-to-severe CKD with an elevated CHA2DS2-VASc score, treatment with reduced doses of direct thrombin or factor Xa inhibitors may be considered . In AF patients with a CHA2DS2-VASc score ≥2 in men or ≥3 in women and a creatinine clearance <15 ml/min or who are on dialysis, it is reasonable to use warfarin or apixaban for oral anticoagulation . The 201post-hoc subanalysis in patients with stage 4 chronic kidney disease (CKD) (CrCl 15–29 mL/min) showed (N = 269) that the effect of apixaban vs. warfarin on the primary efficacy outcome of stroke or systemic embolism was similar in each kidney function category, over a median 1.8 years follow-up . Major bleeding event rates were numerically lower in patients receiving apixaban compared with warfarin, irrespective of kidney function category (CrCl <30 mL/min vs. ≥30 mL/min), which was consistent with the overall population. In patients with CrCl <30 mL/min, the median apixaban drug exposure was 5,512 ng/mL*h in 12 patients assigned the 5 mg dose and 2,792 ng/mL*h in 19 patients assigned the 2.5 mg dose  <25–30 mL/min (Cockcroft-Gault), including those on dialysis, were excluded from the major NOAC trials. However, results from an ARISTOTLE  mg dose .2). In this population-level, retrospective cohort study from Canada 27,552 new NOAC users were matched to 27,552 new VKA users. The anticoagulation was indicated for the prevention of thromboembolism in atrial fibrillation or deep venous thrombosis. NOACs compared to VKAs were associated with lower risk of cardiovascular events or mortality. Interestingly, this association was strongest among those with reduced eGFR. No interaction of eGFR and anticoagulant class was detected for the hemorrhage outcome (A retrospective cohort study of Medicare beneficiaries comparing ESRD patients receiving warfarin and NOAC apixaban found that patients receiving standard-dose apixaban (5 mg) had a lower risk of stroke/embolism than those receiving low-dose apixaban (2.5 mg) and warfarin. Standard-dose apixaban was associated with a lower risk of death than that observed with low-dose apixaban and warfarin, and there was a lower risk of major bleeding with apixaban than with warfarin . A recen outcome .Several randomized trials are currently underway to definitively assess the treatment effects of NOACs compared with warfarin for stroke prevention in patients with advanced kidney disease , 133. InThrombolysis with tissue plasminogen activator (tPA) is a clinical challenge in CKD patients. This patient group has such subclinical manifestations as transient infarcts, lacunar infarcts and microbleeds. ESRD patients are even more complex because of comorbidities, such as atrial fibrillation, anemia, diabetes mellitus and hypertension . Further2. These discrepancies may lead to great practice variations. In the UK more than 3 million people with CKD and no cardiovascular disease are not prescribed aspirin but ~1 million receive aspirin for primary prevention  diabetic CKD patients on clopidogrel showed increased cardiovascular and overall mortality compared with those on placebo (p for interaction 0.019)  . Ticagren 0.019) , 157.In summary, the use of anticoagulants and antiplatelet medications has to be rationalized and balanced due to the increased risk of bleeding in CKD patients.As kidney function declines cardiovascular system develops various pathologies. Indeed cardiovascular morbidity and mortality has been a focus for nephrologists for decades. However, chronic kidney disease (CKD) affects brain function and structure as well. Kidney and brain disorders share common pathophysiologic mechanisms. Common risk factor modifications include treatment of high blood pressure in order to prevent hypertension induced chronic kidney disease, stroke and silent brain infarction. Brain imaging tests could be routinely used in patients with CKD to detect silent brain infarctions, white matter lesions and cerebral microbleeds as these asymptomatic conditions may portend fatal consequences.In summary, CKD has a direct damaging effect on the brain, and the mechanisms are complex and further investigations are needed. As the renal and cerebral disorders are inextricably linked, their management should include a close collaboration between nephrologists and neurologists.All authors contributed significantly to this work and supported the publication of the manuscript. MM, UC, MJ, and AV devised the research plan. MM, UC, MJ, and AV wrote the manuscript. MM and MJ modified and polished 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.


Acute kidney injury, based on AKI staging, should be regarded as an independent risk factor for postoperative delirium after cardiac surgery.Recent data indicate that acute kidney damage leads to inflammation in the brain and other distant organs. The purpose of this study was to investigate the effect of acute kidney injury (AKI) according to the Kidney Disease Improving Global Outcome (KDIGO) criteria on the occurrence of postoperative delirium in patients undergoing coronary artery bypass grafting (CABG). We performed a retrospective cohort analysis that included all consecutive patients undergoing elective CABG. The CAM-ICU (Confusion Assessment Method for Intensive Care Unit) was used for delirium assessment. Patients were divided into four groups, depending on the occurrence of AKI in the perioperative period according to KDIGO criteria. Overall, 902 patients were included in the final analysis, the mean age was 65.95 ± 8.01 years, and 76.83% were males (693/957). The majority of patients presented with normal kidney function-baseline creatinine level of 0.91 ± 0.21 (mg/dL). The incidence of AKI in the perioperative setting was 22.17% (200/902). Postoperative delirium was diagnosed in 115/902 patients (12.75%). Compared with no AKI, the odds of developing POD were increased for KDIGO stage 1 ,  Acute kidney injury (AKI) is common in the perioperative setting in patients undergoing cardiac surgery and in critically ill patients and can contribute to increased morbidity and mortality by affecting distant organ function ,2,3. LikPostoperative delirium and other postoperative neurological disorders  are common, yet they are underdiagnosed symptoms of brain dysfunction in the intensive care unit, and their mechanisms are insufficiently understood ,7. ExperNumerous studies have shown that acute kidney injury has a significant influence on the function of extrarenal organs, including the brain . It has The vast majority of cardiac surgery operations are performed with the use of extracorporeal circulation, which may cause major harm to renal performance. Scientific studies deliver conflicting results regarding the influence of cardiopulmonary bypass on development of acute kidney injury ,14. HoweTherefore, the purpose of this study was to determine whether acute kidney damage in the perioperative period is associated with postoperative delirium in patients undergoing cardiac surgery and the impact of these disorders on early and long-term prognosis. We hypothesized that acute kidney damage during the perioperative course of cardiac surgery is independently associated with postoperative delirium.2. We performed a retrospective cohort analysis that included all consecutive patients undergoing planned coronary artery bypass grafting (CABG) surgery at a university cardiac surgery department, between year 2014 and 2018. We excluded patients undergoing emergency surgery, with known cognitive impairment (diagnosis of dementia or cognitive dysfunction), patients without sequential serum creatinine measurements (preoperative and at least one postoperative result), with a diagnosis of chronic renal failure, patients who received chronic renal replacement therapy prior to surgery, and those with an initial estimated glomerular filtration rate (GFR) of less than 20 mL/min/1.73 mAll demographic, medical, and laboratory data, including creatinine levels, were collected retrospectively from electronic medical records. All patients were assessed for the presence of postoperative delirium until the 5th day after surgery. The primary outcome was the presence of postoperative delirium. We analyzed the POD in relation to the difference between baseline serum creatinine before surgery and the maximal serum creatinine values within 48 h after surgery. Mental state  was assessed daily, using the Polish version of the ICU Confusion Assessment Method (CAM-ICU) and Richmond Agitation and Sedation scale (RASS) . All patPatients were divided into 4 groups, depending on the occurrence of acute kidney injury in the perioperative period, diagnosed according to the KDIGO  classification, using plasma creatinine concentration . The folKDIGO 0 (no-AKI): maximum increase in serum creatinine after surgery <0.3 mg/dL or increase <50% relative to baseline creatinine before surgery.KDIGO 1 (Stage 1): maximum increase in serum creatinine after surgery ≥0.3 mg/dL or increase ≥50% from baseline creatinine before surgery.KDIGO 2 (Stage 2): maximum increase in serum creatinine after surgery equal to ≥100% increase in baseline serum creatinine.KDIGO 3 (Stage 3): maximum increase in serum creatinine after surgery at the level of ≥200% compared to baseline serum creatinine or the need for renal replacement therapy.The study was performed in accordance with the Declaration of Helsinki and Good Clinical Practice. It received a waiver from the Bioethical Committee of the Pomeranian Medical University due to its retrospective observational character (decision no. KB-0012/237/12/19).p-value of <0.05 was regarded as statistically significant. To identify independent risk factors, we performed a multivariable analysis and included only those parameters that had a significance of p < 0.001 in the univariable analysis. Further analysis included KDIGO staging and the risk of POD development adjusted by age, sex, BMI, EF, and ESL. All data were analyzed, using licensed software Statistica 12 . The study group characteristics are presented, using the mean, standard deviation, and percentages. To evaluate the normality of the distribution of the studied variables, we used the Shapiro–Wilk test. The odds ratio (OR) of postoperative delirium was obtained through the use of univariable logistic regression. The results of regression were presented with the value of the odds ratio, with 95% confidence intervals and the statistical significance value. A 2. A total of 902 patients were included in the final analysis, as depicted by the study flowchart . The incidence of AKI in the perioperative setting was 22.17% (200/902). Among AKI patients, 159/902 were classified as KDIGO 1 (17.63%) and 30/902 as KDIGO 2 (3.33%). Of the 200 patients with AKI, 11/902 received RRT and fulfilled the KDIGO 3 criteria (1.22%). The perioperative laboratory data and KDIGO classification are visible in The majority of patients presented with normal kidney function prior to the operation, with the mean baseline creatinine level of 0.91 ± 0.21 and mean baseline GFR of 82.32 ± 16.02  and AKI staged due to KDIGO classification are independent risk factor for developing POD in this group of patients , p = 0.005; and highest for KDIGO stage 3 with OR equal to 9.729 , p = 0.001, as visible in Compared with no AKI, the odds of developing postoperative delirium was statistically significantly increased in the setting of KDIGO stage 1 with OR 2.401 , We performed an analysis of a large cohort of patients undergoing planned coronary artery bypass grafting procedure and found that acute kidney injury, regardless of its staging according to KDIGO criteria, is associated with an increased incidence of postoperative delirium. After adjusting for potential confounders, KDIGO stage 1 doubles the risk, stage 2 triples the risk, and stage 3 increases the risk of delirium nine times. Our results indicate that acute kidney injury and acute brain dysfunction may be regarded as practical confirmation of the kidney–brain crosstalk. No previous study has been presented to prove this relationship in patients undergoing cardiac surgery. The strength of our study is in the homogeneity of the population under analysis. We included patients undergoing only one type of cardiac surgery, with a relatively low potential for triggering acute kidney injury, without previous diagnosis of chronic renal failure, with normal mean preoperative creatinine level and glomerular filtration rate. We used the KDIGO classification to stage acute kidney injury, because the definition of stage 1 AKI according KDIGO is very sensitive, with small, short increases in creatinine classified as acute kidney damage ,17,18.The results of our study are in line with the reports provided by other authors but performed in the ICU setting. Although they used different AKI criteria, Pisani et al. were the first to demonstrate that acute changes in kidney function, diagnosed as an admission creatinine level above 2 mg/dL, were associated with the development of ICU delirium . Siew etThe mechanism of the interplay between acute kidney injury and acute brain dysfunction called the “brain–kidney crosstalk” has not been fully elucidated ,20. The It has been shown that, after experimental renal ischemia, distant organ changes occur that include cytokine induction, leukocyte infiltration, and apoptotic cell death. The effect of AKI on distant organs has been shown by an elegant study by Grigorieyev et al., who tested the hypothesis that AKI may lead to a vigorous inflammatory response and produces distinct genomic signatures in the brain and lungs . The autLiu et al. have reported short-term effect of ischemic AKI on inflammatory and functional changes of the brain in mice . The autAs the study presented by us is of observational character, the data showed a strong correlation only between the level of AKI and the incidence of postoperative delirium. However, it is not evidence of a direct interplay between the kidney and the brain. There may be, but it will be extrapolating by saying the data suggest that the kidney is affecting the brain or vice versa. Further studies are necessary to investigate this observation.Our study is not without limitations. First, this is a single-center observation; therefore, its generalizability may be limited. Second, in this analysis, we used only the serum creatinine change over time as the diagnostic criterion for AKI. Based on the KDIGO criteria, the acute kidney damage may be diagnosed according to the “creatinine” criterion  or percentage increase in serum creatinine greater than or equal to 50% (1.5-fold from baseline)) or the “diuresis” criterion . Many researchers believe that the creatinine criterion should be combined with the diuresis criterion for greater diagnostic sensitivity; therefore, the lack of the “diuresis” criterion in our study may be regarded as a limitation. Third, only creatinine was available as a biomarker of kidney dysfunction. In the future studies, it is worth considering using other markers for early identification of acute kidney damage, such as NGAL or cystatin C .This large observational study provides data that acute kidney injury, based on AKI staging, should be regarded as an important and independent risk factor for postoperative delirium after cardiac surgery. Acute kidney injury stage 1, according to KDIGO, doubles the risk, KDIGO stage 2 triples the risk, and KDIGO stage 3 increases the risk of delirium by a factor of nine, after adjusting for potential confounders. All patients should undergo preoperative and postoperative creatine-level assessment to stage AKI, as AKI staging has been shown to be independently associated with delirium. Further studies are necessary to elucidate the underlying mechanism of acute brain dysfunction during an acute kidney disorder.


NFKB2, NFATC3, DUSP1, DUSP2, DUSP5 and DUSP16. In this study, we observed an altered expression of miR-1246, miR-5100 and miR-338-3p after eight weeks of benralizumab administration, which could be used as early response markers.Severe eosinophilic asthma poses a serious health and economic problem, so new therapy approaches have been developed to control it, including biological drugs such as benralizumab, which is a monoclonal antibody that binds to IL-5 receptor alpha subunit and depletes peripheral blood eosinophils rapidly. Biomarkers that predict the response to this drug are needed so that microRNAs (miRNAs) can be useful tools. This study was performed with fifteen severe eosinophilic asthmatic patients treated with benralizumab, and serum miRNAs were evaluated before and after treatment by semi-quantitative PCR (qPCR). Patients showed a clinical improvement after benralizumab administration. Additionally, deregulation of miR-1246, miR-5100 and miR-338-3p was observed in severe asthmatic patients after eight weeks of therapy, and a correlation was found between miR-1246 and eosinophil counts, including a number of exacerbations per year in these severe asthmatics. In silico pathway analysis revealed that these three miRNAs are regulators of the MAPK signaling pathway, regulating target genes implicated in asthma such as  Asthma is a chronic inflammatory disease of the airways that affects more than 300 million people worldwide . This paSevere asthma comprises a small group of asthmatic individuals, between 5–10% of people with asthma who have a higher risk of severe exacerbation, clinical worsening and poor control. Among these patients, an estimated 40–60% have eosinophilic airway inflammation, which is associated with severe asthma, despite high-inhaled corticosteroids (ICS) and long-acting β2-agonists (LABAs) therapies . Accordiα receptor , depending on the clinical characteristics of patients. Benralizumab is a humanized afucosylated monoclonal antibody (IgG1κ) that binds with high affinity to the IL-5α receptor on the surface of human eosinophils and basophils , and FEV1/forced vital capacity [FVC] ratio) neither asthma control test (ACT) values  values . Finallythmatics .In view of these data, benralizumab is able to improve asthma clinical parameters in severe eosinophilic patients.p < 0.05; p < 0.05; p < 0.05; In this study, fifteen severe asthmatic patients were recruited and serum miRNAs were evaluated at baseline and eight weeks after the first doses of benralizumab were received. Among the miRNAs checked, we found a significant decrease in the expression levels of three miRNAs after eight weeks of treatment: miR-1246   b,c. On tThese results show that there is an alteration of three miRNAs after benralizumab therapy in severe eosinophilic patients, which could serve as early response markers to treatment.1). We highlight that ΔCt values of miR-1246 were inversely correlated with the number of exacerbations at baseline . Among the target genes found, there were some relevant genes implicated in asthma pathogenesis, including the nuclear factor of activated T-cells, cytoplasmic 3 (NFATC3), mitogen-activated protein kinase kinase kinase 2 (MAP3K2), dual-specificity phosphatases family  and nuclear factor kappa β subunit 2 (NFKB2)  signaling pathway ( (NFKB2) .The target genes and signaling pathways that are regulated by these miRNAs could be indicative of a restoration of altered processes in severe asthma after benralizumab treatment.This is the first report that shows an altered expression of miRNAs  after eight weeks of benralizumab administration, confirming that they could be used as early response markers.Benralizumab is a monoclonal, afucosylated antibody used as a treatment in severe eosinophilic asthma that binds to IL-5 receptor subunit alpha (IL-5Rα) and depletes, almost completely, peripheral blood eosinophils, being more effective than other anti-IL-5 therapies such as mepolizumab and reslizumab ,21. In tHowever, several studies have described the biomarkers for eosinophilic severe asthma, with peripheral eosinophils being considered the best predictor biomarkers for anti-IL-5 and anti-IL-5Rα therapies . HoweverAccording to our results, the altered miRNAs found in patients post-treatment have been linked to or dysregulated in asthma pathogenesis ,23,24,25DUSP1, DUSP2, DUSP5 and DUSP16, are the major regulators of the MAPK signaling pathway and they are implicated in the control of anti-inflammatory responses, mainly in References [MAP3K2 was significantly decreased in asthmatic patients after ICS treatment [NFATC3 and NFKB2 play a central role in cytokine regulation in several types of immune cells [In relation to signaling pathways regulated by these miRNAs, MAPK signaling is essential in the allergic inflammation of airways, and subsequently, in asthma pathogenesis . We founferences ,34,35. Areatment . This fane cells ,38. One Here, we report, for the first time, three miRNAs that could be used as biomarkers of early benralizumab response in severe eosinophilic asthmatic patients. The downregulation of miR-1246, miR-5100 and miR-338-3p eight weeks after the first benralizumab dosage could indicate a recovery of control mechanisms of asthma in these patients, and subsequently, an improvement of their health.


The importance of kidney damage in obese patients is due to the increasing incidence of nephropathies associated with metabolic disorders, their predisposition to a progressive course of the disease, and the need to optimize early disease detection.The purpose of our work is to study the level of cystatin C, ghrelin, and their interrelation in patients with early stages (I-II) of chronic kidney disease (CKD) against the background of obesity.The indicators of daily microalbuminuria in patients of both groups were studied, and it was found that in patients with stage 2 CKD with obesity, it was 1.2 times higher than in patients with stage 1 CKD with obesity. Patients of the second group revealed a direct middle correlation between daily albuminuria and body mass index (BMI), which indicates deterioration in the functional state of the kidneys against the background of obesity.We obtained an increase in the serum concentration of cystatin C in stage 2 CKD with obesity, reflecting the state of glomerular filtration and the degree of renal function decrease. Correlation analysis showed a positive relation of cystatin C with increased urinary albumin excretion in both groups, plasma creatinine content, BMI, and age.Simultaneously with the increase in the level of cystatin C and the decrease in the glomerular filtration rate, there was an increase in ghrelin levels in stage 2 CKD and the progression of obesity, while such dependence was not seen in stage 1 CKD. In recent years, there has been an increase in the incidence of chronic kidney disease (CKD) due to an increase in the number of patients with metabolic disorders such as obesity, type 2 diabetes, and hyperuricemia . Arteriaet al., 5.7% of patients developed CKD [et al. found a faster decrease in glomerular filtration rate due to increased blood pressure after studying the relation between the components of the metabolic syndrome and the progression of CKD [The urgency of kidney damage in obese patients is due to the increasing incidence of nephropathy associated with metabolic disorders, their tendency to a progressive course of the disease, and the need to optimize early disease detection . After 5oped CKD . There in of CKD . On the n of CKD .In recent decades, there has been an understanding that CKD is not only a consequence of various diseases but also a predictor of the progression of certain cardiovascular diseases and mortality, the combination of which is constantly growing . The groSerum cystatin C (sCysC) is a low-molecular-weight protein belonging to the family of cysteine proteinase inhibitors that play an important role in the intrinsic cellular metabolism of various peptides . It is sIn recent years, ghrelin, leptin, and insulin have played an important role in the occurrence of obesity and its impact on renal function and pathology . GhrelinCurrently, studies have been conducted mainly on changes in ghrelin levels in end-stage chronic kidney disease , and theThe purpose of the work was to study the level of cystatin C, ghrelin and their interaction in patients with early (I-II) stages of chronic kidney disease against the background of obesity.One hundred fifty-eight patients with chronic kidney disease who were hospitalized at the department of Arterial Hypertension of the Communal Non-profit Enterprise “Ivano-Frankivsk Regional Clinical Cardiological Centre of Ivano-Frankivsk Regional Council”, Urological and Cardiology Department of the Communal Non-profit Enterprise “Central City Clinical Hospital of Ivano-Frankivsk City Council” in Ivano-Frankivsk City were examined. Of them, 67 are women, and 91 are men. The average age of the examined patients was: 55.36 ± 2.02 years in women and 47.45 ± 2.66 years in men. Stage 1 CKD was diagnosed in 70 patients , stage 2 CKD was diagnosed in 88 patients . The reasons for the development of CKD were as follows: infections of the upper urinary tract in 11.8% cases, urolithiasis in 19.89% cases, 15.76% suffered from glomerulonephritis with symptomatic renal parenchymal hypertension, abnormalities in the development of the urine-reproductive system in 6.9% cases, hypertension in 29.1% cases and coronary heart disease with heart failure in 18.89% cases. The average duration of CKD was 7.1 years. Exclusion criteria were diabetes mellitus, hypothalamic and endocrine obesity, acute myocardial infarction, congestive heart failure IIB – III according to the Vasylenko-Strazhesko system and III-IV according to the New York Heart Association (NYHA) classification, liver failure, stages 3-5 CKD. The control group consisted of 10 apparently healthy individuals (3 women and 7 men), whose average age was 36.7 ± 8.6 years. All patients underwent general clinical examinations. The CKD stage was established according to the 2012 Kidney Disease: Improving Global Outcomes (KDIGO) guidelines  and the Determination of albumin in daily urine was performed using the turbidimetric method with the “Microalbumin” diagnostic kit (Germany) and evaluated in mg/day. Glomerular filtration rate was calculated according to the CRD-EPI formulas based on the level of creatinine, cystatin C and their combination   using the US National Kidney Foundation calculator . Cystatin C level in serum  was examined by enzyme-linked immunosorbent assay using the Human Cystatin C ELISA (Czech Republic) kit on the STAT FAX analyzer (No. 7898). Ghrelin level in serum (pg/ml) was determined by enzyme-linked immunosorbent assay using the Human Ghrelin EIA (CIF) kit on the STAT FAX analyzer.The study protocol was approved by the Ethics Committee of the Ivano-Frankivsk National Medical University, protocol No. 97/17 of 19 October 2017. All patients gave informed consent to participate in the study. The study was conducted in accordance with the principles of the Helsinki Declaration of the World Medical Association “Ethical principles for medical research involving human subjects” of 01 October 2008, No. 900_005.Statistical analysis of the results was performed using the statistical software package Statistica 6.0 using Student’s t-test. The correlation was assessed by Spearman’s rank correlation coefficient. The discrepancy of the results at p<0.05 was considered statistically significant.Urinary albumin excretion is currently considered to be a marker of endothelial dysfunction and atherosclerosis; therefore, it is advisable to determine this indicator in both CKD and metabolic disorders. According to the results of our studies, the level of daily microalbuminuria in patients of groups 1 and 2 exceeded the indicators in healthy people by 7.4 and 8.9 times, respectively . Comparing the indicators of daily microalbuminuria in patients of both groups, it was found that in patients with stage 2 CKD against the background of obesity, it was 1.2 times higher (p>0.05) than in patients with stage CKD on the background of obesity . In patiThe level of cystatin C in patients of both groups also exceeded the respective indicator in healthy people – 1.8 and 2.29 times, respectively . In patients of group 2, cystatin C was 1.25 times higher than those in group 1 (p>0.05). The increase in cystatin C serum levels reflects the state of glomerular filtration and the degree of decrease in renal function . AccordiThe glomerular filtration rate calculated based on cystatin C in patients of group 1 was slightly lower (94.56 ± 1.34) than the one calculated based on creatinine (97.3 ± 1.52), and there was no significant difference in this indicator when calculated by the CRD-EPIcys and CRD-EPIcysC/cr formulas. In patients of group 2, the glomerular filtration rate calculated based on cystatin C was significantly lower than that based on creatinine (p <0.01). The glomerular filtration rate calculated by the formula CRD-EPIcysC/cr indicates a decrease in this indicator in patients of group 2 compared with group 1 by 1.5 times (p <0.001), which confirms renal dysfunction, despite the normal values of creatinine. Reverse causality of glomerular filtration rate, calculated by the CRD-EPIcys formula, with serum cystatin C level was determined in both groups . The level of creatinine and glomerular filtration rate calculated by the CRD-EPIcr formula correlated with BMI. However, the BMI-creatinine relationship was inconsistent . A medium negative correlation between GFR-CRD-EPIcys and BMI-r1 = -0.52 in patients of group 1 and a strong one – r2 = -0.71 in patients of group 2  was determined.The study of total ghrelin level in the serum of patients with stage 1 CKD on the background of obesity indicates a consistent (p <0.01) decrease of 2.5 times. On the contrary, the total ghrelin level in those examined for stage 2 CKD was 1.4 times higher (p <0.05). After performing correlation analysis between cystatin C and ghrelin levels, a direct correlation was found  between the increase in both indicators in patients with stage 2 CKD on the background of obesity. No correlation was found in those examined for stage 1 CKD with obesity. Decreased glomerular filtration rate in patients with stage 2 CKD and obesity had a reverse average correlation , while in patients with stage 1 CKD with obesity, these indicators were not interrelated. Other researchers point to a positive correlation between elevated ghrelin and creatinine levels in higher-stage CKD, which developed on the background of obesity, elevated blood pressure, and metabolic syndrome .et al., the increase in the number of obese patients correlates with the frequency of kidney damage [et al., the main therapeutic goal of obesity treatment is the control and treatment of related complications, including renal pathology [The issue of kidney damage on the background of obesity, and the associated frequency of nephropathy, is relevant today, and early diagnosis of concomitant pathology is based on the identification and assessment of pathogenetic risk factors for their formation. According to Pop y damage . Among tathology . Microalathology . Conversathology . Analysiathology . In mostet al., having compared serum creatinine and cystatin C levels with GFR, found that cystatin C is a more accurate marker of renal function damage than creatinine [et al. found that individuals with high levels of cystatin C without CKD anamnesis had an increased risk of adverse cardiovascular events, and 50% of them were likely to die [Therefore, in recent years, various early specific biomarkers of kidney damage have been studied, among which much attention is paid to cystatin C. In 2005, Deo eatinine . In 2004eatinine . Having y to die . In the y to die . It is ky to die . Althougy to die , which tGhrelin is known to be a circulating hunger hormone, but there is very little data on ghrelin levels in non-dialysis patients with early-stage CKD . The autThus, as can be seen from our study, increased ghrelin level has different meanings at different stages of chronic kidney disease. In particular, in stage 2 CKD, its growth is associated with an increase in cystatin C levels and a decrease in glomerular filtration rate and probably the progression of obesity, while in stage 1, such a relationship is not yet formed. Such changes require new approaches to the treatment of this combined pathology.The authors declare that there is no conflict of interest.