Hypertension (HTN), which frequently co‐exists with diabetes mellitus, is the leading major cause of cardiovascular disease and death globally. This study aimed to develop and validate a risk scoring system considering the effects of glycemic and blood pressure (BP) variabilities to predict HTN incidence in patients with type 2 diabetes. This research is a retrospective cohort study that included 3416 patients with type 2 diabetes without HTN and who were enrolled in a managed care program in 2001–2015. The patients were followed up until April 2016, new‐onset HTN event, or death. HTN was defined as diastolic BP (DBP) ≥ 90 mm Hg, systolic BP (SBP) ≥ 140 mm Hg, or the initiation of antihypertensive medication. Cox proportional hazard regression model was used to develop the risk scoring system for HTN. Of the patients, 1738 experienced new‐onset HTN during an average follow‐up period of 3.40 years. Age, sex, physical activity, body mass index, type of DM treatment, family history of HTN, baseline SBP and DBP, variabilities of fasting plasma glucose, SBP, and DBP and macroalbuminuria were significant variables for the prediction of new‐onset HTN. Using these predictors, the prediction models for 1‐, 3‐, and 5‐year periods demonstrated good discrimination, with AUC values of 0.70–0.76. Our HTN scoring system for patients with type 2 DM, which involves innovative predictors of glycemic and BP variabilities, has good classification accuracy and identifies risk factors available in clinical settings for prevention of the progression to new‐onset HTN. According to the 9th edition of the IDF Diabetes Atlas, the projected number of adults living with diabetes will increase from 463 million (9.3%) to 700 million by 2045 (10.9%).The benefits of predictive models are the quantification of the strength of associations for measurable and modifiable risk factors and generation of risk estimates. These point systems can be utilized by nurse practitioners, physicians, and health professionals without the need for understanding complex statistical models because the point systems require simple calculation. In addition, clinicians can be guided by these point systems for their decision making regarding treatments and assistance in motivating patients to modify their behaviors. Another strength of this point system is that patients can easily estimate and monitor their disease risks over time. Published prediction models have been developed to predict HTN, primarily in general and patient populations, using electronic health records (EHRs).22.1n = 448), patients aged under 30 years and more than 85 years (n = 655), HTN at baseline (n = 13 603), lack of baseline information (n = 251), and follow‐up < 1 year (n = 669). A total of 2747 enrolled diabetic patients were randomly assigned to the derivation and validation sets in a 2:1 ratio. Figure We conducted a retrospective cohort study among patients who enrolled in the Diabetes Case Management program (DCMP) of China Medical University Hospital (CMUH), a case management program set up by National Health Insurance Administration in 2001. Enrollees comprised patients with a diagnosis of type 2 diabetes ; Code of 250). All cases enrolled in the registry between November 2001 and April 2015 had to be continuously enrolled in DCMP until April 2016, new‐onset HTN event, or death. Therefore, this cohort is open or dynamic, that is, each patient joined the study at different time points. The rationale for this criterion is that we involved persons who can provide at least 1‐year of follow‐up to depict the glycemic and BP variabilities. We excluded patients with type 1 diabetes (ICD‐9‐CM code 250.×1/×3), gestational diabetes (ICD‐9‐CM code 648.83) , Hemoglobin A1C (HbA1c), creatinine, urine albumin–creatinine ratio, total cholesterol (TC), triglyceride (TG), high‐density lipoprotein (HDL), and low‐density lipoprotein (LDL). The DCMP provides a unique opportunity to quantify the overall impact of lifestyle factors, including body mass index (BMI), smoking, physical activity, and alcohol consumption. The medication information includes oral hypoglycemic agents, insulin, cardiovascular medications , lipid‐lowering agents , and kidney disease medication. In addition to laboratory and pharmaceutical data regulated by DCMP program for reimbursement, information about education programs for nursing care, nutrition, diet, physical activity, smoking, and weight control behaviors were collected.2.3Upon enrolment in the DCMP program, the study patients had a series of medical tests for urine, blood, lifestyle behaviors, body measurements, and medical history gathered at baseline and annually through standardized computerized questionnaire administered by a case manager.2.3.1The socio‐demographic factors comprised age at baseline, sex, and family histories of diabetes, HTN, hyperlipidemia, and obesity. Lifestyle behaviors of smoking, alcohol drinking, and physical activity were each divided into two subgroups: yes versus no. Diabetes‐related variables included duration and early onset of type 2 diabetes, defined as diabetes onset age ≥ 40 years.2.3.22). Individuals were measured BP in the right arm using the suitable size cuff and a standard tunnel type electronic sphygmomanometer  in a seated position without distraction. The instructions for taking BP measurements ask individuals to roll up the sleeve on their arm, to rest in a chair next to a table for 5–10 min with arm resting comfortably at heart level, sitting up straight with their back against the chair, legs uncrossed, and to rest their forearm on the table with the palm of their hand facing up. Usually individuals had one BP measurement. If an individual had two or more BP measurements in a day, the average of these BP measurements was recorded. BP measurements used for calculating the variability were those within 1 year of entry to DCMP for those who had at least two BP measurements.Weight and height were measured with an auto‐anthropometer , with the patients shoeless and wearing light clothing. BMI was derived from the formula: weight (kg)/(height)2.3.3Blood was drawn from an antecubital vein in the morning after a 12 h overnight fasting and was sent for analysis within 4 h of blood collection. Biochemical markers, such as FPG, HbA1c, HDL, LDL, TC, TG, and creatinine, were analyzed by a biochemical auto‐analyzer  at the Clinical Laboratory Department of China Medical University Hospital. FPG in the obtained blood was measured using NAF TUBE. NAF TUBE contained 5 mg sodium fluoride to inhibit glucose metabolism and 4 mg potassium oxalate to chelate calcium and prevent coagulation. HbA1c level was measured using a boronate‐affinity high‐performance liquid chromatography assay (reference range: 4.6%–6.5%). TC and TG were measured in serum mode. TG levels were determined by an enzymatic colorimetric method. HDL and LDL levels were measured by a direct method. Urine test consisted of protein urinalysis and 24 h urinary protein excretion. Urinary albumin‐to‐creatinine ratio (ACR) in the morning urine sample was determined by urinary creatinine (Jaffe's kinetic method) and albumin (colorimetyl bromcresol purple), which were measured by an autoanalyzer. Urinary ACR ranging from 30 to 300 mg/g creatinine was defined as microalbuminuria and above 300 mg/g creatinine as macroalbuminuria.The estimated glomerular filtration rate (eGFR) was estimated based on serum creatinine levels, in accordance with the Chronic Kidney Disease Epidemiology Collaboration equation.2.3.4The variables for pharmacologic agent use were derived from the dataset of DCMP program. The types of anti‐diabetes treatment containing various oral hypoglycemic agents, such as, metformin, sulfonylurea, thiazolidinedione, meglitinide, and biguanide, and insulin therapy were extracted. Other medication‐related variables included kidney disease medications, HTN medications, cardiovascular medications, and lipid‐lowering medications. All these medications were each divided into two categories: yes versus no.2.3.5Baseline comorbidities consisted of hyperlipidemia, coronary artery disease, severe hypoglycemia, postural hypotension, peripheral neuropathy, nephropathy, diabetic ketoacidosis, and hyperglycemic hyperosmolar nonketotic coma. All the comorbidities were each divided into two classes: yes versus no.2.3.6The main outcome measure was HTN event, which was determined by at least two systolic blood pressure (SBP) and diastolic blood pressure (DBP) measurements. The onset of HTN is defined as one of the following two criteria of 2020 International Society of Hypertension Global Hypertension Practice Guidelines:2.4Means with standard deviations (SDs) of continuous variables and proportions of categorical variables were used to describe baseline characteristics of all study patients. The glycemic and BP variabilities were adjusted for the numbers of visit to reduce measurement bias. The CVs of FPG, HbA1c, SBP, and DBP were divided by the square root of the ratio of total visits to total visits minus one.The derivation set was used to generate a prediction model, and the validation set was used for assessment of the predictive accuracy. Then, the steps from the Framingham heart study was used as guides to construct the risk score function.x2 method. Internal validation was performed to correct the potential for overfitting or “optimism” by using 1000 times of bootstrap resampling.p < .05.The area under curve (AUC) of receiver operating characteristic (AUROC) curve for 1‐, 3‐, and 5‐year of HTN incidence from probabilities of logistic regressions model was applied to assess the predictive accuracy of the HTN risk prediction model. The correct Harrell's C‐statistic of the AUC was also applied to time‐to‐event analysis. The AUC can be used as the index for assessing the capability of the model to correctly discriminate study patients into HTN or non‐HTN cases. The values of AUC ranged from 0 to 1, where a value higher than 0.7 indicates good discriminatory capability of the model. For the assessment of the discriminatory capability of the risk model, we compared three subgroups with low, medium, and high sum risk scores determined by tertiles of the total score in the validation set. Calibration of the HTN risk prediction model for the validation set was tested by Hosmer–Lemeshow 3The derivation and validation sets comprised 2278 and 1138 patients, respectively. The two sets contained 1162 (derivation set) and 576  cases of new‐onset HTN. The mean (SD) duration of follow‐up was 3.40 (2.51) years. Table 2, 7 points; BMI ≥ 25 kg/m2, 8 points; family history of HTN, 2 points; use of hypoglycemic drug, 3 points; SBP of 120–129 mm Hg, 4 points; SBP ≥ 130 mm Hg, 7 points; DBP ≥ 80 mm Hg, 4 points; FPG‐CV of 10.9–20.0%, 1 points; FPG‐CV ≥ 20.1%, 2 points; SBP‐CV of 4.0%–7.1%, 2 points; SBP‐CV ≥ 7.2%, 3 points; DBP‐CV ≥8.1%, 2 points and macroalbuminuria, 4 points. Using the total score from the above variables, a patient's 1‐, 3‐, and 5‐year new‐onset HTN risks were estimated (Table 2 (8 points), had a family history of HTN (2 points), was taking oral anti‐diabetes medicine (3 points), had a baseline SBP of 125 mm Hg (4 points), a baseline DBP of 79 mm Hg (0 point), FPG variation of 15% (1 point), SBP variation of 5% (2 points), and DBP variation of 7% (0 points) has a sum of risk points of 25. Her 1‐, 3‐, and 5‐year risks of HTN should be 24.24%, 48.17%, and 63.08%, respectively.Tables ed Table . For calp > .05), indicating the goodness of fit was acceptable. Subsequently, patients were divided into three groups based on approximate tertiles of the total scores and the proportions of low‐risk group (0–22 points), medium risk group (23–27 points), and high‐risk group (> 27 points) for predictive validation were 30.40%, 35.15%, and 34.45%, respectively. The Kaplan–Meier estimates for the cumulative HTN incidence curves of the three groups are shown in Figure p < .001).In the validation set, the scoring system exhibited good discriminative powers, as measured by the AUROC curve of 0.76 (95% CI: 0.73–0.79), 0.73 (95% CI: 0.70–0.76), and 0.70 (95% CI: 0.67–0.73), for predicting 1‐, 3‐, and 5‐year HTN incidence Figure  using thIn this cohort, sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated at 40%, 50%, 70%, 80%, and 90%, risks, respectively, denoting a high risk , 0.70 (95% CI = 0.68–0.72), and 0.69 (95% CI = 0.67–0.71) for 1‐, 3‐, and 5‐year periods, respectively Figure . Further4This study developed and validated a scoring system for the risk of HTN in patients with type 2 diabetes based on 13 predictors. To our knowledge, this research is the first attempt to establish a simple scoring system for the risk of HTN, with focus on patients with type 2 diabetes. The system had good discriminatory capability with a Harrell's C‐statistic of 0.70 (95% CI: 0.68–0.72) in the validation set. This scoring system considered risk factors that are generally accepted and available in clinical practice and are precisely measured to ensure its acceptability in clinical practice.Diabetes is linked to impaired glucose tolerance or impaired fasting glucose through insulin resistance; concomitant islet beta‐cell injury may lead to insulin deficiency, which affects the utilization of glucose by skeletal muscles, adipose tissues, and hepatic cells.A review paper pointed out that early intervention by lifestyle modifications  in persons with pre‐hypertensive condition can reduce BP or prevent HTN.p < .001), where the probability for summation of likelihood for correctly reclassifying higher and incorrectly reclassifying lower among persons with events of 79.7% and probability for summation of likelihood for correctly reclassifying lower and incorrectly reclassifying higher among persons without events of –50.5%. That is, our scoring system is better than USA score for correct classifying those who will develop HTN, but it is worse for those who will not become hypertensives. The overall reclassification improvement favored the new score. The discrimination of risk based on IDI  in Figure Most existing HTN risk prediction models achieve acceptable good discrimination with an AUC over 0.70,Our risk score system found new predictors such variation in FPG and BP in addition to traditional predictors. There is a barrier for the risk score to be used in clinical practice because of the need for calculating variability with several measurements when computing systems were not available. It can be overcome now because information systems are now common in most of clinical practice. The formula for calculating the variability can be integrated in the information systems and patients’ variability values can be provided for physicians. In addition, a smartphone app can facilitate its use in the settings for diabetes care.4.1The strength of our study is the well‐defined patient group and pioneer scoring system for the early prediction of new‐onset HTN in patients with type 2 diabetes. Our scoring system considers traditional and novel predictors, including education level, physical activity, type of DM treatment, and glycemic and BP variabilities. The system showed a good discriminative capability in predicting 1‐, 3‐, and 5‐year risks. Our study also had potential limitations. First, glycemic and BP variabilities were calculated in persons with at least two measurement records during 1‐year period with 20% of missing values. To minimize the potential selection bias arising from missing data, we analyzed our data by using the MI approach for handling missing data. Using complete case analysis as sensitivity analysis and similar findings were obtained. Second, given the lack of external validation, we did not validate our system in an external or independent sample. External validation can provide evidence on the system's generalizability to various population. However, we performed internal validation with a bootstrapping method, and results showed that our system can be generalized to other populations with similar characteristics. Future research will be needed to examine external validation in independent datasets. Last, we didn't consider type of hypoglycemic drug because some categories such as insulin alone had very small sample size, resulting in the imprecision in estimating their effects. Because the effects of oral hypoglycemic drug use and insulin plus oral hypoglycemic use were similar, we collapsed all hypoglycemic drugs into a category.5We developed and validated a simple point‐based scoring system for HTN risk assessment using a hospital‐based EHR dataset of a managed care program. The scoring system showed good prediction capability, discriminatory power, and calibration. Our scoring system provides a valid and inexpensive tool to estimate medium‐term risks of new‐onset HTN in patients with type 2 diabetes and can help in preventing the progression of new‐onset HTN.There are no conflicts of interest.Tsai‐Chung Li, Cheng‐Chieh Lin, and Chia‐Ing Li were responsible for the conception and design of the work and writing manuscript. Chiu‐Shong Liu, Chih‐Hsueh Lin, and Mu‐Cyun Wang were responsible for data collection and data interpretation. Chia‐Ing Li and Shing‐Yu Yang were responsible for analysis. All authors read and approved the final manuscript.Supporting InformationClick here for additional data file.


Background: Continuous blood pressure (BP) measurement in intensive care units is based on arterial line (AL) transducers, sometimes associated with clinical complications. Our objective was to evaluate continuous BP measurements obtained from a non-invasive, wireless photoplethysmography (PPG)-based device using two distinct configurations (wristwatch and chest-patch monitors) compared to an AL.Methods: In this prospective evaluation study, comparison of the PPG-based devices to the AL was conducted in 10 patients immediately following cardiac surgery. Pulse rate (PR), systolic BP (SBP), diastolic BP (DBP), and mean arterial pressure (MAP) were recorded using both the AL and the PPG-based devices simultaneously for an average of 432 ± 290 min starting immediately after cardiac surgery. Bland-Altman plots and Pearson's correlations were used to assess the accuracy and degree of agreement between techniques.Results: A total of ~4,000 data points were included in the final analysis. AL measurements for PR, SBP, DBP and MAP were significantly (p < 0.001) and strongly correlated with both the wristwatch  and the chest-patch  monitors. Both configurations showed a marginal bias of <1 mmHg for BP measurements and <1 beat/min for PR  compared to AL measurements.Conclusion: The PPG-based devices offer a high level of accuracy for cardiac-related parameters compared to an AL in post-cardiac surgery patients. Such devices could provide advanced monitoring capabilities in a variety of clinical settings, including immediate post-operative and intensive care unit settings.Clinical Trial Registration:www.clinicaltrials.gov, NCT03603860. Post-operative hypotension and hypertension commonly occur specifically after cardiac surgery and are associated with severe outcomes including acute kidney injury, cerebrovascular accidents, myocardial injury and death –4. The fThus, there is a need for alternative methods of continuous BP monitoring that are accurate but also simple to use, non-invasive and ideally wireless. An advanced technology of this sort would allow monitoring of patients who are not routinely monitored due to the technical and logistical shortfalls of traditional measurement techniques such as the AL. Such technology would ultimately assist in early identification of medical emergencies and would enable retrospective investigation of BP when needed, leading to improved patient care –13. In rwww.clinicaltrials.gov (NCT03603860) and was approved by the Institutional Review Board of the Baruch Padeh Medical Center, Poriya, Israel (0077-18-POR). All participants were advised both orally and in writing as to the nature of the experiments and signed an informed consent form before undergoing the surgical procedure.This prospective, comparative clinical trial was registered in Eighteen post-cardiac surgery patients  were recruited for the study. Monitoring started immediately after the surgical procedure, upon arrival to the Cardiac Surgery Intensive Care Unit (CSICU). The research team only received the monitoring devices' serial numbers without receiving any personal identifiers.Patients were transferred to the CSICU immediately after completion of their surgery. In all subjects, an AL  was inserted through the radial artery in the operating room prior to surgery, allowing continuous invasive monitoring of BP and pulse rate (PR). The average of the first three BP measurements obtained by the AL was considered as a baseline calibration measurement for the PPG-based devices. From the moment of calibration, the PPG-based devices were attached to the patients – the chest-patch monitors just left to the fresh sternotomy wound and the wristwatch monitors on the arm without the arterial line – and measurements were taken simultaneously, comparing the three devices  for up to 24 h during the post-operative period . InclusiThe device was previously described –16. In sn = 20/4,305; SBP: n = 20/4,018; DBP: n = 39/4,018; MAP: n = 53/4,018).Mean arterial blood pressure (MAP) was calculated as [DBP+⅓·(SBP-DBP)] for each measurement technique. Data obtained from the AL for PR, SBP, DBP and MAP were screened for outliers according to the following criteria: initially, percentage differences (%Δ) between each value and the preceding and succeeding values were calculated. For each variable separately, the average standard deviation (SD) for the sum of preceding and succeeding %Δ was then obtained. Next, the individual data points (%Δ) were screened, and any value for which the percentage difference from both the previous and next values was > ±2SD was eliminated. In total, 132 out of 16,259 (0.8%) outlier values were excluded from the final analysis . Validity of the non-invasive devices (wristwatch monitor and chest-patch monitor) compared to the gold standard AL was assessed as the devices' ability to correctly identify extreme values   and the AL, linear regressions formulas were defined, Pearson's correlation coefficient were calculated, and the hypotheses that the slopes and intercepts are equal to zero were tested. The level of absolute agreement between AL measurements and those obtained from the chest-patch and wristwatch monitors for PR, SBP, DBP and MAP were evaluated using Bland–Altman plots. Results of the Bland–Altman analyses are reported as mean biases ± 95% limits of agreement (LOA). All other results are presented as means ± SD. Statistical analyses were considered significant if 60 mmHg) , 18 usinOf the 18 patients initially recruited, eight were excluded due to non-continuous monitoring of the AL and thus inability to compare these subjects' data between the wristwatch/chest-patch monitors and AL. Demographic data and characteristics for the remaining ten subjects  including the type of surgery they underwent are presented in There were no adverse events while using the PPG-based devices. The number of comparisons for each variable and mean ± SD values for each variable per device are presented in Pearson correlations and Bland-Altman plots with 95% LOA for each of the BP variables are presented in Percent of observations obtained within the clinical definition of 5, 10 and 15 mmHg between the wristwatch and chest-patch as compared to AL are shown in p < 0.001) and strongly correlated with the wristwatch  and with the chest-patch  monitors. Lastly, PR values obtained by AL were significantly (p < 0.001) and strongly correlated with the wristwatch (r = 0.99) and with the chest-patch (r = 0.99) monitors (As demonstrated in monitors .p < 0.001) and strongly correlated . Lastly, we present the distribution and the median of each vital as compared to the AL  were within ±5 mmHg of those recorded by AL. These percentages also classify the PPG-based sensor as Grade A according to the British Hypertension Society (2) for the observed absolute differences between AL and the PPG-based sensors was > 0.99 for both SBP and DBP.Criteria for cuff-less monitors such as the PPG-based sensor have yet to reach widespread, general acceptance. Based on the European Society of Hypertension's (ESH) International Protocol for the validation of BP measuring devices , post-ho Society  and IEEE Society  . For this reason, we sought to evaluate the PPG-based sensor following pre-established, clinically significant extreme values for BP measures. However, although our cohort included cardiac patients immediately post-surgery, there were not many cases of hypotension  or hypertension (as determined by SBP > 160 mmHg or DBP > 100 mmHg). In fact, apart from DBP <60 mmHg where 1,609 extreme cases were identified (40%), for all other criteria <3% of values were identified as extreme values, technically limiting our ability to obtain meaningful and reliable predictive values and sensitivity/specificity measures.Since the two configurations of the device tested in our study measure vital signs in different locations, we chose to utilize both in order to demonstrate that accurate measurements can be obtained independently of the site of measurement . In the hospital environment, a single use disposable chest-patch monitor is estimated to further reduce infection transmission and the potential for error between patients than a wristwatch that is used on several patients. In contrast, a wristwatch might be more optimal for long-term home monitoring of chronic patients. Beyond in-hospital intensive care and low acuity patients, PPG technology could enable better monitoring, triage and treatment in prehospital scenarios as well. Moreover, the current severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) pandemic highlights the need for frequent, non-invasive and wireless devices for remote monitoring of isolated patients, requiring minimal direct contact of medical staff, while maintaining and not impairing the quality of care .It should be mentioned that during the study, patients were relatively stable, precluding us from seeing many cases of hemodynamic instability despite their being immediately post-operative. Still, short periods of hemodynamic instability were observed, in which we found a high level of agreement between the devices. Although this study did not include a large sample, each individual had multiple (~400) measurement points, and the results show high levels of agreement and strong correlations between devices across a wide range of BP values . Moreover, seeing as one of the strengths of the tested devices is their ability to provide accurate and frequent monitoring, allowing to include a small sample of 10 subjects in this study with high confidence of obtaining large amounts of reliable data.Since the PPG-based device is dependent on pulse wave, it will not suit certain patient populations, such as patients with left ventricular assist device and intra-operative monitoring during the use of cardio-pulmonary bypass. However, post-surgery patients might benefit from a non-invasive sensor that will replace an invasive in-dwelling monitoring device. Beyond the monitoring capabilities of an AL, it is worth mentioning that the purpose using this technique specifically in patients undergoing cardiac surgery goes beyond blood pressure measurement, and blood samples are needed throughout surgery to assess blood gases, coagulation parameters, and more. This feature is not included in the PPG-based platform and might influence the decision whether to use an AL or a non-invasive device.There is a clear need for a reliable, non-invasive technology capable of advanced hemodynamic monitoring that would overcome the limitations of the currently and frequently used AL technique. In this observational clinical study, we report that measurements obtained from the two configurations of a novel PPG-based device offer a high level of accuracy compared to the existing standard invasive technique in post-cardiac surgery patients. Most importantly, this PPG-based technology enables continuous, non-invasive remote patient monitoring and timely focused care, which may minimize morbidity and mortality without compromising measurement accuracy. Future studies should focus on the advanced monitoring capabilities of these devices in a variety of clinical settings, from immediate hospital-based post-operative and intensive care units to post-hospital and ambulatory settings.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by Institutional Review Board of the Baruch Padeh Medical Center, Poriya, Israel (0077-18-POR). The patients/participants provided their written informed consent to participate in this study.EK, DN, SC, and AE: study conception and design. EK, DN, SC, and RL: data collection. KC, DN, AE, and YG: analysis and interpretation of results. KC and YG: draft manuscript preparation. All authors reviewed the results and approved the final version of the manuscript.YG was advisor in the physiology board of Biobeat Technologies Ltd. AE and RL were employees at Biobeat Technologies Ltd. The remaining 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.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Data on the lung respiratory mechanics and gas exchange in the time course of COVID-19-associated respiratory failure is limited. This study aimed to explore respiratory mechanics and gas exchange, the lung recruitability and risk of overdistension during the time course of mechanical ventilation.n = 116) with COVID-19 admitted into Intensive Care Units of Sechenov University. The primary endpoints were: «optimum» positive end-expiratory pressure (PEEP) level balanced between the lowest driving pressure and the highest SpO2 and number of patients with recruitable lung on Days 1 and 7 of mechanical ventilation. We measured driving pressure at different levels of PEEP  with preset tidal volume, and with the increase of tidal volume by 100 ml and 200 ml at preset PEEP level, and calculated static respiratory system compliance (CRS), PaO2/FiO2, alveolar dead space and ventilatory ratio on Days 1, 3, 5, 7, 10, 14 and 21.This was a prospective observational study in critically ill mechanically ventilated patients (2O and 10.0 (9.0–12.0) cmH2O on Day 7. Positive response to recruitment was observed on Day 1 in 27.6% and on Day 7 in 9.2% of patients. PEEP increase from 10 to 14 cmH2O and VT increase by 100 and 200 ml led to a significant decrease in CRS from Day 1 to Day 14 (p < 0.05). Ventilatory ratio was 2.2  in non-survivors and in 1.9 (1.6–2.6) survivors on Day 1 and decreased on Day 7 in survivors only (p < 0.01). PaO2/FiO2 was 105.5 (76.2–141.7) mmHg in non-survivors on Day 1 and 136.6 (106.7–160.8) in survivors (p = 0.002). In survivors, PaO2/FiO2 rose on Day 3 (p = 0.008) and then between Days 7 and 10 (p = 0.046).The «optimum» PEEP levels on Day 1 were 11.0 (10.0–12.8) cmHRS.Lung recruitability was low in COVID-19 and decreased during the course of the disease, but lung overdistension occurred at «intermediate» PEEP and VT levels. In survivors gas exchange improvements after Day 7 mismatched CNCT04445961. Registered 24 June 2020—Retrospectively registered.ClinicalTrials.gov, The online version contains supplementary material available at 10.1186/s12871-022-01600-0. Most patients with COVID-19-associated acute respiratory failure fulfil the criteria of the acute respiratory distress syndrome (ARDS) and often require invasive mechanical ventilation . In thesThe goal of the study was to investigate respiratory mechanics and gas exchange during the first 21 days of mechanical ventilation with the aim for selection of the «optimum» positive end-expiratory pressure (PEEP), evaluation of recruitability and a risk of volutrauma in COVID-19-associated acute respiratory failure.This was a prospective observational clinical study  conducted in intensive care units (ICUs) at three hospitals of Sechenov University  from May 1 to August 14, 2020. The study was approved by the Institutional Ethics Committee (reference number: 16–20). Written informed consent was waived owing to the observational nature of the study.2) > 93%, no visible work of auxiliary respiratory muscles , no fatigue on conventional oxygen therapy (oxygen flow < 15 l/min) or non-invasive ventilation; 2) life-threatening heart rhythm abnormalities and/or systolic blood pressure < 80 mmHg despite norepinephrine at a dose > 2 µg/kg/min; 3) primary lung diseases  or tumor metastases in lungs; 4) chronic decompensated diseases with extrapulmonary organ dysfunction ; 6) atonic coma. We withdrew patients from the analysis if ICU stay was less than 24 h for any reason.All mechanically ventilated patients (both invasive and non-invasive) were daily screened for eligibility. We included patients with COVID-19-associated respiratory failure requiring invasive mechanical ventilation after noninvasive ventilation (NIV) failure. Exclusion criteria were: 1)peripheral oxygen saturation  set at 16–28 to reach arterial carbon dioxide tension (PaCO2) 35–50 mmHg and inspiratory fraction of oxygen (FiO2) set at minimal level to reach SpO2 93–96%. Patients were sedated with a propofol infusion up to the Richmond Agitation-Sedation Score (RASS) -3–4 points and paralyzed if they had inspiratory swings on pressure–time curve and/or visible work of auxiliary respiratory muscles besides RASS-4.At the start of the study all patients were on mechanical ventilation in the assisted pressure-controlled volume-guaranteed mode in supine position with the tidal volume (VT) set at 6–8 ml/kg of the predicted body weight (PBW) and positive end-expiratory pressure set at 8 cmH2O and calculated driving pressure (DP) as Pplat-PEEP and static respiratory system compliance (CRS) on Days 1, 3, 5, 7, 10, 14, 21 and 28 (if applicable) . We set the PEEP level at mentioned time points at the balance point of the lowest DP and the highest SpO2. We observed patients after the PEEP setting for at least 15 min to determine the highest SpO2 and optimal FiO2. After the PEEP setting, we increased tidal volume by 100 ml and 200 ml in 2 steps, respectively, and measured Pplat on each step with DP and CRS calculation (on Days 1 and 7 as part of recruitment maneuver). For the correct calculation of CRS during a volume increase we computed the «normalized» CRS by dividing the tidal volume in ml/kg of the predicted body weight to driving pressure.We measured plateau pressure (Pplat) with the inspiratory hold maneuver for 3 s at PEEP levels of 14, 12, 10 and 8 cmH2 that corresponds to SpO2 90%. Prior to and at the end of the maneuver we measured the plethysmography variability index (PVI) by Radical-7 monitor . We defined RM as effective if SpO2 rose to 95% and higher in 5 min after RM.Also, on Days 1 and 7, we used the recruitment maneuver (RM) doubling the tidal volume for 15 respiratory cycles at a preset PEEP level . Before the maneuver we set FiO2 by more than 5% except for patients with body mass index > 40 kg/m2  and patients in whom the prone position led to an increase in driving pressure. The ventilation mode was switched to the Pressure Support mode if a patient was conscious or sedated up to RASS 0–2, had a stable respiratory and hemodynamic state, no visible work of auxiliary respiratory muscles and a stable respiratory pattern after switching. The pressure support level was set according to Pplat and corrected to achieve the Tobin index (respiratory rate/VT) of less than 70. Tracheostomy was performed on the 3rd day of mechanical ventilation.Patients were placed in the prone position for at least 16 h per day if it led to an increase in SpO2), partial pressure of carbon dioxide in arterial blood (PaCO2), arterial pH, and end-expiratory carbon dioxide tension (PetCO2), and calculated PaO2/FiO2 ratio, alveolar dead space  according to Bohr-Enghoff equation and ventilatory ratio (VR) [Before the PEEP and volume trials we measured partial pressure of oxygen in arterial blood (PaOtio (VR) .Routine blood examinations included 1) complete blood count, 2) coagulation profile—fibrinogen, activated partial thromboplastin time, international normalized ratio and D-dimers, 3) serum biochemical tests . The frequency of tests was determined by the attending physician .2; 2. Number of patients with recruitable lung defined as SpO2 changed from 90 to 95% and more after recruitment maneuver on Days 1 and 7 of mechanical ventilation.The primary endpoints were: 1. «Optimum» PEEP level on Days 1 and 7 of mechanical ventilation balanced between the lowest DP and the highest SpO2/FiO2 ratio and ventilatory ratio on Days 1, 3, 5, 7, 10, 14, 21 of the mechanical ventilation.Secondary endpoints included: 1. «Optimum» PEEP level on Days 3, 5, 10, 14 and 21 (set as described above); 2. Driving pressure at different PEEP levels  and different tidal volumes  at a set PEEP level on Days 1, 3, 5, 7, 10, 14, 21 of the mechanical ventilation; 3. Alveolar dead space on Days 1, 3, 5, 7, 10, 14, 21 of the mechanical ventilation; 4. Plethysmography variation index before PEEP and volume trials and at the end of the recruitment maneuver on Days 1 and 7 of the mechanical ventilation or during the volume trial on Days 3, 5,10 and 21; 5. PaOp < 0.05 was considered statistically significant. Statistical analyses were performed using SPSS Statistics version 19.0 .Descriptive statistics included proportions for categorical and median (interquartile range) for continuous variables. No imputation was made for missing data. To assess differences between survivors and non-survivors, we performed the Mann–Whitney U test for continuous variables, and Chi-square or Fisher exact test for categorical variables. The Friedman test was used for variable dynamics within group. A two-sided We consecutively identified 176 and enrolled 116 patients  resulted in a significant decrease in normalized Cstat on Days 1, 3, 5, 7, 10 and 14 in all patients and on Day 21 in non-survivors .Static compliance at a preset tidal volume and PEEP showed a mild-to-moderate decrease and was not significantly different within and between survivors and non-survivors in dynamics Fig. , Table 22O and 10.0 (9.0–12.0) cmH2O, respectively, with no differences between survivors and non-survivors   cmH«Optimum» PEEP levels on Days 1, 3, 5, 7, 10, 14 and 21 are presented in Table 2/FiO2 levels corresponding to moderate-to-severe ARDS , high alveolar dead space with hypercapnia and high ventilatory ratio with a relatively preserved respiratory system compliance  mmHg vs 136.6 (106.7–160.8), p = 0.002).Table 2/FiO2 ratio were significant between survivors and non-survivors at all study points. In survivors, PaO2/FiO2 ratio rose on Day 3 (p = 0.008) and then between Days 7 and 10 (p = 0.046). In non-survivors, PaO2/FiO2 ratio rose on Day 3 only (p = 0.013), decreased on Day 5 (p = 0.009), and later was stable until Day 10 and again decreased on Day 14 .Differences in PaOp = 0.046 as compared to Day 1) and didn’t change in non-survivors. Accordingly, the ventilatory ratio was increased about two-fold in all patients and reached a statistical significance between survivors and non-survivors on Days 10 and 14  but failed to reach significance within subgroups in dynamics.Alveolar dead space was increased nearly two-fold in all patients, differences between survivors and non-survivors were significant on Days 7 and 10. Alveolar dead space decreased on Day 10 in survivors (2/FiO2 with a stable ventilatory ratio in survivors (n = 4), and a stable PaO2/FiO2 ratio with an increase of the ventilatory ratio in non-survivors after Day 10 (n = 4); survivors showed a relatively small decrease in static compliance after Day 7 with decrease in the «PEEP-dependency», while non-survivors showed a drop in static compliance with marked overdistension at «intermediate» PEEP levels (Table EPatents who survived 28 days demonstrated a continuous increase of PaOn = 99). Non-survivors had a higher prevalence of cardiovascular and renal failure (Table p = 0.831). We didn’t find any significant differences between survivors and non-survivors in the «non-respiratory» characteristics at baseline. The most valuable difference between groups during the observation period concerns catecholamine support—we can see a much higher need in norepinephrine administration in non-survivors from day 3 to day 14.ICU and in-hospital mortality was 84.6% , p < 0.0001) ; Ventilatory ratio on Day 10 > 2.07 , p = 0.006) , dependent lung zones collapse and become susceptible to the PEEP rising . In our 2O with the disproportionately low PaO2/FiO2 [Observational studies comparing COVID with primary non-COVID ARDS found that COVID-ARDS was very close to ARDS due to bacterial and another virus pneumonia: slightly decreased compliance and driving pressure around 10 cmHaO2/FiO2 . This co2O in most measurements during tidal breath that corresponds to severe lung restriction and low lung recruitability. Also, we defined overdistension as an increase in driving pressure exceeding 15 cm H2O based on the study by Amato MB et al. [We hypothesized that SARS-CoV-2- pneumonia is a primary non-recruitable lung injury that results in a gradual decrease in the total vital lung capacity. Definitely, it’s very difficult to define lung overdistension based on the simple airway pressure measurement and usually requires extended respiratory monitoring  to evaluate overdistension (stress and strain). The baby lung concept  showed uB et al.  who foun2 table) cause lung overdistension [2O, lung overdistension at higher PEEP levels and the need in a personalized PEEP titration [2 tables should not be used in COVID-19-associated ARDS. Comparing primary ARDS of non-COVID and COVID origins Brault C et al., Grieco DL et al. and Chiumello D et al. found no major differences between them in the respiratory mechanics and gas exchange, high heterogeneity and the need for a personalized ventilation strategy [. Our “volume trial” found volutrauma at “intermediate” lung volumes that is rarely seen in secondary ARDS. Similar results were obtained in primary ARDS with the upper inflection point on the pressure–volume curve at tidal volumes around 600 ml [So, COVID-19 patients are at the high risk of ventilation-induced lung injury at intermediate PEEP or tidal volume levels like in other primary ARDS where PEEP generates injurious transpulmonary pressures and has a higher transmission to the pleura causing an increase in alveolar dead space . Our datstension , 14, 15.itration –18. We aitration  that PEEstrategy , 21, butd 600 ml .2/FiO2 or ventilatory ratio [Ventilation-perfusion mismatch and high alveolar dead space are of special interest in COVID-19 , 24. We Recent studies have shown significantly lower mortality with early ECMO –27. We s2/FiO2 ratio in patients without extrapulmonary organ failure and signs of impaired lung mechanics such as excessive respiratory muscle load on NIV or high-flow oxygen [At a first glance, our study had higher mortality than others , 6. We uw oxygen , 29.Our study had several limitations. First of all, because it’s observational design. Second, it covered only patients in whom noninvasive ventilation failed and/or organ dysfunction, i.e. the most severe patients. Third, we didn’t measure additional physiologic parameters such as transpulmonary pressure, end-expiratory lung volume etc. Unfortunately, patients can die because of multiple organ failure due to resource shortage during a pandemic .Lung overdistension in COVID-19-associated acute respiratory distress syndrome occurs at «intermediate» positive end-expiratory pressures and tidal volume levels; it reflects severe lung restriction and a very high risk of volutrauma. In survivors gas exchange improvements occurred after Day 7 of mechanical ventilation and mismatched the respiratory compliance which didn’t increase but even decreased. Further research is warranted in order to decrease volutrauma and improve survival in COVID-19-associated ARDS.Additional file 1. Driving pressures (cmH2O) at «optimum» PEEP and the set tidal volume, during «PEEP trial» and «volume trial» during mechanical ventilation courseAdditional file 2. Laboratory values during mechanical ventilation courseAdditional file 3. ROC curve for mortality prediction for arterial oxygen partial pressure to the fraction of inspiratory oxygen ratio (PaO2/FiO2) on Day 7Additional file 4. ROC curves for mortality prediction for the ventilation status parameters on Day 10


Chronic kidney disease affects ~37 million adults in the US, and it is often undiagnosed due to a lack of apparent symptoms in early stages. Chronic kidney disease (CKD) interferes with the body’s physiological and biological mechanisms, such as fluid electrolyte and pH balance, blood pressure regulation, excretion of toxins and waste, vitamin D metabolism, and hormonal regulation. Many CKD patients are at risk of hyperkalemia, hyperphosphatemia, chronic metabolic acidosis, bone deterioration, blood pressure abnormalities, and edema. These risks may be minimized, and the disease’s progression may be slowed through careful monitoring of protein, phosphorus, potassium, sodium, and calcium, relieving symptoms experienced by CKD patients. In this review, the current Kidney Disease Outcomes Quality Initiative (KDOQI) recommendations are highlighted, reflecting the 2020 update, including explanations for the pathophysiology behind the recommendations. The Dietary Approaches to Stop Hypertension, the Mediterranean diet, and the whole foods plant-based diet are currently being examined for their potential role in delaying CKD progression. Biological explanations for why the whole foods plant-based diet may benefit CKD patients compared to diets that include animal products are examined. Strong evidence continues to support the importance of diet meeting the daily requirement in the prevention and progression of kidney disease, and medical nutrition therapy with a registered dietitian is a critical aspect in medical intervention for CKD. The kidneys control many biological mechanisms such as fluid, electrolyte, pH balance, blood pressure, excretion of toxins and waste, vitamin D metabolism, and hormone synthesis. About thirty-seven million US adults are estimated to have chronic kidney disease (CKD), which is more than one in seven  Even morThe kidneys are responsible for a series of life-sustaining mechanisms . The priThe National Kidney Foundation (NKF) defines CKD as either a decline in glomerular filtration rate (GFR) to <15 mL/min/1.73 m² or the presence of kidney damage persisting for at least three months . The preMedical nutrition therapy is imperative for CKD patients because it may slow the progression of the disease through careful monitoring of protein, calcium, phosphorus, potassium, and sodium , relieviThe NKF published the first Kidney Disease Outcomes Quality Initiative (KDOQI), which is a set of nutritional guidelines for patients with end-stage renal disease in 1996 . Since tThe federal Dietary Guidelines for Americans recommend an amount of 0.8 g/kg/body wt/d dietary protein intake for healthy adults . ExceediThe effects of high-protein diets (HPDs) on renal health have been investigated since the 1920s when rats given a HPD presented with increased kidney weight  leads toLow-protein diets (LPDs) have been shown to improve hyperfiltration, reduce nitrogenous waste, and ease the renal workload by decreasing glomerular pressure . ProteinLow-protein diets and very low-protein diets (VLPD) (0.28–0.43 g/kg/body wt/d) may be achieved with nutrition supplementation with essential amino acids (EAAs) and ketoanalogues  to safegAn alternate protein source may be more beneficial to the patient’s health than restricting the amount of protein alone; the protein source may be of greater importance than the quantity ,29. PlanReductions in daily protein have produced some evidence in slowing CKD progression  by retarThe primary role of vitamin D (VD) is to activate intestinal calcium reabsorption , but as The current KDOQI guidelines for CKD nutrition state ergocalciferol or cholecalciferol effectively treats VD deficiency/inefficiency; however, specific dosing should be individualized and derived through a step-by-step approach . This stCalcium balance is regulated by intestinal calcium absorption, kidney reabsorption, and calciotropic hormones that activate calcium exchange from the bone when serum calcium levels are low . InsuffiPhosphorus plays a critical role in bone formation, acid–base balance, and energy production . The bodThe three sources of dietary phosphorus are organic phosphorus from plant foods (bioavailability 20–40%), organic phosphorus from animal protein (bioavailability 40–60%), and inorganic phosphorus found in additives and processed foods (bioavailability ≈100%) . Humans Potassium (K) is the most abundant intracellular ion with a concentration of about 98%; it has many biological functions such as cellular metabolism and acid–base homeostasis . It is aThe ideal potassium intake is difficult to determine because of factors that influence serum potassium levels, such as medications, hydration level, acid–base status, glycemic control, adrenal function, and gastrointestinal complications . It is eAdditionally, Kalemic control is further compounded by extensive use of the renin–angiotensin–aldosterone system inhibitor (RAASI) therapy in CKD patients . DevelopThe true benefit of potassium restriction in CKD is not clear, considering that a diet with a high content of potassium-rich foods, such as plant-based low-protein diets, can be as beneficial on the prognosis. Potassium levels in serum can further be improved using the new K-binders, whose benefits and efficacy are shown in randomized control trials ,79, alloSodium overload in advanced CKD patients induces extracellular volume, which may lead to hypertension and heart failure. Hypertension is a known risk factor for the progression and mortality of CVD; however, the effect of sodium on the advancement of CKD remains inconclusive . A recenA low sodium diet is central to the management of hydro-saline homeostasis, reducing systolic and diastolic blood pressure as well as proteinuria . NeverthNonetheless, sodium restriction is protective for the onset of hypertension. There is plentiful and strong evidence in the efficacy to prescribing a sodium-restricted diet for disease management in CKD . For CKDStudies report that a whole food plant-based (WFPB) diet reduces the risk for T2DM and CVD in CKD patients ,89.WFPB diets provide about 75% of carbohydrates (CHO), emphasizing dietary fiber ,91. FibeWFPB diets do not restrict fat intake; however, the foods promoted are made up of monounsaturated and polyunsaturated fats and limit processed oils and saturated fat . PreviouIt is challenging for patients to comply with a restricted phosphorus diet because it is found in most foods . Many frA WFPB diet is naturally low in sodium due to the restriction of processed foods, assisting the patient with maintaining appropriate sodium levels. Additionally, WFPB diets are generally lower in energy and may be beneficial for weight management. However, caution and careful planning are critical to avoid inadequate energy intake and PEW, which could worsen the patient’s health, increasing their risk for morbidity and mortality . A wide Dietary education and patient counseling provided by a registered dietitian (RD) is essential for preventing and managing CKD. Careful and detailed dietary planning, frequent assessment of nutritional status, and dietary monitoring compliance are critical for successful dietary management.The progressive decline in GFR is a risk factor for the development of metabolic acidosis. The main goal of therapy is to prevent or correct this metabolic acidosis, which has been shown to slow down the progression of CKD to end-stage renal disease . The bigPrimary and secondary studies out of the MDRD study suggest that dietary interventions such as a low-protein diet reduce the rate of kidney function decline and lower the risk of ESKD in CKD patients ,102. DieCKD patients often have or are at risk for comorbidities that entail specific diet management recommendations; this can be challenging and overwhelming. Additionally, CKD diet recommendations alter depending on the disease stage; this can create confusion for the patient. The dietitian has a more significant role than just providing dietary advice and recommendations for the patient. Counseling should be individualized and altered to the patient’s overall health, pre-existing conditions, and personal preferences. Adopting and adhering to a new diet requires the ability to motivate and inspire patients to make changes that will improve their health and prevent morbidities, although the changes may be uncomfortable for the patient. Adequate education about the rationale of the recommendations and how the patient will benefit are essential to convey. Equally as important is to assess the retention and understanding of the patient from the nutrition education. Through a thorough patient assessment and evaluation, the dietician may help prevent kidney disease by carefully monitoring their diabetic, hypertensive, and CVD patients by ordering the appropriate screening labs. It is imperative to regularly screen the patient for CVD, T2DM, malnutrition, and anemia, as they are at high risk of developing them. Providing alternative food options tailored to the patient’s likes and dislikes to replace restricted foods is more productive than focusing on the restrictions. Providing substitution education to the patient is essential to attain and maintain patient compliance and achieve successful dietary management.The major limitation of this review is that although it is a literature review, we did not performed a systematic review of the literature. The literature survey was performed for a narrative review of the currently available studies to attempt to compile available studies under this review. To keep the review within limits, the search strategy was not comprehensive, and the studies were not assessed critically. Furthermore, this review was limited to protein, calcium, phosphate, and VD and electrolytic balance; it does not provide more comprehensive information on the clinical management of CKD.Secondary analysis of the MDRD study showed that patients with low protein intake during follow-up began experiencing uremic symptoms at lower GFR than patients with higher protein intake . The redDespite the large number of clinical trials being performed in the clinical and nutritional management of CKD, very few of these have translocated into clinical practices due to the lack of strong associations, not so clear research design, or low number of study subjects. There is a demand for future research to provide conclusive information that will assist clinicians and dietitians to make the most appropriate recommendations for their patients. Evaluating the impact of MNT on CKD progression by analysis of associated risk factors in patients with comorbidities is needed . The claChronic kidney disease is a growing health crisis in the U.S. Diabetes and hypertension are the leading causes of CKD development; as the US is experiencing an increasing prevalence of both, CKD is expected to remain a critical national health issue. At ESRD, the kidneys have lost their ability function, and as a result, a series of malfunctions occur that lead to adverse health problems and health outcomes. Once diagnosed with ESRD, the patient either will be on dialysis for the rest of their life or receive a kidney transplant. Medical nutrition therapy with a RD is a critical aspect in the intervention for CKD because it is almost solely through nutrition that aids in the delay of the disease’s progression and the prevention of comorbidities and mortality.


In addition, biochemical tests were performed, including kidney function tests, urine collection for proteinuria, and the estimation of GFR by MDRD or CKD-EPI eGFR in CKD patients and healthy controls (n = 17). All subjects underwent SMI, where vascularity is expressed as the SMI index (a low index reflects low vascularity/fibrosis and vice versa). Results: The SMI vascular index was significantly lower in CKD patients as compared with healthy controls . Notably, a moderate correlation between the SMI index and eGFR was found among the CKD patients . Similarly, a strong correlation was found between SCr and the SMI index of the diseased subjects . In patients who underwent renal biopsy, the SMI index corresponded with the histological alterations and CKD staging. Conclusions: This study demonstrated that SMI imaging may be utilized in CKD patients of various stages for the evaluation of chronic renal morphological changes and for differentiation between CKD grades.Background: Superb microvascular imaging (SMI) is an innovative ultrasound image processing technique that provides greater detail and better visualization of small branching vessels. We assume that SMI will provide sufficient information regarding the severity of chronic kidney disease (CKD) and reflecting histological changes. Aims: The aims was to assess the capabilities of SMI imaging regarding the early detection of kidney dysfunction and renal fibrosis in comparison to the reference standard renal biopsy for the early diagnosis of kidney fibrosis. Methods: SMI was performed in patients ( Chronic kidney disease (CKD) is characterized by a decline in glomerular filtration rate (GFR), a progressive increase in proteinuria, elevated blood pressure, and high risk of advanced kidney failure that requires replacement therapy. In addition, advanced CKD is characterized by morphologic renal changes that include varying degrees of fibrosis ,2. For sRenal biopsy plays an important role in the establishment of an exact diagnosis and in determining the degree of active and chronic microscopic changes regardless of the initial cause of the ongoing kidney disease. Thus, renal biopsy is an essential process which helps to assess the severity, prognosis, and treatment of certain renal illnesses. As an invasive medical procedure, biopsy is performed with the assistance of ultrasound or CT scanning. Usually, patients who have had renal biopsy will be observed for at least 24 h before being discharged. Complications such as bleeding, arteriovenous fistula, pain, chronic hypertension, renal insufficiency, and infection may occur at low incidences.Conventional renal ultrasound may reveal reduced renal length and cortical thickness, as well as increased cortical echogenicity, which may suggest the presence of chronic, atrophic morphological changes in a variety of renal diseases. However, as opposed to renal length and cortical thickness, cortical echogenicity is not measurable. Moreover, in diabetic patients, kidneys frequently do not show atrophic change via conventional renal ultrasound, even in advanced diabetic nephropathy (DN) with CKD grades 3 and 4. Therefore, conventional renal ultrasound is, generally, not informative for the evaluation of the progression of DN and not useful for the differentiation between the CKD grades ,2,3.Hassan et al. found that in patients with advanced DN, shear wave elastography (SWE) imaging may be utilized as a simple and practical method for the quantitative evaluation of chronic morphological changes and for differentiation between CKD grades . Thus, SThis was a prospective, open-label analytical study. The participants in this study were patients who regularly visit the out-patient Nephrology Clinic to resume their nephrological follow-up, including the EMMS outpatients’ clinic. The study was approved by the Nazareth Hospital EMMS Human Research Review Committee and carried out at Nazareth Hospital. Informed consent was obtained from all subjects involved in the study. All patients received a proper explanation regarding the SMI test and were asked for their approval to participate in the study (signed consent form). Patients with available biopsy were recruited from HaEmek Medical Center. The demographics  and laboratory data of the studied patients were collected from their medical records and placed in an appropriate Excel table. These data also included the latest routine complete blood count, biochemical analyses, and biopsy results when available. Appropriate patients who met the inclusion criteria underwent SMI no later than 6 months from biopsy.n = 16), hypertension (n = 17), hyperlipidemia n = (14), and heart disease (n = 4). All patients and normal health controls underwent SMI of the kidney as described above, carried out by the same senior physician . The clearest image of the region of interest (ROI) was chosen by Dr. Artul and analyzed accordingly. The selected ROIs represented the generalized vascular obtained mapping of the kidney cortex. Moreover, the analysis of the images was performed by the same physician.This study included 52 patients  and 17 controls . Background diseases among CKD patients included diabetes mellitus (Type 2) .Patients with known CKD, abnormal serum creatinine, and proteinuria levels even when GFR apparently normal.At age ≥18 y.Inclusion Criteria:Acute kidney injury.Pregnant women.Patients with severe liver diseases.Inter-current illness such as fever or sepsis.Allergic rhinitis.Hydro-nephrosis.Exclusion Criteria:Patients diagnosed as suffering from chronic kidney diseases at CKD stages 2–5 and confirmed by the modification of diet in renal disease (MDRD) equation or CKD-EPI were recruited at the Department of Nephrology, Nazareth Hospital between 2017 and 2019 after a signing consent form.All patients underwent blood and urine tests to determine kidney function according to creatinine and BUN levels. The presence and severity of proteinuria was determined either by total urinary protein excretion or the albumin to creatinine ratio. Only patients who exhibited kidney dysfunction were included in the study and underwent single SMI. In the cases where renal biopsy was available, we used the obtained etiology and renal histological changes to compare them with our findings via SMI. It should be emphasized that the radiologist was blinded to the kidney function/histological grading of the patients undergoing the imaging procedure.Only patients who underwent kidney biopsy in the last 3–6 months were included in the comparison between the sensitivity of SMI and biopsy findings. Regarding patients who did not undergo renal biopsy, their blood chemical analysis for SCr and BUN, besides 24-urine collection for GFR (CCT), served as the gold standard for staging renal failure degree.n = 17) served as a control group.Healthy volunteers with normal kidney function  were determined.The obtained results were analyzed for possible correlation with serum creatinine, proteinuria, and GFR. The severity of renal disruption observed via SMI was compared to the degree of fibrosis in renal biopsy when available.p-value ≤0.05 indicated statistically significant changes.The quantity-collected data are exhibited as mean ± SD, median, and range. Qualitative data were described as frequencies and percentages. The statistical differences between SMI and renal biopsy groups were assessed using the Mann–Whitney U test. Correlations between ordinal variables/ordinal and quantity data were determined by applying Spearman’s correlation coefficient test. Correlations between qualitative data were examined via the Chi square test or Fisher’s exact test, while the tests were chosen according to pre-assumptions which were required before using those tests. A Sixty-nine subjects were included in the current study. Subjects were divided into two groups; CKD patients and healthy controls. The first group included 52 participants and the second contained 17 participants; 52% were men and 48% were women in total, with a mean age of 56.8 ± 17.2 years in patients and 36.1 ± 12.3 years in controls. In the CKD group, 11 subjects had CKD stage 1, 13 had CKD stage 2, 23 had CKD stage 3, 3 had CKD stage 4, and 1 person had CKD stage 5; 1 had insufficient collected data to determine the CKD stage. In SMI, 63.8% had good impressions and 64.7% normal-shaped kidneys, 23.2% had intermediate impressions and 25.0% had slightly distorted shapes, 13.0% had poor impressions, and 10.3% had very distorted shapes .n = 13), the albumin/creatinine ratio (ACR) was determined, where the mean value of ACR was 325 ± 593 mg/g . In total, 25% of participants had less than 14 mg/g in their urine, and 75% had less than 331 mg/g. The median, minimal, and maximal values were 39 mg/g, 5 mg/g, and 1785 mg/g, respectively ; 25% of participants had a vascular index less than 46.50%, and 75% had less than 70.00%. The median, minimal, and maximal values of the vascular index were 55.00%, 20.00%, and 90.00%, respectively . The meaControls: In the control group, the mean serum creatinine was 0.78 ± 0.11 mg/dL . In total, 25% of this group had serum creatinine less than 0.74 mg/dL, and 75% had less than 0.84 mg/dL; the median was 0.80 mg/dL, as shown in Considering the radiologic parameters, the mean vascular index was 72.16 ± 12.92% ; 25% of participants had a vascular index less than 60.00%, and 75% had less than 82.00%, The median value of the vascular index was 74.00 C. The mePatients: In the CKD patients group, the mean serum creatinine was 1.33 ± 0.59 mg/dL; 25% of this group had serum creatinine less than 0.88 mg/dL, and 75% had less than 1.62 mg/dL; the median was 1.27 mg/dL, as shown in The mean eGFR was 63.06 ± 29.95 mL/min/1.73 m² and 62.79 ± 30.43 mL/min/1.73 m² by MDRD and CKD-EPI, respectively; . In total, 25% had an MDRD eGFR value less than 41.01 mL/min/1.73 m², and 75% had less than 85.79 mL/min/1.73 m². The median value of MDRD eGFR was 55.04 mL/min/1.73 m² ; 25% of participants had a vascular index less than 33.75%, and 75% had less than 61.90%, The median value of vascular index was 50% C.The mean value of kidney size was 11.19 ± 1.69 cm ; 25% of CKD subjects had a size value less than 10.05 cm, and 75% had a value less than 12.00 cm. The median value of kidney size was 11.00 cm .Correlation analysis was performed for all parameters, and the results are shown in As expected, a strong linear correlation was observed between eGFR and Scr  A,B. The Correlation analysis was performed in CKD patients, and the results are shown in Superb microvascular imaging (SMI) is an innovative ultrasound image processing technique that shows greater detail and better visualization of small branching vessels by using a unique algorithm that offers high frame rates, less clutter, and less tissue motion artifact, which could not previously be achieved without the use of contrast agent . Renal cp < 0.01). Furthermore, a strong correlation between the SMI index and eGFR was found among the CKD patients. Similarly, a strong correlation between the SCr and SMI index of the diseased subjects was found. This correlation is basic, and Scr is an indicator of the kidney’s function; as for the SMI, this fact empowers its reliability and the ability to demonstrate when there is a decrease in the kidney clearance function. In addition, a weak linear correlation was observed between proteinuria and the vascular index, which could be explained by the fact that not all diabetes mellitus patients demonstrate proteinuria in the early years of the disease following the diagnosis or exhibit a nonalbuminuric progressive renal impairment in both type 1 and 2 DM [The present study evaluated the usefulness of SMI in the diagnosis of kidney fibrosis. Specifically, we assessed the capabilities of superb microvascular ultrasound imaging for the early detection of renal fibrosis in comparison to the reference standard renal biopsy in order to determine the usefulness of SMI in the early diagnosis of kidney fibrosis even without major changes in SCr. We clearly demonstrated that the SMI index was significantly lower in CKD patients as compared with healthy controls (72.2 ± 12.9 vs. 49.9 ± 16.7%, and 2 DM ,32. A moDespite the encouraging results of the current study concerning the validity of SMI imaging in detecting early CKD and adverse kidney fibrotic alterations, there are limitations: 1: the numbers of patients and controls were low; 2: some of the healthy controls had slightly lower SMI than the normal limit, which may stem either from the nature of the applied US or the presence of minor histological/vascular changes in the kidney despite normal SCr/GFR; 3: the age of the healthy subjects was not comparable to that of patients; 4: not all patients underwent kidney biopsy. These limitations may be overcome by the mobilization of more CKD patients of various severities and matched healthy subjects.In summary, the most remarkable finding of the current study is the differences in imaging parameters between healthy and CKD subjects. Specifically, this study demonstrates that in patients with CKD of various stages, SMI imaging may be utilized as a simple and practical method for the evaluation of the chronic renal morphological changes and for the differentiation between CKD grades, as we managed to demonstrate how SMI reflects the kidney functional status by translating it to percentages of the vascularity index. In other words, a shorter distance of the cortical end vessel to the kidney capsule indicates the higher sensitivity of SMI in depicting smaller vessels in the cortex near the kidney capsule , and alsThe main contribution of our study is the provision of a noninvasive approach to detect chronic kidney dysfunction and fibrosis, as well as the potential replacement of kidney biopsy as a diagnostic tool for this disease state. Despite remarkable advances in medicine, the detection of kidney dysfunction and fibrosis may be delayed due to the limited accuracy of SCr at early stages of the disease. Moreover, not all patients undergo kidney biopsy, and the available noninvasive images are insensitive. Early detection might help to initiate an appropriate treatment and to prevent progress in kidney fibrosis, with a possible reduction in morbidity, mortality and medical expenditure, including decreasing the need for acute and chronic dialysis. In summary, SMI will provide sufficient information regarding the severity of chronic kidney disease and reflecting fibrotic changes.


Spirulina is a microalga that presents various important pro-health properties, for instance lowering blood pressure in the research. The study aims to appraise the efficacy of Spirulina administration on systolic (SBP) and diastolic blood pressure (DBP). Randomized controlled trials (RCTs) were retrieved by a systematic search of PubMed, Web of Science, and the Cochrane Library databases from inception to June 2021 according to a standardized protocol. The effect size of each study was counted from mean and standard deviation before and after the intervention and shown as Un-standardized mean difference and 95% confidence interval. Sensitivity analyses were performed. Meta-analysis on 5 RCTs with 230 subjects was eligible. The amount of Spirulina ranged from 1 to 8 g per day, and intervention durations ranged from 2 to 12 weeks. Data analysis indicated that Spirulina supplementation led to a significant lowering of SBP (Mean Difference (MD): −4.59 mmHg, 95% Confidence Interval (CI): −8.20 to −0.99, I square statistic (I2) = 65%) and significant lowering of DBP , particularly in a subgroup of hypertensive patients. Spirulina administration might have a supportive effect on the prevention and treatment of hypertension. More exact randomized controlled trials are needed to clarify the effect of Spirulina supplementation on blood pressure. Arterial hypertension is the crucial independent risk factor in cardiovascular diseases for developed countries, characterized by an increasing prevalence in recent years ,2. DespiSpirulina, a microscopic and filamentous cyanobacterium is considered a sustainable and eco-friendly microalga, playing an increasing role in alternative medicine , imputing a correlation coefficient as described in Cochrane recommendations  statistic, ranging from 0 to 100% as I2 > 60% refers to considerable heterogeneity [Spirulina intake and baseline blood pressure. In case of significant heterogeneity random effect analysis was performed. Sensitivity analysis was carried out to explore the inference of each study on overall effect. Potential publication bias was not assessed due to an insufficient number of studies (n < 10), so the power of the tests is too low to differentiate chance from real asymmetry [p values ≤ 0.05 was considered as statistically significant.The effect size of each study was counted from the mean and standard deviation (SD) of the results before and after the intervention, and subsequently shown as Un-standardized mean difference and 95% confidence interval (CI). To extract one mean and one standard deviation in the studies, in which mean ± SD were divided into females and males, the certain transformations were used based on Cochrane’s formulae for combining groups . Standarndations . In studct sizes ,24. The ogeneity . To findsymmetry . Review Spirulina supplementation. The studies containing only the values of SBP or DBP were accepted solely when comprising pre- and post Spirulina supplementation blood pressure values. The next 3 records were rejected because they did not report the results. Finally, 5 studies were available for the main analysis. A flow diagram showing the accurate study selection and identification process is presented in From database searching, 774 records were retrieved in our systematic search. Of these, 233 duplicated records were excluded. Among the remaining, 533 were removed. Reasons for exclusion present as follows: 441 items irrelevant to the topic, 52 trial protocols, 6 animal/non-human studies, 20 review articles and other non-RCTs, and 14 due to lack of data on systolic/diastolic blood pressure values before or after Spirulina ranged from 1 to 8 g per day. The intervention duration was 3 months (12 weeks) for three studies, 8 weeks for one study, and 2 weeks for another. All patients were adults and they suffered from co-existing diseases, for instance, hypertension, diabetes mellitus type 2, chronic joint pain, and ulcerative colitis  separately assessed the methodological quality of RCTs through Cochrane Collaboration’s tool which includes six domains . Each doSpirulina administration on systolic blood pressure was assessed based on 5 RCTs. Pooled analysis revealed that Spirulina intake led to a significant lowering of SBP . There was a significant between-study heterogeneity  in which dose of Spirulina, duration of Spirulina intake, and baseline blood pressure were identified as sources of heterogeneity in the subgroup analysis   compared with the “normotensive” subgroup   . The onlo −0.08) .Spirulina intake significantly lowered DBP  in comparison with the control group. However, the above analysis showed unacceptable heterogeneity (I2 = 81%). Therefore, based on the sensitivity analysis, we found and eliminated the study [Spirulina group  compared with the control group  and no statistically significant changes regarding the diastolic blood pressure [Spirulina. Significant decreases in SBP and DBP were observed in the Spirulina group after three months of treatment with 2 g [Spirulina for 12 weeks showed a significant lowering effect on DBP (p < 0.021) and no significant effect on SBP in the study by Lee et al. [Spirulina and placebo groups regarding SBP and DBP at baseline or after 2 weeks. However, the consumption was associated with a mild reduction in DBP [Spirulina taken 1 g per day by ulcerative colitis patients did not influence blood pressure values (p > 0.05) [In this paper, we present the results of a systematic review and meta-analysis which indicated pressure . Miczke with 2 g . Adminise et al. . Resultsn in DBP . In cont > 0.05) .Spirulina on SBP and DBP, for example, physical activity, diet, and smoking should be taken into consideration. These conflicting outcomes of the studies can depend on the supplementation of different doses of Spirulina in different periods of time. The fact that no significant hypotensive effect was seen after administration of 1 g of Spirulina might suggest the role of the appropriate dosage of the supplement to decrease blood pressure. It is worth mentioning that no significant changes in blood pressure parameters were noted in studies, in which the duration of Spirulina supplementation was below 12 weeks: 2 or 8 weeks, respectively [Spirulina administration showed a significant decrease in at least one component of blood pressure [Spirulina intake did not show any difference between subgroups. Meta-analysis results are evidence of greater importance than analysis of particular studies. It is worth highlighting that Spirulina supplementation resulted in greater SBP lowering in a subgroup of hypertensive patients compared with those with normal blood pressure. It suggests that patients with hypertension might reap greater benefits with Spirulina supplementation. Both dosage and the duration of supplementation require further studies.Discrepancies require further in-depth analyzes. Some other possible confounding factors in assessing the impact of ectively ,19. Studpressure ,16,17. HSpirulina intake and blood pressure values showed that 4.5 g per day for 6 weeks had the positive effect on SBP and DBP reduction in a sample of overweight patients [Spirulina per day for 12 weeks in a Cretan population [Other non-randomized controlled studies assessing a relationship between patients . On the pulation ,31.Spirulina is partially understood. It was supposed that the high content of potassium in Spirulina might have a lowering effect on blood pressure [Spirulina, decreases parameters of blood pressure by strenghtening the expression of endothelial nitric oxide synthase in the aorta after the stimulation of adiponectin [Spirulina platensis decreases blood pressure levels through a PI3K (phosphoinositide-3-kinase)/AKT (serine/threonine kinase Akt)/eNOS  -dependent mechanism [Spirulina in SBP—they observed an increase in glutathione peroxidase (GPx) activity and oxidized glutathione (GSSG) concentrations (p < 0.05) [Spirulina improves endothelial function by reducing arterial stiffness index (SI) [Spirulina contains natural angiotensin I converting enzyme inhibitor (ACEi) peptide. ACEi suppresses the synthesis of angiotensin II that induces the vasoconstriction of blood vessels and the release of aldosterone, resulting in blood pressure increase [The mechanism of lowering blood pressure by pressure . Phycocyponectin ,32. Oxidponectin . In miceechanism . Martíne < 0.05) . Additio < 0.05) . Spirulidex (SI) . Moreoveincrease ,35,36. MSpirulina with antioxidant and hypotensive activity might reduce blood pressure, which potentially reduces cardiovascular risk and prevents serious effects such as stroke or heart attack. Moreover, hypertension is frequently associated with diabetes mellitus and metabolic syndrome. Some studies revealed that Spirulina intake improved glucose and lipid metabolism, reduced oxidative stress, modulated appetite, so it can be considered as a therapeutic nutraceutical not only by reducing blood pressure [Spirulina may potentially reduce blood pressure among hypertensive patients. Supplementation of Spirulina products promoted as “superfoods” is more and more popular due to its health benefits, but recent studies revealed contamination of toxic substances—cyanotoxins, heavy metals, or polycyclic aromatic hydrocarbons (PAHs) [Spirulina and pharmacotherapy.Due to many complications of hypertension, intake of pressure ,32. Accos (PAHs) ,38. FurtSpirulina supplementation on a decrease of blood pressure. In the meta-analysis by Huang H. et al. Spirulina supplements significantly lowered DBP , but not SBP  [Spirulina [The limitations of this meta-analysis were the small number of analyzed RCTs and the lack of possibility to assess publication bias. However, the greatest strength of this paper is the inclusion of two novel studies from 2018 and 2021 ,19. The 2 = 50%) . Differepirulina .Spirulina supplementation might have a supportive effect on the prevention and treatment of hypertension. Spirulina intake had beneficial hypotensive properties, particularly in patients with hypertension compared to those with normal blood pressure. Spirulina should be further used as a nutraceutical food supplement due to its pro-health properties. More RTCs with different dosages and the duration of Spirulina administration are recommended to be conducted to clarify the effect of Spirulina on systolic and diastolic blood pressure and to determine its clinical relevance in hypertension management.In summary, the results of the current meta-analysis indicated that


Cluster of differentiation 93 (CD93), also known as complement component 1q receptor 1 is a transmembrane glycoprotein expressed in endothelial and hematopoietic cells and associated with phagocytosis, cell adhesion, angiogenesis and inflammation. The extracellular part, soluble CD93 (sCD93), is released to body fluids in inflammation. Data on sCD93 in kidney diseases are limited. Our aim was to evaluate serum sCD93 in long-term kidney transplant recipients as a marker of inflammation and endothelial dysfunction that may be potentially useful in early recognition of graft dysfunction. Seventy-eight adult patients with functioning kidney graft and stable clinical state were examined at least one year after kidney transplantation. Serum sCD93 was measured by enzyme immunosorbent assay. Estimated glomerular filtration rate (eGFR) and albuminuria or proteinuria were assessed at baseline and over one-year follow-up. Increased sCD93 was associated with lower baseline eGFR independently of the confounders. Moreover, sCD93 was negatively associated with eGFR during one-year follow-up in simple analysis; however, this was not confirmed after adjustment for confounders. Baseline sCD93 was positively associated with baseline albuminuria and with increased proteinuria during the follow-up. Serum sCD93 was not correlated with other studied inflammatory markers . To the best of our knowledge, this is the first report regarding the concentrations of sCD93 in kidney transplant recipients and one of the first reports showing the inverse association between sCD93 and renal function. Serum sCD93 should be further evaluated as a diagnostic and prognostic marker in renal transplantation. Complement component 1q (C1q) receptor 1  is a 126-kDa type 1 transmembrane glycoprotein expressed in endothelial and hematopoietic cells, initially described as the receptor for C1q distinct from the 60 kDa calreticulin and responsible for C1q-induced phagocytosis . The souCD93 has been identified as a receptor for three structurally similar proteins inducing phagocytosis, namely C1q, mannose-binding lectin and pulmonary surfactant protein A . AlthougThere are single reports linking sCD93 with renal diseases, i.e., diabetic nephropathy in type 2 diabetes , and renRenal transplantation is currently the best therapeutic option in end-stage kidney failure, enabling considerably better quality of life and decreased morbidity and mortality as compared to other renal replacement therapies . Nonetheless, a range of inflammatory conditions including acute or chronic rejection, recurrent or de novo nephropathies, cardiovascular complications or infections are associated with limited survival of kidney grafts and kidney transplant recipients . In clinThe aim of our study was to assess serum sCD93 concentrations in patients with long-term functioning kidney transplant in relation to other inflammatory markers and the longitudinal changes in transplant function.2). The exclusion criteria were: acute kidney injury defined according the KDIGO 2011 [The prospective observational study included ambulatory patients of kidney transplant recipients’ ambulatory, Chair and Department of Nephrology, University Hospital, Kraków, Poland between May and July 2019. The study included adult patients (at least 18 years of age) who had received the kidney transplant at least one year before the start of the study, and had the functioning kidney transplant at the start of the study . On recruitment, patients signed an informed consent for the study. Patients were recruited by the experienced nephrologist during their control ambulatory visit in kidney transplant recipients’ ambulatory, following the detailed history and physical examination. For the purposes of the study, the clinical data at baseline were recorded, including immunosuppressive therapy, comorbidities, date of transplantation, deceased or living donor, first or second transplant, induction therapy, cold and warm ischemia time, delayed graft function and the primary cause of kidney disease based on the available medical records. Moreover, data on pretransplant panel reactive antibodies (PRA) and donor/recipient human leukocyte antigens (HLA) mismatches based on transplantation protocols were collected when available; however, these were available only in cases who had undergone the transplantation procedure in the study center . The follow-up data were recorded in September 2020, i.e., after 12–14 months after patient recruitment and included the medical records on graft function during the follow-up and the causes of graft dysfunction, all available serum creatinine concentrations measured during the follow-up, and the results of laboratory tests performed at the last visit of the patient to the kidney transplant recipients’ ambulatory ward.Fasting urine and venous blood samples for the laboratory tests described below were collected in the morning of the day of the recruitment. The routine laboratory tests were performed on the day of blood collection in the Department of Diagnostics, University Hospital, Kraków, Poland, with the use of automated analyzers . These included complete blood count, serum creatinine, albumin, glucose, triglycerides, total cholesterol, C-reactive protein (CRP), urine albumin and creatinine, and the concentrations of immunosuppressive drugs (cyclosporine and tacrolimus). Urine albumin-to-creatinine ratio (ACR) was calculated by dividing the respective concentrations. Estimated GFR was calculated based on serum creatinine, age, sex and race using the Chronic Kidney Disease Epidemiological Collaboration (CKD-EPI) 2009 formula . For the purpose of the study, additional tests were performed using automated analyzers and dedicated reagent kits: serum concentrations of procalcitonin and interleukin 6 were measured using Cobas 6000 , and serum concentrations of complement components 3 (C3) and 4 (C4) were measured using BN II nephelometer . The excess of serum samples collected for routine tests were aliquoted and frozen in −80 °C for additional tests. Serum concentrations of sCD93 was measured in a series of samples using Quantikine ELISA Human C1qR1/CD93 Immunoassay  and the microplate reader Micro ELISA Reader ELX 808 . The measurements were performed immediately after collection of all samples. Samples were analyzed in duplicate. According to the manufacturer’s data, the minimum detectable dose of human sCD93 ranged from 0.001 to 0.028 ng/mL (mean 0.006 ng/mL) and the serum concentrations in healthy individuals ranged from 90.0 to 223.0 ng/mL (mean 146.0 ng/mL). The measurements were performed at the Department of Diagnostics, Chair of Clinical Biochemistry, Jagiellonian University Medical College, Krakow, Poland.p < 0.1. We reported standardized regression coefficients (β) with standardized errors (SE). The multiple linear regression models were adjusted for clinically relevant covariates, i.e., age, time from transplantation, sex, and diabetes, as shown in Results. The results were considered significant at p < 0.05. Statistica 13.3 software  was used for computations.Categorical data were presented as number of patients and percentage of the studied group. Quantitative data were presented as mean ± standard deviation (SD) for normally distributed variables and median, lower quartile (Q1) and upper quartile (Q3) for non-normally distributed variables. The distributions were assessed with Shapiro–Wilk’s test. Because serum concentrations of sCD93 and other studied inflammatory markers were non-normally distributed, we compared them between subgroups (specified in Results) using non-parametric tests . The baseline and follow-up data were compared using paired t-test or Wilcoxon matched pairs test, according to distribution. Simple correlations were analyzed with Pearson’s coefficient and univariate linear regression, after log-transformation of right skewed variables (including sCD93). Multiple linear regression was calculated using the independent variables that were associated with the outcome variable in simple analysis at The study included 78 patients aged between 26 and 78 years, and between 1 and 22 years post renal transplantation . The staThe baseline results of laboratory tests in the studied group  were witp = 0.1) or log-transformed time from transplantation . The second transplant recipients had significantly higher serum sCD93 concentrations as compared with the patients after first transplantation (p = 0.2) and between patients with or without diabetes (p = 0.8). Patients treated with mTOR inhibitors were characterized with significantly lower concentrations of sCD93 . There was a weak correlation between log (sCD93) and systolic blood pressure  and no correlation with diastolic blood pressure .Serum sCD93 concentrations were higher among men . We did antation . sCD93 cof sCD93 , while wp = 0.1) nor with the maximum  or last pretransplant PRA . Additionally, the sCD93 concentrations were not associated with cold  or warm ischemia time , the use of induction therapy , or the delayed graft function .In the subset of patients with available data on the transplantation procedure, the concentrations of sCD93 (log-transformed) were not correlated with the number of mismatched HLA  in the studied group of kidney transplant recipients did not differ significantly compared to the initial values (p = 0.8 for both variables). Additionally, the mean serum creatinine calculated as the arithmetic mean of all measurements available in the follow-up period  and the eGFR based on mean creatinine  did not differ significantly from the initial values . There was one patient in whom serum creatinine doubled during the follow-up; two started dialysis. During the follow-up period, the attending physicians noted transient decrease in kidney graft function in 14 (18%) patients , and persistent decrease in graft function in eight (10%) patients . The increased proteinuria , serum creatinine concentrations  and eGFR values  at the Baseline serum sCD93 concentrations (log-transformed) correlated significantly with mean and final eGFR during the follow-up . Other sSerum concentrations of sCD93 were significantly positively associated with the adverse renal events during the follow-up, i.e., transient or persistent decrease in graft function recorded by the post-transplant ambulatory physician, and increased or persistent proteinuria . This waThe main finding of our study is the correlation of serum sCD93 with kidney graft function observed in long-term kidney transplant recipients examined at least one year following the transplantation procedure. Increased sCD93 was associated with lower baseline eGFR independently of the confounders. Increased sCD93 was associated with lower eGFR during one-year follow-up, although we were not able to confirm the association after adjustment for covariates. Moreover, sCD93 was positively associated with urine albumin/creatinine ratio at baseline and with increased proteinuria during the follow-up. Of note, sCD93 was not correlated with other studied inflammatory markers, and the observed relationships between interleukin 6, procalcitonin, or C4 and kidney function were weaker and less consistent than the relationships between sCD93 and kidney function. To the best of our knowledge, this is the first report regarding the concentrations of sCD93 in kidney transplant recipients.2 while our patients represented a broader range of eGFR. Furthermore, Ikewaki et al. [The observed association between sCD93 and kidney function is consistent with several previous reports. Lee et al.  measuredi et al.  showed ti et al. . In Japai et al. . Finallyi et al.  observedi et al. , the vasi et al. . In diabi et al. .The negative association between sCD93 and glomerular filtration could be attributed to renal retention of sCD93. However, sCD93 is not a low-molecular-mass protein. Greenlee et al.  observedThe shedding of CD93 from cells is dependent on the degree of O-glycosylation of the protein . Thus, tIncreased sCD93 may also be a sign of chronic inflammation and endothelial dysfunction observed in patients with chronic kidney disease, including kidney transplant recipients. Chronic inflammation in renal insufficiency may be due to several causes, including increased production and renal retention of proinflammatory cytokines, endothelial dysfunction induced by uremic toxins, or enhanced oxidative stress ,33,34,35Interestingly, we observed lower serum sCD93 in patients who developed urinary tract infections during the follow-up than in those who did not. In the study of Ishizaki et al. , sCD93 cIn kidney transplant recipients, treatment with immunosuppressive drugs and corticosteroids may influence the concentrations of sCD93. Although we only observed lower concentrations of the protein in patients receiving mTOR inhibitors, we cannot exclude other relationships, because the immunosuppressive regimens were similar in the majority of our patients. Treatment with inhaled corticosteroids was reported to decrease serum concentrations of sCD93 in allergic diseases . In our Our study has several limitations; therefore, our results regarding serum sCD93 as a predictor of renal transplant function should be considered preliminary. First, we included limited number of patients and the follow-up time was short. For that reason, we were not able to determine the association between sCD93 with such endpoints as doubling serum creatinine, progression to end-stage kidney failure, or mortality , as these endpoints were observed in single patients. Moreover, our report provides incomplete characteristics of patients at the time of transplantation (due to limited availability of data and long time from transplantation in many patients), and incomplete data about the causes of decline in renal graft function observed during follow-up. Larger studies with longer follow-up and preferably with the use of protocol biopsies are needed to confirm and explore the diagnostic and prognostic usefulness of sCD93 in kidney transplant recipients. Experimental studies are needed to explain the mechanism of sCD93 increase in chronic kidney disease. Nonetheless, our results indicate that renal function should be considered as a confounder in epidemiological studies evaluating sCD93 as a marker of diseases.In summary, although based on limited number of studied patients, this is one of the first reports showing the association between serum sCD93 and kidney function, and the first such observation in kidney transplant recipients. In long-term renal transplant recipients, soluble CD93 positively correlated with serum creatinine and urine albumin/creatinine ratio and negatively correlated with eGFR. The association between sCD93 and kidney function should be considered in future studies evaluating sCD93 as a marker of inflammation or endothelial dysfunction. Larger studies with longer follow-up are required to confirm the usefulness of CD93 as a diagnostic and prognostic marker indicating graft dysfunction in kidney transplant recipients.