We observed a statistically significant influence of the presence of diabetes mellitus and dyslipidemia on the dynamics of differences between SP monitoring values. Conclusions: Our study suggests that novel technologies in BP monitoring can be excellent alternatives for BP assessment in hypertensive patients with other cardiovascular risk factors such as diabetes and dyslipidemia. Background: The purpose of this study was to compare home and office BP in the adjustment of antihypertensive treatment. Methods: This study was an open, prospective, noninterventional, multicenter clinical trial that occurred between July 2019 and February 2020, in 34 cities in the territory of the Republic of Serbia, which monitored 1581 participants for 6 months. Depending on the used blood pressure monitoring method used, all patients were divided into control (office BP monitoring) and experimental (home BP telemonitoring) groups. We collected anamnestic data and data about systolic blood pressure (SP), in mmHg, diastolic blood pressure (DP), in mmHg, and heart rate (HR), in beats/minute, from all patients. Results: SP values were significantly different at baseline, and at the second, third, and fourth visits between the two tested groups. Home and office BP decreased significantly ( Currently, hypertension (HTA) is the most significant and prevalent risk factor for cardiovascular diseases (CVD). Data from 2015 indicate that 1.13 billion people in the world suffer from HTA [Adequate blood pressure (BP) measurement method is essential for the correct assessment of hypertension and the need for antihypertensive treatment. Home measurement and office BP monitoring only complement the conventional office BP method regarding the optimal technique for measuring BP ,5.Today, there is growing evidence of the benefits of home blood pressure and heart rate monitoring over standard measurement at medical examinations or office BP monitoring . Home blPrevious studies have reported that antihypertensive therapy based on 24 weeks of either office BP control or home measurement, instead of office control, led to less intensive drug treatment and less BP control with similar costs ,13. The Telemedicine is the application of technological and telecommunication achievements to transmit data over long distances to improve patients’ health . Home teA new approach to the treatment of HTA is home monitoring with the application of new technologies—the so-called “home telemonitoring of BP”. This new method enables BP value data transmission over long distances and their reading by a doctor, who has access to data whenever necessary. This allows a better degree of data analysis and graphical display of BP variation at home, thus achieving more accurate diagnostic and therapeutic decisions without additional hospital visits . Thus faIn s systematic review, Paré et al. point out that the application of telemonitoring leads to an improvement in the control of HTA and other diseases for which this approach has been applied .In the Republic of Serbia, one of the most critical problems is that a large percentage of hypertensive patients have inadequate BP control. Patients are not compliant or sufficiently motivated because the therapy is chronic, and the symptoms are often mild and nonspecific. Doctors do not have enough time to solve the problem of patients’ compliance with taking therapy. In order to adequately control (monitor) BP, it is proposed to use digital forms of communication such as modern applications on “smartphones”. A better motivation of both the doctor and the patient is expected, as well as better patient compliance, conditioned by the information offered by modern technologies.Based on all mentioned facts, we hypothesized that home BP control supported by modern technologies in patients with different comorbidities could be a better choice for achieving the target values of BP, compared with the traditionally controlled patients. Statistically significant better results in achieving the target values of blood pressure are expected in patients who measure and monitor their blood pressure more regularly and more often receive advice/reminders from their doctor via digital devices than in traditionally controlled patients.The purpose of this study was to (1) compare home and office BP in the adjustment of antihypertensive treatment and (2) compare the differences in measuring BP values using a smartphone application, with active advice/reminders from doctors and regular entry of BP values, with the effects achieved in standard HTA treatment.This study was an open, prospective, noninterventional, multicenter clinical trial that occurred between July 2019 and February 2020 in 34 cities in the territory of the Republic of Serbia and in 47 health care institutions at primary, secondary, and tertiary levels. 2; atrial fibrillation and/or other significant arrhythmias; pregnancy; inability to use telemedicine systems; significant cardiovascular, cerebrovascular, or peripheral vascular event in the previous 6 months; significant sleep apnea syndrome and any condition, including alcohol or drug use, that may interfere with the completion of the study. The study cohort included 1581 participants of both genders who were previously diagnosed with unregulated arterial hypertension grade I/II  with(out) cardiovascular complications of hypertension. The main inclusion criteria were age from 18 to 90 years, both genders, diagnosed treated or untreated arterial hypertension, and written informed consent. The main exclusion criteria were systolic blood pressure (SBP) above 180 mmHg or diastolic blood pressure (DCP) above 110 mmHg; expected difficulties in BP home monitoring; patients working at night or shift workers; body mass index above 35 kg/mThe initial pre-entry screening was carried out by 85 physicians , who enrolled and monitored 1581 participants for 6 months (minimum of 10 patients per physician). All patients were treated on an outpatient basis in one of the Centers for Hypertension in the Republic of Serbia. Patients who met the inclusion criteria were assigned to one of the following groups: Group 1 home BP telemonitoring group : Patients whose HTA was managed based on home BP telemonitoring data. These patients had an installed application “mojpritisak.rs”. Patients would have measured their BP at least twice a week at home during the study and entered the appropriate data  into their smartphone app. Patients in this group could track their BP measurement data, which were also presented in a form of a graph. Doctors had access to these data at their clinics and were obliged to monitor the patient’s measurements. By communication window within the app, doctors were able to send instructions via SMS/email to patients if their BP was not well regulated. In addition, patients also received generated SMS/emails with tips for cardiovascular risk reduction and lifestyle changes, based on the presence of different risk factors . Moreover, smartphone apps, BP devices, and patient progress would be checked on follow-up visits. Group 2 usual care (control group): Patients whose HTA management was based on office BP measurements performed at regular checkups on an outpatient basis. After inclusion, physicians monitored patients from this group over 4 visits, when their BP was measured and therapy was evaluated, according to the study protocol.Patient selection was made based on inclusion and exclusion criteria and the patient’s willingness to home monitor BP. As for the generated SMS/emails with tips for cardiovascular risk reduction and lifestyle changes, they contained short tips for lipid reduction, the importance of physical activity, and the danger of obesity and diabetes. Messages were sent on a monthly basis, via email or SMS. Doctors were only obliged to send messages to patients regularly when they would see poorly regulated HTA in patients’ virtual files. The first visit was the introduction of the patient to the study ;The second visit occurred after 30 + 14 days;The third visit occurred after 90 + 14 days;The fourth visit occurred after 180 + 14 days.Patients who met the inclusion criteria and who had no identifiable cause for exclusion were included in the study and were followed during the period of 24 weeks, which included four visits to the doctor: During the first visit, we obtained a medical history for all patients and performed a standard physical examination. A detailed history was collected from all patients using a questionnaire with a special emphasis on data related to cardiovascular risk factors such as hypertension, smoking, dyslipidemia, physical activity, stress, diabetes, family history, drug tolerance, salt and alcohol consumption, presence of depression and other mental disorders, social history, sleep apnea screening, level of health education and social history, BMI, waist and hip circumference, and age and sex of patients. Before the pre-entry screening period, all patients received individual guidance about the study protocol and how to measure BP correctly. Blood pressure monitoring was applied according to the recommendations of the European Society of Hypertension . That meFrom all patients, we collected data about systolic blood pressure (SP), in mmHg, diastolic blood pressure (DP), in mmHg, and heart rate (HR), in beats/minute. An average of two or more measurements was taken. If the first two measurements differed by more than 15 mmHg, we took additional measurements and averaged BP or HR.Home BP telemonitoring was performed by a validated home device  for measuring BP and entering all data into the mobile phone application. After 5 min of rest in the sitting position, patients performed two consecutive self-measurements of BP twice a day, in the morning between 6 and 11 a.m., before taking medication, and in the evening between 5 and 10 p.m., before taking the evening meal. Patients wrote down the BP values and time of day. The self-measured BP included the average values of all readings during all follow-ups of six months. Patients received appropriate verbal and written advice regarding blood pressure measurement. Office BP monitoring was performed in 0, 1, 3, and 6 months from the first visit on all patients using a validated Bp measuring device  in the morning (6 a.m. to 11 p.m.) and at night time (11 p.m. to 6 a.m.). Blood pressure was measured during each patient’s visit to the clinic the using BP measurement method available at the clinics.2 test in the case of categorical variables. The influence of categorical variables on the dynamics of BP changes and differences in both groups was tested using multivariate analysis of variance (MANOVA). The statistical significance level was set to 0.05 (5%). Database analysis and management were performed using SPSS Statistics software, version 22.0 . All data were tested for normality and then presented using methods of descriptive statistics . The between-group differences in continuous measurements were calculated by subtracting the mean changes from baseline in the home BP group from those of the office BP group using Mann–Whitney or Wilcoxon tests for continuous variables or χThe study sample was calculated according to the assumption of a margin error of 5% and a confidence interval of 95%. Using the online Raosoft sample size calculator, a sample of 1450 respondents was calculated, which was rounded up to 1500 participants.In this study, 1581 patients met the inclusion criteria and underwent randomization, 780 in the office BP (control) group and 801 in the home BP telemonitoring  group . The basp < 0.000) during the 6-month follow-up. In comparison to baseline values, SP values were significantly lower after follow-up (at the fourth visit), as were values of DP and HR in all groups. Additionally, SP values were significantly different at baseline, as well as at the second, third, and fourth visits between the two tested groups . On the In order to explain the results as precisely as possible, we presented results of the dynamics of BP in the form of a comparison of differences between measurements in the control and experimental group . For example, the mean differences in systolic blood pressure between the second and baseline measurement were −10.712 ± 0.582 in the control group and −2.637 ± 0.341 in the experimental group , with a In our study, we performed a multivariate analysis of variance (MANOVA) in the study population depending on the presence of diabetes mellitus, dyslipidemia, smoking, hereditary factors, and time. We observed a statistically significant influence of the presence of diabetes mellitus and dyslipidemia on the dynamics of differences between SP monitoring values . On the other hand, a nonsignificant trend persisted in diabetes mellitus and dyslipidemia relative to DP and HR values, as well as in the influence of the presence of smoking and positive hereditary factors in relation to SP, DP, and HR values . p = 0.011, partially eta square = 0.008. There was also a significant separate (basic) effect of time, Wilks’ lambda = 0.765, p = 0.000, partially eta square = 0.235, with a decrease in patient pressure obtained during the four examinations in both groups. The separate effect of diabetes mellitus was significant, p = 0.000, which means that this comorbidity affects systolic pressure  effect of time, Wilks’ lambda = 0.746, p = 0.000, partially eta square = 0.254, with a decrease in patient pressure obtained during the four examinations in both groups. The separate effect of dyslipidemia was significant, p = 0.000, which means that this comorbidity affects systolic pressure  influence of time was found, Wilks’ lambda = 0.800, p = 0.000, partially eta square = 0.200, with a decrease in the pressure of patients obtained during the four examinations in both groups. The separate effect of diabetes mellitus was not significant, p = 0.472, which means that this comorbidity does not affect diastolic pressure , but there was no statistical significance. In addition, their results indicate better titration of therapy when using home BP monitoring and telemonitoring and better patient compliance, as well as the possibility of application at the level of primary health care with a reduction in the workload of physicians .Furthermore, a study on the cost effectiveness of the TASMINH 4 trial economically justified self-monitoring of HTA, with or without telemonitoring, for monitoring and treatment of HTA with a reduction in cardiovascular mortality .Similar to previous studies, a randomized controlled trial conducted by McKinstry et al. compared the effect of telemonitoring and standard HTA management on the reduction in BP values measured by office BP monitoring; after 6 months of follow-up, SBP was lower by 4.3 mmHg and DBP by 2.3 mmHg . AlthougIn a cluster-randomized study, in addition to the use of home BP telemonitoring, consultation with a pharmacist was used as an intervention. After 12 months of follow-up, it showed a difference in SBP by 9.7 mmHg and DBP by 5.1 mmHg, and a significant difference persisted for 18 months after intervention .Recent meta-analysis studies ,12,41 alAdequate therapy and control of BP significantly affect the occurrence of CVD: reduction in SBP by 10 mmHg and DBP by 5 mmHg reduces the risk of cardiovascular events by ~20%, total mortality by ~10–15%, risk of stroke by ~35%, risk of a coronary event by ~20%, and heart failure by ~40% [One of the problems of poor regulation of BP is poor therapeutic adherence of patients —some resThe obvious disadvantage of introducing new technologies such as smartphones in the control of HTA is their poor applicability among the elderly, due to poorer technological literacy , althougNumerous studies have examined the impact of new technologies on patient behavior. A qualitative study examining patients’ impressions on using telemonitoring highlighted the usefulness of the application in terms of communication with medical staff and empowerment of patients to self-monitor BP but raised concerns about increased health anxiety and technology unsustainability over time . ConversAs regards issues related to doctors, the greatest concern was fear of potentially increased workload , which hIn our study, there were no significant objections from patients and physicians. All doctors received instructions and training in running the application on the patient’s phone, which they accomplished without major difficulties. The simplicity of application use was praised by doctors and patients, as well as the option of additional communication with the patient.Based on the results of our cohort study, it seems that home monitoring should be used in conjunction with office monitoring as a complementary method of BP assessment. Home BP monitoring may have practical advantages in being used on a regular basis in the clinical setting. Home blood pressure monitoring may be easier to implement and, with increasing telehealth and computing capabilities, may be incorporated, for example, into the care of hypertensive dialysis patients, as one of the seriously ill populations. However, whether such an approach results in reducing hypertension-related adverse clinical outcomes remains to be seen in future clinical studies.To the best of our knowledge, this is the first study of the implementation of new technologies for HTA management and CVD risk factors reduction in the Republic of Serbia.The study included patients from 34 cities in all regions of the country, which enables an overview of the success of HTA control, as well as other important data (such as distribution of risk factors for CVDs) at the state level. Of the doctors who participated in the study, 85 belonged to all levels of health care  at which the control and treatment of patients with HTA were carried out. They are also doctors of various specialties—general practitioners, specialists in internal medicine, cardiology, and endocrinology, which makes our analysis more comprehensive. Furthermore, the recent COVID-19 pandemic showed the benefits of using telemedicine in different health areas ,44,45 whIn this study, the examined group used BP measuring devices with data storage, but the measured values themselves were entered into the application on the phone “manually” by the patients. Similar studies have used BP devices that automatically transmit measured values to a mobile phone app via a Bluetooth device. This way of connecting the device and the application reduces the possibility of errors in data collection, and the measurement process itself is somewhat simpler. Nevertheless, our results indicate good compliance in terms of application use. The problem of the relevance of entered values was overcome by the possibility of doctor–patient communication via the app. In addition, regular control visits secured an objective overview of the regularity of measurements, therapy intake, and the success of BP regulation. Moreover, generic SMS/email messages with tips for risk factor reduction were sent monthly and not more often due to technical limitations of the system we used.Another disadvantage of the study is that patients were followed for 6 months, which is enough to assess the success of the application of new technologies but not to assess the sustainability of this method of monitoring BP in practice. Further research in this direction is planned for the future.This study successfully showed that home BP telemonitoring has a significant impact on lowering SBP and DBP in patients with unregulated HTA. It also showed positive responses and acceptance of telemonitoring of BP by patients. This may represent a foundation for further research on the implementation of this approach in primary practice in Serbia.


We conducted a systematic review and meta-analysis of the cardiovascular, kidney, and safety outcomes of sodium-glucose cotransporter 2 inhibitors (SGLT2i) among patients with diabetic kidney disease (DKD).We searched electronic databases for major randomized placebo-controlled clinical trials published up to September 30, 2021 and reporting on cardiovascular and kidney outcomes of SGLT2i in patients with DKD. DKD was defined as chronic kidney disease in individuals with type 2 diabetes. Random-effects meta-analysis models were used to estimate pooled hazard ratios (HR) and 95% confidence intervals (CI) for clinical outcomes including major adverse cardiovascular events , kidney composite outcomes , hospitalizations for heart failure (HHF), deaths and safety events .2). The relative risks (95% CI) for adverse events were 3.89 (1.42–10.62) and 2.50 (1.32–4.72) for mycotic infections in men and women respectively, 3.54 (0.82–15.39) for DKA, and 1.29 (1.13–1.48) for volume depletion.A total of 26,106 participants with DKD from 8 large-scale trials were included . SGLT2i were associated with reduced risks of MACE , kidney composite outcomes , HHF , cardiovascular death , MI , stroke , and all-cause death , with no significant heterogeneity detected. Similar results were observed among participants with reduced estimated glomerular filtration rate (eGFR: < 60 mL/min/1.73mAmong adults with DKD, SGLT2i were associated with reduced risks of MACE, kidney outcomes, HHF, and death. With a few exceptions of more clear safety signals, we found overall limited data on the associations between SGLT2i and safety outcomes. More research is needed on the safety profile of SGLT2i in this population.The online version contains supplementary material available at 10.1186/s12933-022-01476-x. Type 2 diabetes (T2D) remains highly common in the United States . Nearly Sodium-glucose cotransporter 2 inhibitors (SGLT2i) have recently emerged as a new class of oral glucose-lowering agents with pleiotropic effects including reduction in cardiovascular and kidney outcomes among patients with T2D –11. SGLTThis systematic review and meta-analysis was registered with PROSPERO (CRD42021282869) and repo2 and/or urine albumin-to-creatinine ratio (UACR) ≥ 30 mg/g. Two reviewers (ADK and MZ) independently identified articles and sequentially screened them for inclusion, starting with titles and abstracts, then full-text review. Additionally, reference lists of identified studies were manually scanned, and citing references screened through the ISI Web of Knowledge database, for possible additional eligible studies.We conducted a comprehensive search of PubMed and Embase for major randomized, placebo-controlled clinical trials of SGLT2i published up to September 30, 2021 and reporting on cardiovascular and kidney outcomes as well as adverse events among adults with DKD. The SGLT2i included empagliflozin, dapagliflozin, canagliflozin, ertugliflozin, and sotagliflozin. Sotagliflozin is an SGLT2i that also inhibits gastrointestinal sodium glucose cotransporter 1 receptors in the gastrointestinal tract. DKD was defined as the presence of CKD in individuals with T2D, defined as estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 mStudies were considered eligible if they met all of the following criteria: (1) the study design was a randomized controlled trial (RCT) of cardiovascular or kidney outcomes of SGLT2i; (2) the study reported on cardiovascular, kidney, or adverse events of SGLT2i among individuals with DKD; (3) the hazard ratio (HR) or relative risk (RR) and its corresponding 95% confidence interval (CI) or enough data to calculate them were reported. We excluded studies in people without diabetes or CKD. Two investigators (ADK and MZ) independently abstracted data from eligible studies and conducted quality assessment. Data were extracted from the primary trials’ reports as well as from secondary data analyses where available , 19–25. The efficacy outcomes assessed in this meta-analysis include: 1) major adverse cardiovascular events (MACE) defined as a composite of nonfatal myocardial infarction (MI), nonfatal stroke, or cardiovascular death; (2) hospitalization for HF (HHF); (3) cardiovascular death; (4) fatal and nonfatal MI; (5) fatal and nonfatal stroke; (6) all‐cause mortality; and (7) kidney composite outcomes. The kidney composite outcome definitions varied across trials , volume depletion, amputations, fractures, urinary tract infections (UTI), acute kidney injury (AKI), and hyperkalemia.I2 statistics [For this meta-analysis, we used published data; and not individual participant-level data. For each outcome, we sought to identify HRs and 95%CIs of the effects of SGLT2i in participants with DKD from individual studies. As HRs were not always available for adverse events, we used in order of preference HRs, then rate ratios or risk ratios to maximize the use of trial‐level data. The pooled effect estimates and associated 95% CI were computed using random-effects meta-analysis models. The random-effects model is the most conservative approach as it makes allowances for within and between-study heterogeneity . For eacatistics , 29. Pubatistics . FurtherP-value was deemed statistically significant. All analyses were performed using Stata software .A two-sided The study selection process is summarized in Additional file 1C ranged from 7.1 to 8.3%. The proportion of patients with a history of established CVD at baseline varied from 37.4 to 100%.We included data from 26,106 participants, with a median follow-up of 2.5 years (interquartile range: 1.9–3.1). Across the 8 trials, the mean age of participants ranged from 61.8 to 69 years, the proportion of women from 29.7 to 41.8%; White individuals made up the majority of participants (53.2–93.2%). The mean HbAI2 = 33.8%, P for heterogeneity = 0.183, n = 21,913, Fig. I2 = 0.0%, P for heterogeneity = 0.844, n = 22,346), cardiovascular death , fatal and nonfatal MI , fatal and nonfatal stroke .Meta-analyses for the effect of SGLT2i on clinical outcomes are summarized in Table I2 = 0.0%, P for heterogeneity = 0.949, n = 21,195, Fig. A total of 1,197 participants experienced a kidney composite outcome. SGLT2i were associated with a 34% reduction in the risk of a kidney composite outcome  regardless of albuminuria status , SGLT2i remained associated with lower risks of MACE , HHF , cardiovascular death , nonfatal and fatal MI , nonfatal and fatal stroke , and kidney composite outcomes . There was a trend towards a reduction in all-cause mortality, though confidence intervals included the null hypothesis value .The meta-analyses of the effects of SGLT2i on clinical outcomes by baseline eGFR are displayed in Table I2 = 0.0%, P for heterogeneity = 0.444, n = 9,216), HHF , cardiovascular death , all-cause mortality , and kidney composite outcomes . There was a trend towards a reduction in MI  and stroke , although confidence intervals included the null value. Among participants with moderately increased albuminuria, the HRs were 0.92 (95% CI 0.79–1.07) for MACE, 0.60 (95% CI 0.47–0.77) for HHF, 0.70 (95% CI 0.35–1.38) for cardiovascular death, 1.01 (95% CI 0.77–1.32) for MI, 1.06 (95% CI 0.76–1.48) for stroke, 0.78 (95% CI 0.47–1.28) for all-cause mortality, and 0.98 (95% CI 0.62–1.57) for kidney composite outcomes  extends to people with DKD. These findings corroborate results from a prior meta-analysis of four SGLT2i trials which found that SGLT2i reduced the MACE composite irrespective of baseline atherosclerotic CVD, HF, or kidney function status . LikewisIn our meta-analysis, SGLT2i provided the highest risk reduction for kidney composite outcomes and HHF compared to placebo. We found a 34% reduction in the risk of kidney composite outcomes. This finding was consistent across kidney function levels and in patients with moderate or severe albuminuria. A possible mechanism for this association relates to the role of SGLT2i in reducing the risk of sustained eGFR decline or ESKD . Our finOur observation of a beneficial effect of SGLT2i on HHF in patients with DKD is consistent with prior published meta-analyses of individuals with T2D , 34. TheWe found a protective effect of SGLT2i on the risk of stroke in patients with DKD. This finding confirms that from two recent meta-analyses , 33, altWith respect to safety outcomes, our review identified a knowledge gap as most trials were not powered to assess adverse effects of SGLT2i in the subgroup of patients with DKD, neither did they report safety information in this population. Additionally, data from the safety outcomes in this review were derived from a total of 2 to 4 studies. Consistent with prior reports, we found that the most commonly reported side effects of SGLT2i also extend to patients with DKD , 7, 11. The public health and research implications of our findings are manifold. Our findings confirm the relevance of SGLT2i in the therapeutic scheme of patients with DKD. As SGLT2i prescription rates for patients with DKD are increasing , our fin2; therefore, our findings may not be generalizable to individuals with advanced DKD. Second, the included SGLT2i trials did not always report the effect estimates for all the relevant outcomes specifically among participants with DKD ; and we did not have access to individual participant data that could have been used to calculate the effect estimates for the unreported outcomes or perform meta-regression analyses. Likewise, the individual trials did not report data specifically in the subset of participants with albuminuria and eGFR ≥ 60 mL/min/1.73 m2; thus, we could not evaluate the effects of SGLT2i on outcomes in this subgroup. Third, the limited number of available studies limited our ability to perform meaningful subgroup analyses such as analyses by age, gender, or race/ethnicity, for example. Fourth, we defined DKD as the presence of CKD in individuals with T2D and the individual studies did not exclude causes of CKD other than T2D among the participants. Finally, the definition of the kidney composite outcomes was not consistent across the trials. These limitations notwithstanding, our review has several strengths. First, this is a comprehensive review of all information available to date on the efficacy and safety outcomes of SGLT2i in patients with DKD. Second, we used random-effects meta-analysis models, a more conservative approach which makes less assumptions about the effect of SGLT2i across included trials. Third, only placebo-controlled RCTs with low risk of bias were included. Fourth, we appraised the quality of studies using a standard quality assessment tool. Finally, our review is quantitative and highlights the magnitude of the associations between SGLT2i and various clinical outcomes.The limitations of this study should be acknowledged. First, most of the trials included in this meta-analysis excluded participants with eGFR less than 30 mL/min/1.73 mIn conclusion, our findings confirm the beneficial effects of the SGLT2i class on cardiovascular and kidney outcomes, as well as mortality in patients with T2D and DKD. Our data support the current recommendations to prioritize the prescriptions of SGLT2i in patients with DKD, independent of glycemic control . FurtherAdditional file 1: Fig S1. Selection of studies for inclusion in the meta-analysis. Fig S2. Effects of SGLT2 Inhibitors on fatal and nonfatal stroke among individuals with Diabetic Kidney disease. Table S1. Definition of kidney composite outcomes across included trials. Table S2. Characteristics of Clinical Trials Included in the Meta-analysis. Table S3. Risk of Bias Assessment.


These sequences were further optimized using in vivo assays of the attenuation of acute kidney injury in a rat-model of unilateral clamp ischemic reperfusion. This process uses a Structure Variance Analysis algorithm (SVA) to identify structure/activity relationships. One member of this family, THR-184, is an agonist of BMP signaling and a potent antagonist of TGFβ signaling. This small peptide mimetic inhibits inflammation, apoptosis, fibrosis and reverses epithelial to mesenchymal transition (EMT) by regulating multiple signaling pathways involved in the cellular injury of multiple organs. Its effects have been shown to control Acute Kidney Injury (AKI). THR-184 has progressed through phase I and II clinical trials for the prevention of Cardio-Vascular Surgery (CVS) associated AKI. This work provides a roadmap for the development of other growth factor mimetics and demonstrates how we might harness their therapeutic potential.Growth Factors have been evaluated as therapeutic targets for the treatment of a broad spectrum of diseases. Because they are proteins with pleiotropic effects, the quest to harness their beneficial effects has presented challenges. Most Growth Factors operate at the extracellular-receptor level and have natural feedback mechanisms that modulate their effects. As proteins, they are difficult and expensive to manufacture. Frequently proteins must be administered parenterally, may invoke an immune response, and may be neutralized by naturally occurring inhibitors. To circumvent these limitations, we have undertaken an effort to develop mimetics for the Bone Morphogenetic Protein (BMP) signaling pathway effects that incorporate the beneficial effects, eliminate the deleterious effects, and thereby create effective drug-like compounds.To this end, we have designed and tested a family of small peptide BMP mimetics. The design used the three-dimensional structure of BMP-7 to identify likely active surface regions. Lead sequences were then optimized based on  Homeostasis, both during development and in the adult, is achieved through a careful balance of signaling pathways which transmit signals through ligands circulating through the body and then through cell surface receptors and their downstream signaling pathways. Most human diseases arise from either inappropriate activation or inhibition of these signaling pathways. One of the ubiquitous regulators of physiological, and cellular processes is the transforming growth factor β (TGF-β) superfamily. The TGF-β superfamily contains more than 30 structurally related polypeptide growth factors including TGF-βs, bone morphogenetic proteins (BMPs), activins , inhibins , and growth differentiation factors including myostatin and nodal . The TGFOur hypothesis is that we can develop small peptide mimetics of BMP that are effective against multiple diseases, for example, Acute Kidney Injury (AKI), LV dysfunction in aortic stenosis, Diabetes, Diabetic nephropathy, Idiopathic Pulmonary Fibrosis (IPF) and Pulmonary Arterial Hypertension (PAH).To test this hypothesis, we embarked on a project wherein we designed and developed peptide mimetics of Bone Morphogenetic Protein-7 (BMP-7) for the treatment of Acute Kidney Injury (AKI). There are several reasons for the choice of BMP-7. In general, repair and regeneration of a tissue reflect many aspects of its embryologic development. BMP-7 is an important developmental factor for soft tissues such as the kidney. The generation of BMP-7-deficient mice has provided vital evidence that this growth factor regulates many morphogenetic processes including, but not limited to, skeletal development. BMP-7 acts as an early inducer of glomeruli formation and is required for skeletal patterning. Not only is BMP-7 involved in the differentiation of several organs during development but also suggests that mutations in the BMP seven gene itself, or in the genetic pathway, could be responsible for several human genetic diseases in which glomerulus formation is impaired . BMP-7 aHere, we have taken a novel approach to the design of BMP-7 mimetics. In this approach, peptide mimetics are designed to target the control of various pathological processes such as inflammation, apoptosis, EMT and fibrosis that are critically involved in acute and chronic diseases. Also, considered in the design is, the elimination of the bone-inducing property of BMP which is an adverse event in soft tissues. Ischemia and reperfusion injury often results in AKI, a pernicious condition that when extensive enough, leads to the loss of renal function and increased mortality. Furthermore, if AKI remains untreated it can progress into chronic kidney disease (CKD) which can lead to a higher morbidity and mortality . A set oTHR-184 is an optimized BMP-7 mimetic that we chose to test for safety and efficacy in pre-clinical and clinical Phase I and II trials. The phase II clinical trial (NCT01830920) evaluated THR-184 for its safety and efficacy in preventing AKI in ‘at risk’ patients undergoing cardio-vascular surgery that employs a cardio-pulmonary bypass pump (CPB). The recruitment of these patients was practical because CVS-CPB is a common surgical procedure. Also, it is an elective procedure performed in a controlled environment where protocols can be more easily managed.The starting point for the peptide mimetics considered herein were structural analogs of small regions of BMP-7 that we identified as likely receptor binding sites. The first criterion is that they have to be accessible for receptor binding. Once the three-dimensional structure of BMP-7 had been determined, the solvent-accessible regions were identified using the “rolling water probe” method of Lee and Richards . It shouin vitro activity and receptor binding assays. Once one or more lead peptides were identified, the same assays are used to optimize the sequence for desired activities. Binding assays measured the ability of the peptides to compete with BMP-7 in binding to cloned extracellular domains of ALKs 2, 3 and 6 as well as of BMPR-II. For cell-based in vitro assays, the HK2 immortalized human kidney cell line was used to look at the proinflammatory response with and without peptides of interest compared to BMP-7. In vitro assays were also used to look at intracellular signaling and actions such as the ability of candidate peptides, relative to that of BMP-7, to stimulate the phosphorylation of Smad-1,5,8, to block apoptosis, and to control the cell cycle. Of particular interest was the relative ability of the peptides to block the epithelial-to-mesenchymal transition (EMT) which is induced by TGF-beta signaling and is key to fibrosis development.From this point forward the process for selection and optimization of these mimetics was based not on any assumed structural theory of receptor binding, but via their observed activity using biologically relevant per se. This profile was then used to score the peptide sequences and to predict other likely active sequences. The optimization process proceeded as cycles of synthesizing new candidates, assaying them, and using the new data to update the structure/activity profile, etc. Once leads had been optimized, they were further evaluated in iv vivo animal models for kidney injury such as the Unilateral Clamp Model for ischemia/reperfusion injury. This is the optimization process used to derive THR-184 from early leads, such as THR-123.The peptide optimization process employed a peptide model in which each residue position is represented by a binary vector wherein each bit represents the presence 1) or absence (-1) of a physical-chemical feature such as charge, polarity, size, secondary structure propensity, etc. Based on the results from the above assays each candidate sequence is classified as either active 1) or inactive (-1). Each bit value in each sequence is multiplied by the activity classification value to create a preference value for each bit in each sequence. A statistical method, such as Bayesian analysis  was emplOne important area for mimetic development is the TGFβ/BMP pathways (serine/threonine kinase receptor pathways). In addition to having important and ancient roles in all stages of development, these pathways have significant roles in the adult. The BMP pathways maintain homeostasis of epithelial and endothelial cells/tissues , while tThe TGF beta/BMP pathways are mediated by their specific Type I and Type II receptors. Upon ligand binding, two type I and two type II receptors form an oligomeric receptor complex . BMP binThe selective activation of these pathways relies on the selective binding and activation of these receptors. Selective activation can thus target the desired effects and eliminate the unwanted effects.BMPs play important roles in regulating numerous physiological processes including cell proliferation, differentiation, apoptosis, and specification of developmental fate during embryogenesis and in adult tissues . AberratGenetic deletion of BMP-7 in mice leads to severe impairment of kidney development, resulting in perinatal death . GeneticIn the adult, the primary biological role of BMP-7 is to maintain epithelial/endothelial cell homeostasis. BMP-7 also inhibits the induction of inflammatory cytokine expression , attenuaThere have been a number of publications describing efforts to design and test BMP mimetics see . Most ofin vivo but did not induce the side effects observed with BMP-2 , palliated structural damage (hypertrophy and fibrosis) and alleviated left ventricular (LV) dysfunction in a thoracic aortic constriction animal model  endocrine cells with a capacity for rapid reversal of diabetes in vivo . This woal model .A mimetic peptide of BMP-7 was designed and optimized using the process outlined above. The sequences of the approximately 30 members of the human BMP subfamily of the TGF-beta superfamily have several strictly conserved residues throughout the sequences, which suggests a high degree of structural homology across the subgroup. The x-ray structure of BMP-7, which retains a high degree of three-dimensional structural homology with other superfamily members , was usein vitro assay activity, indicating half maximal effective concentrations (EC50) of the lead peptide variants, were used for structure/activity analysis to arrive at THR-184 as the prime clinical candidate.The receptor binding and The THR-184 and THR-123 are members of the BMP-7 mimetic family. The family of BMP mimetics are agonists that signal through the activin-like kinase three receptor (ALK3). The BMP-7 mimetics are effective in initiating the phosphorylation of Smads 1, 5 and 8, blocking apoptosis, and have the ability to suppress renal tubule cell inflammation. Also, the mimetic (THR-123) failed to induce ectopic bone formation in a rat implant assay . PreclinImaging studies of radio-labeled mimetic injected via the tail vein in rats showed distribution primarily to the kidney cortex .As mentioned previously, several lines of evidence indicate that the kidney would be a good target organ for the clinical investigation of a BMP mimetic. The kidney is the major site of BMP-7 synthesis during embryogenesis and in the adult . ExpressA particularly pernicious consequence of ischemic injury is Acute Kidney Injury (AKI). AKI is defined as an abrupt (within hours) decrease in kidney function that encompasses both renal structural damage and loss of kidney function. The term AKI has largely replaced Acute Renal Failure (ARF), reflecting the recognition that smaller decrements in kidney function that do not result in overt organ failure are, nevertheless, of substantial clinical relevance and are associated with increased morbidity and mortality. Recent evidence from both basic medical science and clinical research, is beginning to change our view of AKI from a single-organ failure syndrome to a syndrome where the kidney plays an active role in the progress of multi-organ dysfunctions .Injury induced by ischemia can result in damage to both the tubular and the microvascular compartment. Resolution of vasoconstriction appears effective at reducing injury when administered prophylactically, but not following established injury. Resistance may be due to exacerbated inflammation, which may impart reductions in RBFMortality in patients admitted to the hospital with AKI has been estimated to be 20% in patients not in the ICU and 50% in patients admitted to the ICU. Thus far, AKI has defied attempts to find an effective treatment, let alone a cure . The patAKI tends to occur in the sickest patients, often requiring the most complicated treatments. These patients are typically undergoing major surgery and/or in need of critical care . CurrentThe complexities of AKI constitute the kind of pharmacotherapeutic challenge that suggests a more robust approach, such as the use of growth factors, might be more effective. The results of several such trials are mixed. Exogenous IGF-1, which is beneficial in the recovery after kidney injury in mouse models, failed to demonstrate the efficacy in patients with acute renal failure (ARF) . A doublA successful AKI therapeutic would also likely lead to major improvements in quality of life during aging and to major annual health budget savings. Recent studies have demonstrated a relationship between AKI and the subsequent development of chronic renal insufficiency, a progression to hemodialysis and other severe consequences . Even miThus, there is a large body of evidence indicating that AKI can lead to chronic kidney disease CKD. AKI is thought to be driven by inflammation and apoptosis. The long-term effects of these processes lead to CKD and are known to involve fibrosis.The current standards for the diagnosis of AKI rely on the loss of functional markers, such as serum creatinine-based estimates of GFR, but such functional markers do not accurately reflect the degree of actual renal injury. Ultimately, an AKI incident that escapes detection could lead to the development of CKD for which hemodialysis is a maintenance treatment, but not a cure.The incidence of cardio-vascular disease requiring surgical treatment is high and often leads to the development of perioperative AKI. The incidence of AKI during and after cardio-vascular surgery in which a cardiopulmonary bypass pump (CVS-CPB) is used , or thatiData Research estimated that there were 340,000 Coronary Artery Bypass Graft Surgery (CABG) procedures done in the US in 2017, and over 900,000 cardiac surgeries performed each year prior to 2018. Approximately 84.2% of these surgeries were performed with the use of cardiopulmonary bypass . CABG prThe choice of CVS-AKI for the Phase two clinical trial was determined by the sizeable patient population having CVS-CPB surgery and an unmet need for a way to control the morbidity and mortality due to perioperative AKI. The primary factor of concern with this model, however, is that serious preoperative comorbidity such as CKD and diabetes, while adding to the incidence of AKI, also renders the trial results more difficult to interpret.The primary functional marker for AKI is the glomerular filtration rate (GFR). While a drop in GFR is a clear sign of nephrological problems, a normal GFR is no guarantee of kidney health. This is because the kidney has excess clearance capacity that masks underlying renal injury. It has been estimated that an individual needs only 10% of their normal kidney filtration capacity to have adequate function.Added to the fundamental limitations of GFR as a measure of injury, the primary surrogate marker for estimating GFR (eGFR) is the level of creatinine in blood serum (sCr) and urine. sCr is a GFR marker that is a product of muscle secreted creatinine in blood serum, which is removed by clearance through the kidney nephron. A steady state is achieved when the rate of creatinine production equals the rate of creatinine clearance. A rise in sCr is, therefore, the combined result of a decrease in the rate of renal clearance and an increase in the rate of Cr production due to metabolic abnormalities or high muscle mass. Determining the degree to which Cr production is a factor is difficult. Consequently, sCr is a noisy surrogate marker of kidney function, let alone kidney injury.Furthermore, 20–40% of the creatinine found in urine from a normally functioning kidney, avoids filtration through the glomerulus by being secreted by the renal tubules and reabsorbed by the distal tubules. This process, referred to as creatinine excretion, becomes more prevalent when there is injury to the proximal tubules. It masks issues such as blockage in the nephron’s Loop of Henley due to cells sluffed off because of injury. Thus, Cr-based eGFR is a poor marker for renal injury in that it can overestimate the true GFR.There have been many different attempts to prevent AKI after CVS that target single pathways. Observational studies using calcium channel blockers , Bergma, Colson failed tThus, intensive investigations of AKI reflect the fact that none of these therapeutic strategies could regulate the multiple pathways involved in inflammation, fibrosis, mitochondrial function, apoptosis, oxidative stress, and hemodynamics while simultaneously promoting regeneration. Details have been well described in recent reviews . There iA reliable ischemia-reperfusion animal model for testing the protective and therapeutic power of BMP mimetics proved to be the Unilateral Clamp Ischemic Reperfusion rat model developed by Bruce Molitoris . This mo50 of ∼10–30 µg/kg, with maximal efficacy (65% reduction in serum creatinine levels) measured with a 1 mg/kg dose. That is a ∼100-fold ED50 shift toward greater potency from the bolus to the infusion.In this rat model THR-184 produced a dose-dependent reduction in serum creatinine levels with an ED50 ∼10 μg/kg. Longer infusion times (4 and 24 h) provided no additional efficacy compared to the 1 h infusion. In a pre-ischemic injury model, the same reduction in sCr at 24 h was obtained via slow infusion using ∼30x less THR-184 than was required via bolus injection , the drug (THR-184) was administered as slow intravenous infusions in a total of 40 adult healthy male and female volunteers. The study drug or placebo was administered once on the morning after a 10-h overnight fast. The solution was administered by slow injection via an indwelling catheter, at an infusion rate of 1 ml/min over 60 min. Five dose levels were studied: 0.3 mg/kg, 1 mg/kg, 3 mg/kg, 6 mg/kg and 10 mg/kg. Adverse events were recorded continuously during the study. There were no serious adverse events observed and the most frequently observed adverse event was headache which occurred equally in the placebo and THR-184 treated subjects. No significant adverse events or deaths were reported during this study. No adverse events required the use of medications. No significant abnormal laboratory values, vital signs, ECG’s, physical examinations, or neurological examinations were observed in any subject.In the second study, THR-P-428 (MAD), THR-184 was administered as a slow intravenous infusion in a total of 24 adult healthy male and female volunteers, once daily over five consecutive days. THR-184 or the placebo was administered on the morning after a 10-h overnight fast. The solution was administered by slow injection via an indwelling catheter, at an infusion rate of 1 ml/min over 60 min. Three dose levels were studied: 0.3 mg/kg, 1 mg/kg, and 3 mg/kg. Adverse events were recorded continuously during the study. There were no serious adverse events observed and the most frequently observed adverse event was somnolence which occurred equally in the placebo and THR-184 treated subjects. No significant adverse events or deaths were reported during this study. No adverse events required the use of medications. No significant abnormal laboratory values, vital signs, ECG’s, physical examinations, or neurological examinations were observed in any subject.In summary, this Phase 1 Trial of THR-184, as described in “Perioperative THR-184 and AKI after Cardiac Surgery” , found nThe objective of the Phase II clinical trial, NCT01830920, , was to 50 by a factor of 30 when the compound THR-184 was administered prior to renal injury and a factor of 100 when it was administered immediately after the injury  and Arear Under the Curve (AUC). The magnitude of this variability is on the order of the measured serum levels themselves, which confound any measured beneficial effects in the kidney. As mentioned previously, in animal studies, it has been observed that changing from a bolus injection to an infusion decreased the EDe injury . The serThree factors - 1) the primary effect on tubular secretion, 2) short half-life of the compound in plasma and 3) the large variability of C Max and AUC - are certainly confounding factors that make it difficult to see the beneficial effect measured by serum creatinine in patients with AKI. A longer infusion or co-administration with an ACE inhibitor could dramatically increase the beneficial effect in the clinical trial. Taken together, these results suggest that changes to the protocol with a higher sample size per cohort could produce a statistically significant effect of THR 184 on the incidence of AKI in patients undergoing cardio-vascular surgery.We believe that our data is best understood when analyzed by a valid alternative method: comparison between the groups can be based on the proportion of group members (%) yields a more accurate view of the clinical trial outcome because of the inherent high variability of creatinine values observed, and the small sample size in each cohort. In a recent phase two study (NCT01286727) to evaluate the efficacy and safety of HGF/SF mimetic (ANG-3777) for improving kidney function in patients at high risk for delayed graft function after kidney transplantation , Bromber2, responded well when treated with THR-184 as indicated by an 11–17% reduction in AKI. Patients in this subgroup that also received an ACE inhibitor post-surgery had an even greater reduction (25 vs. 34%) (There were 40 patients (out of 104) that entered the high dose arm of the trial with pre-existing CKD . Despitevs. 34%) . In the vs. 34%) . There wHowever, the results based on the KDIGO endpoint did not show a statistically significant difference between the AKI and placebo groups. It has been pointed out that when the outcome variability is high and the sample size is small, a valid alternate way to compare the groups can be based on the proportion of group members being classified in an outcome category. This is a better way than relying on level of significance for comparison of the groups .It is noteworthy that the compound showed reduced incidence of AKI in the population with pre-existing chronic kidney disease. The reduction of AKI was even more dramatic in those patients with pre-existing chronic kidney disease that received concomitant treatment with an ACE inhibitor .Dose definitions (One Pre/Three Post surgery): Arm 2 - 0.02-mg/kg/0.02-mg/kg; Arm 3 - 0.12-mg/kg/o. o2-mg/kg; Arm 4 - 0.46-mg/kg/0.02-mg/kg; Arm 5 - 0.46-mg/kg/0.46-mg/kg. KDIGO criteria for diagnosing AKI: Increase in SCr by ≥ 0.3 mg/dl (≥26.5 μmol/L) within 48 h OR Increase in SCr to ≥1.5 times baseline, which is known or presumed to have occurred within the prior 7 days OR Urine volume <0.5 ml/kg/h for 6 h. KDIGO Cr: The full KDIGO criteria minus the Urine volume criterion. sCr >0.3: Increase in sCr by ≥ 0.3 mg/dl (≥26.5 μmol/L) within 48 h sCr >50%: Increase in serum creatinine >50% within 7 days. SAE: number of Serious Adverse Events. Stage 1 AKI: sCr 1.5 - 1.9 times baseline OR sCr≥0.3 mg/dl (≥26.5 μmol/L) increase, Urine output <0.5 ml/kg/hr for 6–12 h.• AKI after cardiac surgery is pathophysiologically multifactored and complex, thus simple strategies targeting a single pathophysiological factor and/or single pathway will most likely fail.• End points based on GFR, and especially sCr-based eGFR, will show little effect except in those patients entering the trial with low renal capacity.• eGFR is a non-linear and low sensitivity indicator of underlying acute renal injury that, left untreated, can lead to loss of renal capacity and lead to the development of CKD.• When the clinical outcome variability is high, and renal injury varies from mild to severe, the patient pool participating in the dosed arm vs. placebo should be sufficiently large.• Finally, most clinical data come from trials conducted on low-risk patient populations that have a lower prevalence of AKI.For the reasons outlined above, AKI is a difficult disease to treat. Clinical trials are confounded by several complexities which are hard to control in a randomized clinical trial. Cardio-vascular surgery has many confounding variables that can affect the occurrence of AKI. These include time on cardiopulmonary bypass, hypotension, anesthetic agents, pressors, inotropes, diuretic use, intravascular volume shifts, and blood loss. Currently, there is no pharmacological intervention that has consistently been associated with renal protection see . This faBiomarkers such as KIM1 and NGAL, although not yet approved as clinical surrogate endpoints, have the advantage of being early markers of renal injury because their concentration rises within a few hours after injury . The avaAKI is increasingly recognized as a major risk factor for progression to CKD after cardiac surgery . MultiplPatient population definition is critical in situations where functional endpoint markers can be insensitive to the targeted clinical condition. Most clinical data come from trials conducted on low-risk patient populations. In the case of this trial, where the functional marker, eGFR, is sensitive to the underlying injury only after there is a significant loss of renal capacity, clinical significance is much easier to achieve when the patient pool is limited to those with pre-existing low renal capacity.Clinical trial designs are problematic where the injury condition does not affect functional markers in the near term but, if left untreated, does have ultimate long-term implications for function. Trials having long term endpoints require long term follow-up, but the per-protocol patient population decays with time due to the inevitable follow-up protocol violations. This kind of long-term trial will be very large, long, and expensive.In the report “Perioperative THR-184 and AKI after Cardiac Surgery” on the results of the Phase two clinical trial , the triThere were two important findings in this publication. The first concerns the safety of the compound, THR-184. THR-184 at all doses tested was well tolerated by the patients and was shown to have no adverse effects in treated patients compared to the Placebo. The second finding concerns the efficacy of THR-184 on AKI after cardiac surgery in high-risk patients. The study pointed out that “a higher postoperative THR-184 dose arm showed lower incidence of post-surgery AKI relative to placebo; the difference, although not statistically different, was more pronounced among patients with preexisting CKD in the per protocol dataset” . This isWhile the phase two trial did not show statistically significant effects, it did provide data that points to the next steps for clinical development. We understand Phase two Clinical Trials as defined by the Food and Drug Administration:“In Phase two studies, researchers administer the drug to a group of patients with the disease or condition for which the drug is being developed. Typically involving a few hundred patients, these studies are not large enough to show whether the drug will be beneficial.https://www.fda.gov/patients/drug-development-process/step-3-clinical-research).“Instead, Phase two studies provide researchers with additional safety data. Researchers use these data to refine research questions, develop research methods, and design new Phase 3 research protocols”  is similar to that in other recently completed randomized clinical trials” . This, wIn Because of the afore-mentioned correlation between incidences of AKI and ultimate development of CKD , it is iBecause AKI can exist without detection via functional markers in patients that have little or no pre-surgery CKD, markers of cellular injury are important in an AKI study for two reasons. First, AKI events contribute the eventual development of CKD. Second, AKI that is not detected by functional markers still puts stress on the remaining nephrons, which can lead to a spreading of the AKI. Functional detection of this spiraling injury may come too late in the process to be halted therapeutically leading to patient death.Given the excess capacity issue with using functional markers of GFR to diagnose AKI, discussed above, these biomarkers could be more sensitive to the condition in a patient population having pre-existing CKD.Given the significance of undiagnosed AKI, injury markers such as KIM-1 and NGAL could improve the clinical outcome of AKI trials. The correlation between therapeutic treatment and the levels and duration of injury markers will likely give a better assessment of mimetic efficacy, even when functional markers are negative.Protease degradation of drug candidates can shorten their in-plasma half-life to the point that therapeutic exposure is severely compromised resulting in loss of efficacy. We have observed that the serum half-life of THR 184 was 5 minutes, which increased to 60 min when the compound was administered with an ACE inhibitor, suggesting that an ACEi could improve the bioavailability of the BMP mimetic. This result , taken wThe beneficial pleiotropic effects of ACE inhibitors go far beyond blood pressure reduction . It is nin vitro and in vivo assay data and algorithms that identify structure-activity relationships. They are optimized to selectively possess beneficial effects and eliminate the unwanted deleterious effects of naturally occurring full-length BMP. They are simple and economical to synthesize.Growth factors and cytokines regulate complex signaling networks. Through their multiple interactions they initiate repair and alter the growth, differentiation, and metabolism of target cells. As therapeutics, growth factors have presented challenges because they are proteins with pleiotropic effects, are difficult and expensive to manufacture, and frequently require parenteral administration. We have undertaken an effort to develop compounds that mimic the beneficial effects of the naturally occurring ligands/growth factors while having more drug-like properties and the potential to be orally administered. We have chosen to focus on the BMP family of growth factors. There are at least 30 different, naturally occurring members in the human BMP family. All of them possess structural homology and diverse activities. They act through an array of specific receptors that stimulate multiple signaling pathways. They regulate the downstream pathways to effect homeostasis and the repair of specific tissues and organs. Newly developed BMP mimetics can use the pleiotropic effects of the BMPs to advantage by selectively activating the BMP receptors. These properties make the BMP mimetic system a useful model for the development of other growth factor mimetics. The BMP mimetics discussed here are novel peptide agonists of the BMP signaling pathways. They are relatively small and are designed using The primary biological role of BMP-7 is to maintain epithelial/endothelial cell homeostasis. As a proof of concept, we designed a family of BMP mimetics that binds specifically to the kidney receptors. These mimetics initiate a signaling cascade that decreases renal epithelial inflammation and apoptosis, reduces tubular damage, and augments renal regeneration. These effects produce an attenuation of renal dysfunction. One member of the family of BMP-7 mimetics, THR-184, has progressed through Phase 1 and Phase 2 clinical trials. The goal of the phase two proof-of-concept study was to provide guidance for future work by assessing the dosing, safety, and efficacy of THR-184 in patients at high risk of AKI induced by cardiac surgery involving cardiopulmonary bypass. The compound was shown to be safe and well tolerated. The results of this trial provide a roadmap for future trials to develop treatments for renal injury.The results based on a KDIGO endpoint did not show a statistically significant difference between THR-184 treated and placebo groups of AKI, but there was a noticeable reduction in the incidence of AKI in the patient subgroup with pre-existing CKD treated with the highest dose of THR-184. The results also showed an even higher reduction in AKI patients with mild chronic renal insufficiency who were also treated with an angiotensin-converting enzyme inhibitor (ACE inhibitor). This suggests that patients with chronic renal insufficiency would be a better choice for a clinical trial.There are other markers to consider, such as Kim-1 and NGAL, that are more sensitive markers for the detection of renal injury. The use of these in AKI clinical trials could provide better diagnosis of renal injury and help forecast the long-term effects.We believe that the development of growth factor mimetics, and in particular the BMP-7 mimetics, offers great promise for the treatment of acute kidney injury and other serious debilitating diseases. This novel approach may point the way toward the development of therapeutics that capture the potential inherent in growth factors. The ability of the BMP-7 mimetics to block apoptosis, the inflammatory response to injury, reverse fibrosis and regulate differentiation in soft tissues could provide therapeutics with broad applications to the treatment of acute and chronic diseases. The potential for regulating cellular differentiation and reversing EMT could open the door for therapeutics that regenerate the damaged tissue in failing organs.Naturally occurring growth factors are critical agents that control a myriad of biological processes. The design of growth factor mimetics holds the potential for the development of therapeutics that could repair and regenerate injured tissue and control cancer. Growth factors themselves have several barriers to their use as therapeutics. This Hypothesis/Theory articulates methods by which the power of the biological processes controlled by growth factors could be harnessed to develop therapeutics with drug-like properties. For example, the process of developing BMP mimetics can produce compounds that incorporate the beneficial properties and eliminate the deleterious effects of the naturally occurring growth factors. This process of designing small peptide mimetics with drug like properties activating the BMP-7 signaling pathways provides a roadmap for the design and the clinical development of many therapeutics. These mimetics could treat, and potentially cure, a myriad of diseases by repairing and regenerating injured tissues. The magnitude of this impact would be momentous and represents a new paradigm in drug development.


The literature on the relationship between kidney and cardiovascular diseases is continuously expanding. Scientists have elucidated many of the neurohormonal and hemodynamic pathways involved in cardiorenal disease. However, little is known about kidney disease in patients with congenital heart disease. Given advances in the medical and surgical care of this highly complex patient population, survival rates have dramatically improved leading to a higher percentage of adults living with congenital heart disease. Accordingly, a noticeable increase in the prevalence of kidney disease is appreciated in these patients. Some of the main risk factors for developing chronic kidney disease in the adult congenital heart disease population include chronic hypoxia, neurohormonal derangements, intraglomerular hemodynamic changes, prior cardiac surgeries from minimally invasive to open heart surgeries with ischemia, and nephrotoxins. Unfortunately, data regarding the prevalence, pathophysiology, and prognosis of chronic kidney disease in the adult congenital heart disease population remain scarce. This has led to a lack of clear recommendations for evaluating and managing kidney disease in these patients. In this review, we discuss contemporary data on kidney disease in adults with congenital heart disease in addition to some of the gaps in knowledge we face. The article highlights the delicate interaction between disease of the heart and kidneys in these patients, and offers the practitioner tools to more effectively manage this vulnerable population. Disruptions of the heart-kidney interrelation fall within the realm of an entity called “cardiorenal syndrome”. The medical literature on cardiorenal syndrome is expanding given its clinical implications on morbidity and mortality.  However,CHD affects around 1% of births per year in the United States.  CHD can Rajpal et al. examined the prevalence and prognosis of albuminuria in 612 ACHD patients.  AlbuminuThese data highlight the high burden of kidney disease in patients with CHD. Significantly, patients with CHD constitute a unique population requiring combined specialized care by surgeons and cardiologists with expertise in this field. Children born with CHD now undergo increasing cardiac interventions leading to a higher survival rate. This may require a trade-off at the expense of decreased kidney function, whether related to the CHD physiology itself or to the multiple interventions to which the patient may be exposed. Understanding the complexities of cardiorenal interaction in this special population could lead to improvement in their management and outcomes. This review will discuss contemporary data related to CKD in patients with CHD and review the complexities of altered renal physiology in CHD. Furthermore, the article will provide a roadmap for developing prevention strategies, monitoring modalities, and ultimately reversing or delaying progression of kidney disease in this special population by ensuring adequate specialized nephrology care.2) have a 5-fold and 3-fold increase in their 6-year mortality rate compared to those with normal (≥90 ml/min/1.73 m2) and mildly reduced GFR (60–89 ml/min/1.73 m2) respectively.  and less efficient ventilation; this association was present only among patients with biventricular physiology but not with Fontan circulation. . The authors also examined 404 adults with CHD who underwent cardiopulmonary exercise testing (CPET) and noted that albuminuria was associated with a significantly lower peak oxygen consumption  and transforming growth factor-β (TGF-β) which are likely responsible for the nonvascular abnormality above.  of clinically relevant CKD, defined as eGFR <60 ml/min/1.73 m2, urine protein-to-creatinine ratio (UPCR) > 0.5 g/g, or urine albumin-to-creatinine-ratio (UACR) > 30 mg/g. The authors also noted a significantly higher incidence of CKD among patients who received palliative compared to corrective heart surgery (44 vs. 13%), and those who received more contrast-enhanced imaging studies (61 vs. 31%). (p = 0.041). .  To bette 0.041). in vivo Tc-99m DTPA measurement of GFR and UACR. Fifty-seven percent of subjects had either measured GFR <90 ml/min/1.73 m2 or an elevated UACR. .  after CHD surgery in children. They have also examined the long-term relationship between CHD surgery in children and the risk of developing CKD. The greatest challenge in collectively summarizing the incidence of AKI and CKD is the heterogeneity in defining AKI and CKD. These studies have used Acute Kidney Injury Network (AKIN), Kidney Disease Improving Global Outcomes (KDIGO) or Pediatric Risk, Injury, Failure, Loss, End-Stage Renal Disease (pRIFLE) classifications for their definitions of AKI which has been largely heterogenous. A meta-analysis performed by Van den Eynde et al. included 61 studies examining cardiac surgery associated AKI in pediatric patients (<18 years old) showed that the pooled estimated incidence of AKI was 34.3% .  Overall, 96.8%). The most  96.8%).  In addit 96.8%). Fuhrman et al. reported that persistent kidney dysfunction on discharge was noted in one third of 195 ACHD patients admitted to cardiac intensive care units who developed AKI. Moreover, the authors reported that all patients who died within the first year after hospital discharge had CKD.  Another 2) or microalbuminuria (UACR >30 mg/g), and hypertension (HTN) (17%) at 5 years follow up. Interestingly, this high prevalence of CKD and HTN was not specifically associated with postoperative AKI. Patients who developed CKD sustained more kidney insults including nephrotoxins and more cardiac surgeries and contrast enhanced studies. (2), 0.9% had proteinuria, 7.6% had α1-microglobinuria, 19.7% had hypertension.  study is one of the largest prospective studies exploring the relationship between AKI and CKD in children undergoing CHD surgery requiring cardiopulmonary bypass. Fifty-seven of 131 children had postoperative AKI. This study demonstrated a high prevalence of CKD (22%), defined as impaired eGFR  creatinine equation without race, in addition to CKD-EPI cystatin C equation and the measurement of UAC. A large prospective cohort study by Opotowsky et al., in 2019 compared creatinine-based eGFR to cystatin C-based eGFR in ACHD patients from the Boston Adult Congenital Heart Disease Biobank. In this population, cystatin C-based eGFR was a significantly better predictor than creatinine-based eGFR for clinical events including all-cause mortality. The poor agreement between creatinine-based and cystatin C-based eGFR was especially notable in patients with Fontan circulation. 2 as compared to 0% of general population. This was more discriminating than eGFR by creatinine where no difference between Fontan patients and the general population was reported. Fontan patients had significantly higher UACR (23.2 vs. 3.6 mg/g), N-acetyl glucosaminidase (NAG) (1.8 vs 1.1 U/g) and KIM-1 concentrations (0.91 vs. 0.33 ng/mg) but no significant difference in urinary neutrophil gelatinase-associated lipocalin (NGAL) concentration compared to normal controls. NAG, KIM-1 and NGAL are few of the novel biomarkers in development. An increased incidence of a composite endpoint for non-elective cardiovascular hospitalization or death was noted among Fontan patients with reduced eGFR by cystatin C, elevated urinary KIM-1 and elevated urinary NAG but not in patients with microalbuminuria.  and significantly lower urinary concentrations of tissue inhibitor of metalloproteinases-2 (TIMP-2) and insulin-like growth factor binding protein 7 (IGFBP7). These biomarkers could potentially be used to detect early tubular injury before abnormalities in traditional biomarkers of kidney dysfunction are apparent. The identification of more accurate and sensitive diagnostic tools and biomarkers of kidney function is currently a research priority. Further studies that include younger patients with CHD are needed as currently used biomarkers were primarily validated in adult patients. More reliable identification of kidney dysfunction would allow earlier intervention to delay progression of kidney disease such as targeting renin-angiotensin-aldosterone system and properly dosing medications to minimize nephrotoxin exposure. Other benefits of accurate estimation of kidney function include more precise peri-operative risk stratification, and more personalized care including guiding the appropriate use of radiocontrast studies and routine catheterizations, and timely consideration of heart or heart and kidney transplant evaluations.2 and/or if albuminuria is present, we recommend earlier referral to nephrology to assist in the care of these complex patients. Frequency of monitoring of renal function should be performed at the discretion of the nephrologist on a case-by-case basis given anatomical variability of heart defects and the type of heart surgeries performed. We recommend special attention to patients with cyanotic CHD given their significantly increased risk of developing CKD compared to their acyanotic counterparts. We also recommend closer follow up of patients requiring subsequent cardiac surgeries and/or prolonged hospitalizations with particular emphasis on checking eGFR by cystatin C rather than eGFR by creatinine within 3 months of these events.Based on currently available evidence, we recommend assessing eGFR by cystatin C at first visit in addition to obtaining a routine renal panel and UACR. If eGFR by cystatin C is < 60 ml/min/1.73 mUnfortunately, there are no evidence-based recommendations regarding the management of kidney disease in ACHD patients. This is in part due to the paucity of published data, and the small sample sizes of the available ones. More specifically, there are no published guidelines for the selection and frequency of monitoring kidney disease in ACHD patients. Given the higher risk for CKD and its associated adverse outcomes in this population, it would seem prudent to perform regular screening with measurement of eGFR and UACR at every visit, at least annually for stable patients or biannually for patients with severe CHD or unstable kidney function with referral to a nephrologist for more specialized testing and risk-stratification should CKD be present.It is reasonable to speculate that the available and well-studied data demonstrating slowing or prevention of kidney disease progression in the general adult population can also be applied to this specific younger population, including the use of renin-angiotensin-aldosterone system blockade agents (RAAS inhibitors), mineralocorticoid receptor antagonists (MRAs), and sodium-glucose co-transporter 2 (SGLT2) inhibitors. We are currently in need of well-designed randomized trials to assess the benefits of these pharmacologic agents in ACHD patients with CKD. Meanwhile, we recommend that nephrologists assist cardiologists in optimizing volume status and hemodynamics with close monitoring of medication dosing per renal function and optimizing medications perioperatively if needed.With rapidly advancing medical therapies, patients with CHD are living longer allowing previously unseen complications to occur in other organs including the kidneys. Understanding the impact on the kidneys of CHD and its treatments, whether medical or surgical, may allow healthcare providers to prevent the development of kidney disease and/or delay its progression in ACHD patients. Further studies on physiological changes that lead to kidney impairment secondary to CHD and resulting ramifications are severely lacking. Moreover, there are no evidence-based recommendations on how to best manage CKD in ACHD patients.Despite these limitations, recommendations can be made: First, the assessment of kidney function using eGFR by cystatin C testing in this population is warranted due to alterations in physical activity and growth affecting muscle mass leading to altered creatinine unrelated to true GFR. Second, at least annual assessment of UAC is indicated as an early biomarker of CKD while we await research into other novel biomarkers. Third, we need collaboration between nephrology and cardiology to optimize hemodynamics and volume status of these patients, tailor medications appropriately to eGFR and help address risks of contrast and other nephrotoxins. Such recommendations may also encompass a more conservative approach to the use of radiocontrast imaging, cardiac catheterizations, consecutive surgeries, and potentially nephrotoxic medications in patients based on risk-stratification and the degree of kidney disease present.As nephrologists and cardiologists, we should work on further strengthening our partnership to better understand and manage the cardiorenal syndrome in ACHD patients with CKD, which differs from other forms of cardiorenal syndromes. This can be achieved by including CHD on the curriculum of nephrology fellowship training as it is largely absent at present, integrating and expanding the awareness of kidney disease and care in the curriculum of CHD training among cardiology fellows, and by convening multidisciplinary meetings involving nephrologists, cardiologists, pharmacists, and social workers at the local and national level.• Patients with CHD are living longer, allowing previously unseen complications to occur in other organs including the kidneys.• Patients with cyanotic CHD are at a significantly increased risk of developing CKD compared to patients with acyanotic CHD.• Assess eGFR by cystatin C in addition to obtaining a routine renal panel and UACR at first visit. We recommend repeating these tests annually for stable patients or biannually for patients with severe ACHD or unstable kidney function.2 and/or if albuminuria is present, we recommend earlier referral to nephrology for more specialized testing and risk-stratification.• If eGFR by cystatin C is < 60 ml/min/1.73 m• Frequency of monitoring of renal function remains at the discretion of the nephrologist on a case-by-case basis, given anatomical variability of heart defects and the type of heart surgeries performed.• Patients requiring subsequent cardiac surgeries and/or prolonged hospitalizations necessitate closer follow up with checking eGFR by cystatin C rather than eGFR by creatinine within 3 months of these events.• Slowing or preventing kidney disease progression by considering the use of RAAS inhibitors, MRAs, and SGLT2 inhibitors.• We encourage collaboration between nephrology and cardiology to optimize hemodynamics and volume status of these patients, tailor medications appropriately to eGFR and help address risks of contrast and other nephrotoxins.


Mean arterial pressure was < 65 mmHg in 27 patients (29%). After propofol administration, heart rate returned to baseline, and stroke volume index and cardiac index remained stable. After tracheal intubation, there were no clinically important differences compared to baseline in heart rate, stroke volume index, and cardiac index, but arterial pressure and systemic vascular resistance index remained markedly decreased. Anesthetic induction with sufentanil, propofol, and rocuronium reduced arterial pressure and systemic vascular resistance index. Heart rate, stroke volume index, and cardiac index remained stable. Post-induction hypotension therefore appears to result from arterial dilation with reduced systemic vascular resistance rather than venous dilation or reduced myocardial contractility.It remains unclear whether reduced myocardial contractility, venous dilation with decreased venous return, or arterial dilation with reduced systemic vascular resistance contribute most to hypotension after induction of general anesthesia. We sought to assess the relative contribution of various hemodynamic mechanisms to hypotension after induction of general anesthesia with sufentanil, propofol, and rocuronium. In this prospective observational study, we continuously recorded hemodynamic variables during anesthetic induction using a finger-cuff method in 92 non-cardiac surgery patients. After sufentanil administration, there was no clinically important change in arterial pressure, but heart rate increased from baseline by 11  bpm (P < 0.001). After administration of propofol, mean arterial pressure decreased by 23 (17 to 28) mmHg and systemic vascular resistance index decreased by 565 (419 to 712) dyn*s*cmThe online version of this article (10.1007/s10877-021-00653-9) contains supplementary material, which is available to authorized users. Intraoperative hypotension is associated with myocardial injury, acute kidney injury, and death –7. The hAnesthesia is often induced with a combination of sufentanil, propofol, and rocuronium. The neuromuscular blocking agent rocuronium probably has little effect on arterial pressure besides hemodynamic effects related to paralysis itself . HoweverA better understanding of pathophysiologic mechanisms contributing to post-induction hypotension may guide management and reduce hypotension. We therefore sought to assess the relative contribution of various hemodynamic mechanisms to hypotension after induction of general anesthesia with sufentanil, propofol, and rocuronium in adults having non-cardiac surgery.This was a prospective observational study performed in the Department of Anesthesiology, Center of Anesthesiology and Intensive Care Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany between April and August 2018. The study was approved by the Ethics Committee of the Medical Association of Hamburg on January 9, 2018. All patients provided written informed consent. This observational study adheres to the STROBE guidelines.We included adults with American Society of Anesthesiologists (ASA) physical status class I-III scheduled for elective gynecologic, urologic, otolaryngologic, or oral and maxillofacial surgery with general anesthesia and tracheal intubation. Patients were excluded if they had heart failure , atrial fibrillation or other high-grade cardiac arrhythmias, peripheral artery occlusive disease (Fontaine stage II or higher), took beta blockers, had edema of the hands or fingers, had a history or suspicion of difficult airway, or an indication for rapid sequence induction. Patients were also excluded when regional anesthesia was performed before induction of anesthesia.−1), propofol (1.5–2.5 mg*kg−1), and rocuronium (0.5–0.9 mg*kg−1). Patients' tracheas were intubated and mechanical ventilation was initiated with a tidal volume of 6–8 mL*kg−1 at a positive end-expiratory pressure of 5 mbar. After induction, general anesthesia was maintained with either propofol or inhaled sevoflurane.Patients were not premedicated. Preoxygenation was performed with a sealed face mask at a positive end-expiratory pressure of 5 mbar. Anesthesia was induced with sufentanil . The CNAP system was calibrated to brachial arterial pressure obtained from the system's upper-arm cuff. The CNAP system provides continuous arterial pressure values and waveforms. Using pulse wave analysis, the CNAP system also estimates advanced hemodynamic variables including cardiac output and systemic vascular resistance. The CNAP system was validated in several clinical studies showing that it reliably estimates arterial pressure and cardiac output –25.We recorded arterial pressure, heart rate, cardiac index, stroke volume index, and systemic vascular resistance index at the following time points Fig. : before Data are presented as mean ± standard deviation (SD) for continuous variables and n (%) for categorical variables. Linear mixed effects models were used to estimate change from baseline  in various hemodynamic variables to 6 time points during induction using an autoregressive (AR (1)) covariance structure. The overall significance level was 0.05; Bonferroni correction was used to control the type I error for 7 outcomes and 6 comparisons within each outcome, and the significant level for each comparison was 0.0011 .We enrolled 125 patients but excluded 28 who were given norepinephrine (14 patients) or additional doses of propofol (14 patients) during the study period. We also excluded 5 patients because of technical problems during data recording. We thus included 92 patients in the final analysis.Participating patients were young, with a mean ± SD age of 36 ± 13 years and relatively healthy with 91% having ASA physical status class I or II  bpm (P < 0.001). As there was no clinically important change in stroke volume index after sufentanil administration the increase in heart rate resulted in a slight increase in cardiac index of 0.5 (0.3 to 0.7) L*min-5*m2 . After propofol administration, mean arterial pressure was < 65 mmHg in 27 patients (29%). Heart rate returned to baseline after administration of propofol, and stroke volume index and cardiac index remained stable compared to baseline.After administration of propofol, mean arterial pressure decreased by 23 (17 to 28) mmHg and systemic vascular resistance index decreased by 565 (419 to 712) dyn*s*cmAfter administration of rocuronium, mean arterial pressure, systemic vascular resistance index, and heart rate all were below baseline values , but transiently increased to baseline levels after tracheal intubation.180 s after tracheal intubation, there were no clinically important differences compared to baseline in heart rate, stroke volume index, or cardiac index. However, arterial pressure and systemic vascular resistance index remained well below baseline. 180 s after tracheal intubation, mean arterial pressure was 15 (10 to 20) mmHg lower than at baseline and it was < 65 mmHg in 21 patients (23%).Supplemental Figure S1 shows Spaghetti plots for individual patients and Supplemental Figure S2 shows boxplots of changes in hemodynamic variables over time.In this prospective observational study, we sought to assess the relative contribution of various hemodynamic mechanisms to hypotension after induction of general anesthesia with sufentanil, propofol, and rocuronium in adults having non-cardiac surgery.Heart rate and cardiac index increased after sufentanil administration, but presumably not due to a pharmacological effect of sufentanil. Instead, the increases likely reflect stress-induced sympathetic activation in anticipation of anesthetic induction. Propofol caused a clinically important reduction in arterial pressure. In addition, systemic vascular resistance index decreased significantly, by about 25%, after propofol administration. Heart rate returned to baseline after administration of propofol, and stroke volume index and cardiac index remained stable compared to baseline. Hypotension after propofol administration thus was linked to a decrease in systemic vascular resistance. Rocuronium administration had no additional clinically relevant effect on cardiovascular dynamics.A controversy remains about propofol-induced post-induction hypotension. The main mechanisms proposed are a decrease in myocardial contractility, venous dilation with a decrease in venous return, and arterial dilation with a decrease in systemic vascular resistance –20. ExpeAbout a third of our patients had mean arterial pressures < 65 mmHg after propofol administration. While there is strong evidence that intraoperative hypotension is associated with postoperative organ failure and death –7 researThis reinforces the need to mitigate the potential cardiovascular effects of induction of general anesthesia. Our results indicate that post-induction hypotension results largely from arterial dilation, and therefore that vasopressors will generally be the most appropriate treatment. Which vasopressor(s) might be best remains unclear as there are sparse data related to the treatment or prophylaxis of post-induction hypotension by using vasopressors. In a preliminary study, phenylephrine and norepinephrine boluses effectively counteracted intraoperative hypotension caused by propofol anesthesia . AlthougIn our study, induction agents were standardized, but exact doses were not and remained at the discretion of the attending anesthesiologist. Additionally, we used a non-invasive finger-cuff method to assess advanced hemodynamic variables. The non-invasive monitoring system we used is well validated for the measurement of continuous blood pressure –23 and cIn patients having non-cardiac surgery, anesthetic induction with sufentanil, propofol, and rocuronium was associated with a clinically important  reduction in arterial pressure and systemic vascular resistance index. Heart rate and stroke volume index, and therefore cardiac index, basically remained stable during anesthetic induction. Post-induction hypotension therefore appears to result from arterial dilation with reduced systemic vascular resistance rather than venous dilation or reduced myocardial contractility. Future research should evaluate strategies for early detection and avoidance of post-induction hypotension, especially the (preemptive) use of vasopressors.Hemodynamic variables during the induction of general anesthesia in individual patients. Spaghetti plots are showing the changes in hemodynamic variables during the induction of general anesthesia in individual patients. Black and blue lines therefore show individual trajectories of hemodynamic variables over time. MAP, mean arterial pressure; SAP, systolic arterial pressure; DAP, diastolic arterial pressure; SVRI, systemic vascular resistance index; HR, heart rate; SVI, stroke volume index; CI, cardiac index. Supplementary material 1 (TIF 32885 kb)Hemodynamic variables during the induction of general anesthesia (change from baseline). Boxplots showing the change of hemodynamic variables during the induction of general anesthesia compared to baseline. Boxplots show mean (triangle) and median  with 25th-75th percentile (box). Whiskers extend to the most extreme observations within 1.5 times the interquartile range of the first and third quartiles, respectively. Circles represent outliers. MAP, mean arterial pressure; SAP, systolic arterial pressure; DAP, diastolic arterial pressure; SVRI, systemic vascular resistance index; HR, heart rate; SVI, stroke volume index; CI, cardiac index. Supplementary material 2 (TIF 12696 kb)Supplementary material 3 (PDF 74 kb)Below is the link to the electronic supplementary material.