Continuous non-invasive monitoring of blood pressure is one of the main factors in ensuring the safety of the patient’s condition in anesthesiology, intensive care, surgery, and other areas of medicine. The purpose of this work was to analyze the current patent situation and identify directions and trends in the application of non-invasive medical sensors for continuous blood pressure monitoring, with a focus on clinical experience in critical care and validation thereof.The research results reflect data collected up to September 30, 2022. Patent databases, Google Scholar, the Lens database, Pubmed, Scopus databases were used to search for patent and clinical information.An analysis of the patent landscape indicates a significant increase in interest in the development of non-invasive devices for continuous blood pressure monitoring and their implementation in medical practice, especially in the last 10 years. The key players in the intellectual property market are the following companies: Cnsystems Medizintechnik; Sotera Wireless INC; Tensys Medical INC; Healthstats Int Pte LTD; Edwards Lifesciences Corp, among others. Systematization of data from validation and clinical studies in critical care practice on patients with various pathological conditions and ages, including children and newborns, revealed that a number of non-invasive medical sensor technologies are quite accurate and comparable to the “gold standard” continuous invasive blood pressure monitoring. They are approved by the FDA for medical applications and certified according to ISO 81060-2, ISO 81060-3, and ISO/TS 81060-5. Unregistered and uncertified medical sensors require further clinical trials.Non-invasive medical sensors for continuous blood pressure monitoring do not replace, but complement, existing methods of regular blood pressure measurement, and it is expected to see more of these technologies broadly implemented in the practice in the near future. At present, one of the most important tasks facing medicine is to improve the quality of the monitoring process of a patient’s condition and provision timely medical assistance. The speed and quality of the mentioned monitoring process acquire the greatest value in the field of critical care medicine, as a healthcare sector dealing with the extreme degree of manifestation of a pathological process rapidly developing in time.Monitoring of physiological and biochemical parameters is an important part of the complexity of intensive care medicine and, in a timely manner, indicates a deterioration in the patient’s condition and also helps to assess the effectiveness of the treatment.As is known in medical practice, continuous monitoring and display of blood pressure measurements is required not only in life-threatening situations, surgical interventions, and anesthesiologic patient support .Hypertension continues to be considered a very powerful predictor of population disability, and its complications, primarily brain stroke and myocardial infarction, largely determine the structure of total mortality. The main task of treating patients with arterial hypertension, and one of the goals during emergency operations in such patients, is to reduce the risk of cardiovascular complications by achieving the target level of blood pressure and organ protection. Monitoring blood pressure can reduce the risk of complications and improve the prognosis of the patients’ outcomes , 3.In this regard, continuous blood pressure monitoring, as opposed to discrete measurement, allows for the early detection of hypo- but also hypertension, the assessment of its duration, the possible reduction of ischemic injuries, particularly to the kidney and myocardium, and the improvement of patient management by lessening the severity of postoperative multiple organ failure and mortality.Continuous measurement and display of blood pressure is essential in clinical practice to prevent serious disorders and their potentially detrimental consequences. Obviously, non-invasive continuous research methods are of particular importance to critically ill patients.Following extracardiac surgery, changes in systolic, mean, and pulse pressure in the radial arteries were associated with myocardial and acute renal injury, according to a retrospective analysis by Ahuja et al. . SystoliQualitative monitoring of blood pressure in life-threatening situations, surgical interventions, and anesthesiological support of patients reduces mortality rates and complications, as well as the length of stay in the intensive care unit. It is important to choose a safe and accurate blood pressure monitor to assess blood pressure, since such a device will provide accurate and reproducible measurements.There are two ways to continuously monitor blood pressure: invasive or non-invasive. Continuous invasive blood pressure monitoring is the “gold standard” in modern anesthesiology and intensive care medicine and has high accuracy. It is per-formed by installing an intra-arterial catheter and connecting it to a monitoring system. It should be noted that continuous invasive blood pressure monitoring has a risk of complications such as trauma, bleeding, infections, thrombosis, embolism, distal ischemia, and pseudoaneurysm formation, to name the most common and severe , 8.The majority of surgical operations employ an oscillometric tonometer to measure blood pressure because it is a simple, non-invasive process. However, this method can only offer intermittent readings, does therefore not really monitor continuously, and does not always accurately and promptly reflect changes in blood pressure. During intraoperative anesthetic treatment, intermittent blood pressure monitoring can miss up to 20% of hypotensive events .Currently, improving the quality of the monitoring process during cardiopulmonary resuscitation is associated with the implementation of modern research methods based on non-invasive medical sensors. One of their main tasks is maximum automation of measurements—thus minimizing the role of a person during the measurement processes .Numerous works by scientists, including Quan X., Tamura T., Meidert A.S., and others, are devoted to issues of achievements in the field of continuous non-invasive blood pressure monitoring –13. The Despite ongoing comparative studies of the accuracy of non-invasive continuous monitoring of blood pressure with other measurement methods, this issue continues to be debated in intensive care in critically ill patients. Methods for continuous non-invasive monitoring of blood pressure have both advantages and limitations, which determines the need for further scientific research in this area.The development and implementation of an increasing number of medical devices, including those for non-invasive continuous blood pressure monitoring, capable of generating, collecting, analyzing, and transmitting data creates the Internet of Medical Things (IoMT). The IoMT generates information to help improve the speed and accuracy of diagnostics and target treatments more effectively. Additionally, it has the ability to reduce costs, increase effectiveness, and improve patient outcomes. Between 2022 and 2028, the global IoMT market is anticipated to expand at a CAGR of 24.6%.Patent information is indispensable in the course of scientific research since it allows to assess the novelty and technical level of inventions, thereby reducing research time and costs. Patent analysis may also highlight potential avenues for future research and new perspectives in medical practice –16. In wPaying tribute to the contribution of scientists to the theory and practice of non-invasive medical sensors for continuous non-invasive monitoring of the condition of patients, it should be noted that the issues of their patent protection and their validation in intensive care require further comprehensive research.With the present work, we aim to analyze the current patent situation and identify directions and trends in the application of non-invasive medical sensors for continuous blood pressure monitoring, with a focus on clinical experience in critical care and validation thereof.The review will be of interest to the heads of the departments of patent and invention work, heads of research departments, medical researchers, and clinicians who are willing to deploy IoMT solutions.This study relied on methods such as system analysis, content analysis, scientific synthesis, logical generalization, graphical depiction, and patent research, among others.The research results are presented as of September 30, 2022. Patent databases, Google Scholar, the Lens database were used to search for patent information. For forming a portfolio of patent documents reflecting the most complete set of solutions in the field of non-invasive medical sensors for continuous monitoring of blood pressure, a search was conducted on the following keyword: non-invasive continuous blood pressure. We used all the keywords with the operator AND. The search was carried out on the title of the patent, abstract, and claims.The patent search request was limited to the classes of International Patent Classification and Cooperative Patent Classification , 18. IntA patent search turned up 1,104 patents and 564 simple families containing the keyword “non-invasive continuous blood pressure.” Then we analyzed the resulting array of patents using Patent Classification codes.As a result, the study of medical sensors for continuous non-invasive blood pressure monitoring covered 573 patents, including 284 families with priority after January 1, 1980. The legal status of the 573 retrieved patents was automatically calculated in the Lens database and is subject to change. At the time of the study, 379 valid patents were identified for the specified search query. The trends of patenting inventions in various technological segments were studied, and the top 20 patent applicants, leading patent security countries, and key inventions were identified.In order to assess the validation of patented medical sensors for continuous non-invasive blood pressure monitoring, an analysis was made of their registration in the FDA medical device database,Clinical data of patented medical sensors were studied in the PubMed, Google Scholar, and Scopus databases using their trademarks and commercial names of manufacturers as keywords.The analysis of the patent landscape in patent databases  in the field of modern medical sensors for non-invasive continuously measuring blood pressure demonstrates a high interest in the use of non-invasive continuous monitoring. This confirms a significant number of patents for this technology in the databases under study. The dynamics of patent and application publications of medical sensors for non-invasive continuously monitoring blood pressure is shown in The presented data indicates the presence of an increase in patent activity in this area, which is associated with the prospects for the commercial production of medical sensors for non-invasive continuous monitoring of blood pressure and practical interest in medical practice. It should be noted that the number of patents in this area began to grow in 1999 and has continued to remain at a high level until present, which indicates an unquenchable interest and ongoing research in this area.Structuring patents by patenting country makes it possible to single out the United States, occupying a leading position, which accounts for 45% of all publications.The next positions are taken from patents under the Patent Cooperation Treaty, the European Patent Office, and China . The remaining analyzed countries do not exceed 10% of patent publications.Among the leading companies, the top 20 applicants of patents are included in As evident from the data presented in According to the WHO’s technical specifications, devices for measuring arterial pressure are divided into invasive and non-invasive group. Non-invasive devices, in turn, are divided into devices with the application of external pressure (cuff-based devices) and without the application of external pressure (cuffless devices). Further, the blood pressure monitoring classification reflects specific quantification methods that are used: pulse transit time, ultrasound or magnetic, photoplethysmography, etc. .Analysis of the patent landscape of non-invasive medical sensors for continuous blood pressure monitoring confirms 2 main directions for non-invasive blood pressure monitoring: cuffed and cuffless devices.Cuff-based devices widely use the volume-clamp method first introduced in 1973 by Penaz . A littlThe CNAP  system is based on the volume-clamp method. The CNAP system uses plethysmography to monitor blood flow in the cuff area of the finger and transmits its fluctuations, transforming them into a constant pulse wave of blood pressure.The CNAP system is disclosed in patent US 8814800 . The patTechnically, the device consists of two cuffs mounted on the patient’s fingers and a pressure sensor mounted on the forearm.Constant pressure in the finger can be accompanied by venous congestion distal to the cuff, the occurrence of “blue finger syndrome,” which can limit the duration of monitoring. To avoid this, two adjacent fingers are sometimes used, which allows the measurement to be switched periodically from one finger to the other, avoiding prolonged venous stagnation. However, this method has limitations in patients with vascular diseases and finger pathology.Moreover, the arm blood pressure measurement is time-separated from the finger blood pressure measurement and does not address the inherent weaknesses of the arm measurement method used, which therefore results in incorrect blood pressure signal conversion in patients with severe arrhythmia and severe pressure variation .Despite the outlined limitations, as the literature data shows, the CNAP device had reasonable agreement with intermittent oscillometric measurements in the emergency department in 130 patients. The difference between methods for measuring systolic and diastolic blood pressure was −5 mmHg (±22 mmHg) and −2 mmHg (±15 mmHg), respectively. The authors noted that clinically significant hypotensive events can be immediately recognized with continuous arterial pressure monitoring, whereas they are missed or only detected later with intermittent arterial pressure assessment . This cln = 51), the CNAP technology showed good agreement when compared with the pulmonary artery catheter (n = 47) undergoing major open abdominal surgery (In cardiothoracic surgery patients (catheter . Hemodyn surgery .n = 60) undergoing neurosurgical intervention, the absolute and prognostic correspondence between pulse pressure, the invasive blood catheter measured, and the CNAP system was moderate. The predictive agreement between the methods was 82%. An important report is the information provided by Nicklas et al., who established that continuous, non-invasive CNAP monitoring is more effective in determining hypotensive phases during complex gastrointestinal endoscopy of the gastrointestinal tract (n = 90) than intermittent blood pressure monitoring , whereby it was revealed that some differences in the accuracy of CNAP monitoring were noted during surgical interventions in pediatric practice  device , which is also based on the volumetric clamp technique and is presented in patent application WO2020176207 . In an iThe effectiveness of the ClearSight system has been demonstrated in patients undergoing surgery. In 54 patients, invasive intra-arterial blood pressure monitoring during heart surgery was compared to non-invasive blood pressure measurement utilizing the ClearSight vascular unloading technology (Edwards Lifesciences Corp) . The perResearchers investigated the effect of ClearSight monitoring on blood pressure stability during general anesthesia in 160 orthopedic patients in a randomized trial . The autn = 125) in China   . Moreoven = 20) .n = 40) and traditional oscillometric blood pressure monitoring to reduce the incidence of hypotension during caesarean sections was investigated by Juri et al.  under a central neuraxial anesthetic while using ClearSight, a non-invasive continuous blood pressure monitor, the difference between the diastolic and mean arterial blood pressure and the reference method is acceptable (n = 20). The device displayed high levels of accuracy, consistency, and precision . It has been established that the ClearSight system-derived cardiac index is insufficiently accurate in patients undergoing off-pump coronary artery bypass graft surgery who have a lower ejection fraction  systems with direct arterial catheterization . The stuA widely accepted standard of evidence-based medicine is a meta-analysis of the results of multiple studies. The meta-analysis of 10 studies showed that photoplethysmography technologies  are poorly interchangeable with bolus thermodilution in ICU and cardiac surgical settings . It shouIt should be noted that the presented meta-analysis was carried out for the period 2010–2018. A number of randomized and controlled clinical trials in recent years have shown that Clearsight allows preventive clinical decisions in cardiac surgery, orthopedics, GI endoscopy, and caesarean section. The accuracy of the obtained BP values using the ClearSight system was moderately consistent with the data of invariant measurement in obese patients.The Lidco hemodynamic monitor for non-invasive continuous monitoring of blood pressure also merited consideration. It is disclosed in patent EP 2914168 A1 . According to the authors, the technology must be improved for this indication. However, with the Lidco device, numerous instances of early postoperative hypotension have been found  kept the Lidco device in place until the end of a 12 h period of continuous postoperative follow-up . Finapres/Finometer technology is disclosed in patent application EP 2319408 . 4 documThis device also uses photoplethysmography based on the determination of relative changes in blood volume in blood vessels in the dermis and subcutaneous fat. n = 24) (There is data from studies of the Finapres system under conditions of emergency care. Cardiovascular monitoring was performed using Finapres during early mobilization after breast cancer surgery (n = 24) . OrthostData from clinical randomized trials of Finapres in intensive care and anesthesiology have not been identified over the past 5 years.Systems and methods for indirect, oscillometric, digital blood pressure monitoring that provide self-calibration to obtain absolute blood pressure values are used in the VitalStream device. It is described in patent application WO 2019/010416 A1 . 8 documThe VitalStream sends vital sign data from a wearable device to a mobile app, cloud portal, or integrates with other monitoring systems.n = 24), continuously non-invasive blood pressure measurement with the CareTaker, and invasive intra-arterial pressure measurement . The overall correlation between complexes was 0.99  disclosed in patents EP 1538971, US 10952675 , 50. 30 There is validation data for the T-Line system in intensive care. In 28 patients receiving intensive care, a femoral arterial catheter and the T-Line TL-200 system were used to measure blood pressure simultaneously . A low en = 50) after cardiothoracic surgery (It has been presented data on the comparative measurements of cardiac output using the T-Line system and intermittent thermodilution of the pulmonary artery using a pulmonary artery catheter in patients ( surgery . The pern = 23) with multiple organ dysfunction syndrome  with severe comorbid heart disease , which are disclosed in patent application WO 2021/067893 A1 . Four doNon-invasive blood pressure monitoring technologies cannot completely replace permanent, invasive blood pressure monitoring in children during surgical interventions. Ilies et al. discuss that the reason for this lies in the low efficiency of these devices during periods of sharp fluctuations in blood pressure and hypotension . In theiThe first studies of the Boppli device  in 120 patients aged 4 to 87 years and 16 patients aged 1 to 8 days from intensive care units, pediatric intensive care units, and cardiovascular intensive care units at Stanford University Medical Center show the good accuracy of the device . The pulThe FDA has awarded the Boppli device a Breakthrough Device Designation (BDD), which addresses an unmet need for blood pressure monitoring in critically ill children when an invasive arterial catheter cannot be used due to the risk of complications and adverse effects. The FDA BDD program is designed to promote the development and accelerate the review of advanced medical device technologies. The data presented show that the Boppli application has positive results in various age groups.Another promising technology in the development of medical sensors for non-invasive continuous blood pressure monitoring, involving the acquisition and analysis of a pulse wave, is a cuffless device developed by Aktiia (Switzerland), disclosed in patent application WO 2021/229276, US2021315464 , 61. AktThe validation of the optical bracelet Aktiia in various positions of the body for continuous monitoring of blood pressure in 91 patients with blood pressure levels from low to hypertensive was carried out . It is sn = 86) in an outpatient setting met test criteria 1 and 2 of the ISO81060-2 standard in the sitting position  with radial artery catheterization in the intensive care unit  (A positive effect of using the Biobeat device during labor based on reflective photoplethysmography has been reported (n = 81) . Furthern = 81) . SimilarKachel et al. compared blood pressure measurements with a Biobeat device and with arterial line sensors in 10 patients immediately after cardiac surgery . The autn = 7) was conducted in the general intensive care unit of cardiac output measurements obtained with the Biobeat photoplethysmography-based non-invasive chest patch and a pulse circuit cardiac output device (r = 0.906). The authors conclude that the device has enhanced monitoring capabilities in a variety of clinical settings without the complications associated with invasive devices.A prospective, comparative clinical study  and HealthPatch  was carried out in a pilot study on 20 patients . MeasureA prospective 5 month pilot study of the ViSi Mobile device was conducted in a neurological/neurosurgical department for adults . Againstn = 312), including data from studies NCT02156154 and NCT02996227, the ViSi Mobile system was used to monitor blood pressure in patients after abdominal surgery  presented in patent EP 1704820 B1 , the pulIn a prospective study of 71 patients over 24 h, a significant difference was found between the measurements of different devices . Blood pValidation of Somnotouch-NIBP in compliance with ESH (European Society of Hypertension) protocols was satisfactorily completed. However, after the initial calibration, this validation only requires 30 min of testing. When certifying cuff-free blood pressure measurement equipment, the Lancet Commission on Hypertension Group suggests using the current ISO recommendation –78.The BPro system  is based on the patented applanation tonometry blood pressure measurement technology (patent HK 1077185 A1) . 25 docun = 25). The authors conclude that tonometric and cuff blood pressures are comparable (A comparison was made between blood pressure measurement with the BPro system and an oscillometric cuff device in patients with diabetes mellitus (mparable .n = 45) for measuring blood pressure during pregnancy and gestational hypertension .Of interest is also the development of the SeismoWatch bracelet by inventors from the Georgia Tech Research Institute and Northwestern University. Its principle is disclosed in the application WO 2021/188878 and is based on a combination of photoplethysmography and seismocardiography . ApplicaSeismocardiography is a method of measuring the vibrations of the chest caused by the heartbeat. The bracelet, applied to the sternum for a short time (about 15 s), registers the fluctuations of the chest associated with heart contractions. This data allows wrist photoplethysmography to calculate the pulse transit time, on the basis of which blood pressure is calculated. It should be noted that the instrument requires periodic calibration.The pilot study showed that the SeismoWatch bracelet significantly outperformed the conventional pulse arrival time system based on wearable blood pressure assessment .Clinical trials of the SeismoWatch bracelet for non-invasive blood pressure measurement in anesthesiology and intensive care therapy have not been conducted to date, but the available results indicate the prospect of this system. The device is under research and development.An analysis of data from 1980 to the end of September 2022 of the patent landscape of non-invasive medical sensors for continuous blood pressure monitoring suggests a significant increase in interest in the development and implementation of new devices in medical practice, especially in the last 10 years.According to the received data we can conclude about positive dynamics of the patenting, including the following companies Cnsystems Medizintechnik; Nellcor Puritan Bennett Ie; Sotera Wireless INC; Gen Electric; Tno; Sethi Rakesh; Tensys Medical INC; Healthstats Int Pte LTD; Edwards Lifesciences Corp, among others. It has been established that patents for cuffed devices have earlier priority dates , to a greater degree. Priority dates for inventions related to patenting uncuffed devices are more recent , to a greater degree. It should be noted that medical sensors for continuous pressure monitoring are characterized by comprehensive patent protection. Devices are usually protected by several patents. The patents shown above are only for illustration and do not constitute a limitation. There are a number of other inventions in the field of non-invasive medical sensors for continuous monitoring of blood pressure. In the last two decades, the scientists have actively created and patented developments in this direction.The value of blood pressure as a major predictor of the development of cardiovascular and postoperative complications explains the interest in investigating medical sensors for continuous blood pressure monitoring, especially in the intensive care unit. As a result, it is possible to identify early hypo- and hypertension cases, assess their duration, and improve patient management by lowering the severity of postoperative insufficiency and mortality. Non-invasive medical sensors for continuous blood pressure monitoring also allow for the avoidance of the risks of complications such as trauma, bleeding, infections, thrombosis, embolism, distal ischemia, among others, that may occur after the use of invasive medical sensors.The overview of the literature showed that for patented non-invasive medical sensors for continuous blood pressure monitoring, a number of studies have been conducted in the intensive care unit, resuscitation, and surgery on patients of various ages, including children and newborns, suffering from various pathological conditions.The characteristics of cuff-based devices for non-invasive continuous monitoring of blood pressure are listed in Analysis of cuff-based devices for non-invasive continuous blood pressure monitoring allows the following briefly characterization. The CNAP device showed promising results in the emergency department, cardiothoracic surgery, and complex gastrointestinal endoscopy of the gastrointestinal tract, whereby cardiac monitoring in pediatric practice using CNAP requires further research.The ClearSight device demonstrated the ability to quickly detect hemodynamic disorders in cardiac surgery, orthopedics, gastrointestinal endoscopy, and caesarean sections. However, the correlation of measurements using the ClearSight system and an arterial catheter was moderate in obese patients, as well as in those who underwent coronary artery bypass surgery with a lower ejection fraction.The Lidco monitor has been found to detect numerous cases of early postoperative hypotension. But, at the same time, it was noted that there is a restriction in the movement of patients when using it.Data from clinical randomized trials of the Finapres device in intensive care and anesthesiology over the past 5 years have not been identified. Further research is needed to validate the latter device in such setting. The device developed by Caretaker also showed a high correlation with invasive blood pressure measurements in the intensive care unit.* . This indicates the measurement accuracy of these devices.Analysis of the patent landscape of non-invasive continuous blood pressure monitoring cuff-based medical sensors suggests that the devices CNAP , ClearSight , LiDCO Hemo-dynamic Monitor , Finapres/Finometer , and VitalStream  are FDA-approved and commercialized on the market. These cuff-based devices are certified according to ISO 81060-2, ISO 81060-3, ISO /TS 81060–5 standards . The disadvantages of these devices include limiting the movement of the hand and the movement of patients when using them, as well as causing discomfort in patients by their prolonged presence under the continuous observation of the cuff on the finger.To overcome the limitations of the method of Penaz , other methods of non-invasive blood pressure monitoring are used in cuffless devices. Generalized features of the clinical use of cuffless devices are given below.According to the literature, the T-Line TL-200 system and the Aktiia bracelet allow for additional continuous blood pressure monitoring in intensive care. Nevertheless, the T-Line system’s use in patients with multiple organ dysfunction syndrome or morbid obesity is limited. Furthermore, when the hand moves or a few seconds pass after the cessation of any physical activity, effective measurement with the Aktiia bracelet is not provided.There is evidence to support the possibility of accurate blood pressure monitoring by the Biobeat device during childbirth and heart surgery. The advantages of using the Biobeat device should be noted, in particular, the independence of the measurement results from the body mass index or skin color and the use of a cloud platform.The use of the ViSi Mobile device reduced the number of patient transfers (by 25%) to intensive care. With the ViSi Mobile device, there was also a decrease in unplanned mortality. However, this difference regarding mortality was statistically unreliable.Validation of Somnotouch-NIBP according to the ESH (European Society for Hypertension) protocols has been successfully completed, and FDA approval is pending. Data from BPro system studies revealed that caution should be exercised in patients with confirmed preeclampsia. It should be noted that more research is needed on Senti-Cor-100 device to monitor blood pressure during intensive therapy and resuscitation.There are a number of patented cuffless devices under development and research that have shown their advantages: the possibility of using them not only in adults but in children, including newborns, on the arm or leg (Boppli); the use of seismocardiography (SeismoWatch).The characteristics of cuffless devices for non-invasive continuous monitoring of blood pressure are listed in An analysis of the clinical trials showed that a number of non-invasive medical sensor technologies (cuff-based and cuffless) are quite accurate and comparable to the “gold standard” continuous invasive blood pressure monitoring, and are approved by the FDA for medical application and certified according to ISO 81060-2, ISO 81060-3, ISO/TS 81060-5. Their advantages include the ability to detect hemodynamic disorders quickly, allowing for timely intervention and treatment, as well as improved monitoring capabilities in a variety of clinical settings without the complications associated with invasive devices. In addition, it should be noted that it is possible to use them as additional tools along with standard monitoring in children to improve perioperative safety, as well as in children in critical condition when an invasive arterial catheter cannot be used due to the risk of complications and side effects. It should be emphasized that unregistered and uncertified medical sensors require further clinical trials.* – Association for the Advancement of Medical Instrumentation (United States), 1987, 1992, and 2002; British Hypertension Society, 1990, 1993; German Hypertension League (Deutsche Hochdruckliga), 1999; European Society of Hypertension, 2002, 2010; ISO, 2009; American National Standards Institute, Association for the Advancement of Medical Instrumentation and International Organization for Standardization, 2009, 2013; Association for the Advancement of Medical Instrumentation, European Society of Hypertension and International Organization for Standardization, 2018.** – According to ISO 81060-2 for non-invasive sphygmomanometers, the mean overall difference is ±5 mm Hg and the standard deviation is within 8 mm Hg. The mean difference among patients is based on the mean difference in blood pressure and the standard deviation.The present review of patent and clinical data has established the effectiveness of a number of non-invasive medical sensors for continuous blood pressure monitoring (cuff-based and cuffless), their accuracy, and their comparability to the “gold standard” of continuous invasive blood pressure monitoring. However, there were also disadvantages and limitations to the use of some devices (as detailed in the discussion section).Currently, non-invasive medical sensors for continuous blood pressure monitoring do not completely replace but complement existing methods of regular blood pressure measurement, and in the long term, it is hoped that these devices will be further refined and will shape the future of blood pressure monitoring in clinical settings.OL, OK, AA, and HW: conceptualization. OL: formal analysis and writing—original draft preparation. OL, AB, EP, JN, MK-P, OK, AA, and HW: writing—review and editing. All authors contributed to the article and approved the submitted version.This study was supported by a fund from the Ludwig Boltzmann Gesellschaft (OL was a fellowship recipient).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Diabetic kidney disease (DKD) is a leading cause of chronic kidney disease (CKD) for which many treatments exist that have been shown to prevent CKD progression and kidney failure. However, DKD is a complex and heterogeneous etiology of CKD with a spectrum of phenotypes and disease trajectories. In this narrative review, we discuss precision medicine approaches to DKD, including genomics, metabolomics, proteomics, and their potential role in the management of diabetes mellitus and DKD. A patient and caregivers of patients with lived experience with CKD were involved in this review.Original research articles were identified from MEDLINE and Google Scholar using the search terms “diabetes,” “diabetic kidney disease,” “diabetic nephropathy,” “chronic kidney disease,” “kidney failure,” “dialysis,” “nephrology,” “genomics,” “metabolomics,” and “proteomics.”A focused review and critical appraisal of existing literature regarding the precision medicine approaches to the diagnosis, prognosis, and treatment of diabetes and DKD framed by a patient partner’s/caregiver’s lived experience.Distinguishing diabetic nephropathy from CKD due to other types of DKD and non-DKD is challenging and typically requires a kidney biopsy for a diagnosis. Biomarkers have been identified to assist with the prediction of the onset and progression of DKD, but they have yet to be incorporated and evaluated relative to clinical standard of care CKD and kidney failure risk prediction tools. Genomics has identified multiple causal genetic variants for neonatal diabetes mellitus and monogenic diabetes of the young that can be used for diagnostic purposes and to specify antiglycemic therapy. Genome-wide-associated studies have identified genes implicated in DKD pathophysiology in the setting of type 1 and 2 diabetes but their translational benefits are lagging beyond polygenetic risk scores. Metabolomics and proteomics have been shown to improve diagnostic accuracy in DKD, have been used to identify novel pathways involved in DKD pathogenesis, and can be used to improve the prediction of CKD progression and kidney failure as well as predict response to DKD therapy.There are a limited number of large, high-quality prospective observational studies and no randomized controlled trials that support the use of precision medicine based approaches to improve clinical outcomes in adults with or at risk of diabetes and DKD. It is unclear which patients may benefit from the clinical use of genomics, metabolomics and proteomics along the spectrum of DKD trajectory.Additional research is needed to evaluate the role of the use of precision medicine for DKD management, including diagnosis, differentiation of diabetic nephropathy from other etiologies of DKD and CKD, short-term and long-term risk prognostication kidney outcomes, and the prediction of response to and safety of disease-modifying therapies. Precision medicine aims to go beyond this by identifying individual patient characteristics that contribute to prognosis or treatment outcomes. The aim of this review is to discuss what is currently known about the clinical landscape of diabetic kidney disease (DKD) as well as precision medicine in DKD with respect to diagnosis, prognosis, and treatment, as highlighted by lived experience from a partner and caregiver of a patient with DKD.Precision medicine has the potential to provide patients with tailored treatments based on their individual characteristics, including genetic and environmental factors. Examples of precision medicine approaches in nephrology include apolipoprotein L1 (APOL1) risk variants and the treatment of APOL1-associated focal segmental glomerular sclerosis with APOL1 inhibitorsMy husband was diagnosed with type 2 diabetes, which we did not take very seriously at first. He did not follow any of the advice given to him by the doctors and nurses and made no real effort to change his lifestyle. This led to many health complications along the way, including the life changing diagnosis of chronic kidney disease. We also did not realize how serious this diagnosis was, and it still did not lead to any efforts to control his diabetes. Things became much more serious 15 years after his diagnosis when he was told he needed to go on dialysis. We were both in shock and I remember thinking we had to live our whole lives in a matter of moments because my husband was now on a rapid track to losing his life. At this point, he finally made the lifestyle changes his care team had been asking him to, but ultimately, it was too late. My husband was on dialysis for 4 years, and this time was filled with many serious health complications, including heart attacks, bypass operations, infections, and blood clots. He passed away at home after a 20-year healthcare journey. As I reflect on this journey, I wonder if my husband had taken better care of his diabetes, would he have delayed the development of chronic kidney disease and would he still be alive today. Living in denial cost my husband his life and cost me my happily ever after story with the person I loved most. I also often wonder if we would have had more precise information about Glen’s risk of developing kidney disease and when he was first diagnosed with diabetes and his risk of kidney failure when he was later diagnosed with kidney disease, if it would have changed his illness and our journey .To highlight how a patient’s diagnostic and therapeutic journey with DKD can be enhanced through novel metabolomic, proteomic and genomic precision medicine approaches.Original research articles were identified from MEDLINE and Google Scholar using the search terms “diabetes,” “diabetic kidney disease,” “diabetic nephropathy,” “chronic kidney disease,” “kidney failure,” “dialysis,” “nephrology,” “genomics,” “metabolomics,” and “proteomics.” We synthesized the existing literature regarding the precision medicine approaches to the diagnosis, prognosis and treatment of diabetes and DKD framed by a patient partner caregiver’s lived experience. A glossary of terms used through the review is shown in 6 It is a growing global epidemic with an estimated 536.6 million people currently living with diabetes and this estimate is projected to rise significantly to 783.2 million by 2045. Uncontrolled diabetes may cause several complications, including coronary artery disease, stroke, chronic kidney disease (CKD) and kidney failure, peripheral vascular disease, retinopathy, and neuropathy.6 Moreover, the Global Burden of Disease Study 2016 highlighted diabetes mellitus as a leading cause of deaths and disability globally.9Diabetes mellitus is a metabolic disorder of multiple etiologies, characterized by hyperglycemia due to disturbances of carbohydrate, fat, and protein metabolism originating because of inadequate insulin secretion, insulin action, or both. Diabetic nephropathy is a specific pathological diagnosis defined by glomerular basement membrane thickening, mesangial expansion, and nodularity with the accumulation of extracellular matrix proteins, such as collagen, fibronectin, and laminin, and podocytopathy1113 classified by moderately increased albuminuria , severely increased albuminuria  or overt nephropathy (>300 mg/day). Non-albuminuric DKD is associated with hypertension, dyslipidemia, smoking, and includes classic diabetic glomerulopathy, tubulointerstitial disease, and vascular disease. Specific pathological classifications for diabetic nephropathy include class I: glomerular basement membrane thickening; class II: mesangial expansion without nodular sclerosis (Kimmelstiel-Wilson lesions) or global > 50% glomerulosclerosis; class III: nodular sclerosis (Kimmelstiel-Wilson lesions); and class IV: advanced diabetic glomerulosclerosis with global >50% glomerulosclerosis with other clinical or pathologic evidence that sclerosis is attributable to diabetic nephropathy.Diabetic kidney disease is a clinical diagnosis based on decreased estimated glomerular filtration rate (eGFR) and/or the presence of albuminuria in the setting of type 1 or type 2 diabetes. Several mechanisms, including auto-oxidation of glucose, advanced glycation end products (AGEs) that act on receptors for AGEs (RAGES), glycolysis, the polyol pathway, glucose-6-phosphate dehydrogenase, the hexosamine pathway, and increased activity of NADPH (nicotinamide adenine dinucleotide phosphate hydrogen) oxidase (Nox) involved in the generation of reactive oxygen species (ROS).17 Hyperglycemia-induced oxidative stress has been reported to be responsible for the development and progression of diabetic vascular complications including nephropathy by upregulating the transforming growth factor-b1 (TGF-b1) and the extracellular membrane (ECM) protein expression in the glomerular mesangial cells. Reactive oxygen species are also known to induce TGF-b1 expression, and this further activates stress-activated signaling pathways in diabetic kidney. In addition, the interaction of TGF-b1 with its receptors induces the phosphorylation and nuclear translocation of the receptor-regulated Smad2 and Smad3 transcription factors. Mesangial cells express Smad2/3 and Smad4, which mediates TGF-b1-induced gene expression, including ECM genes, such as plasminogen activator-1 and type I collagen and fibronectin. Preclinical and clinical studies using various antioxidants, such as lipoic acid, vitamin E, and curcumin, have been reported to prevent the progression of diabetic nephropathy.Oxidative stress plays a major role in the development of diabetic nephropathy. Angiotensin II, one of the most important components of RAAS, shows pro-inflammatory, growth stimulatory, fibrogenic, and free radical promoting activities that provoke the development of kidney failure and diabetic nephropathy26 mainly acting on Angiotensin II type 1 receptor (AT1R). Angiotensin II also shows most of its pathological effects, such as pro-inflammatory response, hypertrophy, proliferation, and/or apoptosis via AT1R. Angiotensin II has a prominent role in activation of the nuclear factor kappa B (NF-κB) signaling pathway in diabetic nephropathy. A number of in vivo and in vitro studies show that NF-κB regulates the production of pro-inflammatory cytokines like interleukin-1β and chemokines, such as MCP-1 (monocyte chemoattractant protein-1), TGF-b1, ICAM1 (intercellular adhesion molecule 1), VCAM (vascular cell adhesion molecule), RANTES , and TNF-α .30 Nuclear factor kappa B activity in macrophages, and glomerular and tubular parenchymal cells, has been linked with parameters of severity of diabetic nephropathy, such as proteinuria, oxidative stress, and inflammation. Several studies have shown that the elevated levels of Angiotensin II and ACE in patients with diabetes and blockade of the RAAS were protective in the progression of DKD.The renin-angiotensin-aldosterone system (RAAS) plays a crucial role in the progression of DKD. Renin breaks down systemic angiotensinogen to Angiotensin I, which then further breaks down to Angiotensin II by the action of angiotensin-converting enzyme (ACE).2 per year but is less with standard of care therapy, including blood pressure control, RAAS inhibitors, and sodium-glucose cotransporter-2 (SGLT2) inhibitors, and is dependent on baseline eGFR, albuminuria, and blood pressure.3436 Of course, the structural and functional changes in the kidney as a result of normal aging, which include decreased kidney volume, nephrosclerosis, and reduced nephron number, also influence the rate of eGFR decline as patients with DKD are often older and have had a longer course of diabetes.Diabetic kidney disease is a complex disease with a wide range of phenotypes. The natural history of diabetic nephropathy (particularly in the setting of type 1 diabetes) was initially thought to be uniformly linear over years with stages that include hyperfiltration, microalbuminuria, macroalbuminuria, overt nephropathy, and subsequent eGFR decline. However, it is now known that the trajectory is variable, ranging from rapid decline in kidney function to remission of initial symptoms of DKD, especially if risk factors are aggressively controlled. Predicting DKD trajectory is challenging due to the variability in individual patient risk factors, co-interventions, and response to therapy. In DKD, the mean rate of eGFR decline is typically 5 to 10 mL/min/1.73 m A kidney biopsy is needed to distinguish DKD from non-DKD, but it is typically not pursued in many settings because of the risks related to percutaneous biopsy and the conclusion that a biopsy is unlikely to change management. A meta-analysis of 48 studies and 4876 patients with diabetes who underwent kidney biopsy identified systolic blood pressure, hemoglobin A1c, diabetes duration, and retinopathy as factors in meta-regression that explained some of the heterogeneity in DKD and non-DKD diagnosis. A kidney biopsy also cannot reliably identify causal mechanisms of kidney injury if multiple diagnoses are present, which may also be intertwined . It is unknown how often a kidney biopsy results in a definitive diagnosis of DKD and/or non-DKD across different clinical settings and patient phenotypes but presumably varies by populations and pretest probability.Distinguishing diabetic nephropathy from age-related decline can be challenging as clinical factors cannot reliably discriminate between diabetic nephropathy and other DKD and non-DKD phenotypes. For example, a meta-analysis that included 26 studies and 2322 participants showed that independent predictors of non-DKD included the absence of diabetic retinopathy, shorter duration of diabetes, hemoglobin A1c, blood pressure, lipid level, and body mass index, but not age, GFR, or proteinuria. Whether the adverse outcomes of diabetes that are associated with race and ethnicity are a result of genetic ancestry or systemic racism is a complex issue that needs to be considered in any clinical or research setting of DKD with careful attention to all geographic, sociocultural, and environmental factors.42Traditional modifiable and non-modifiable risk factors for the development of DKD include increased age, male sex, non-European race , lower socioeconomic status, obesity, smoking, poorer glycemic control, microvascular complications , and hypertension. Risk factors for the progression of DKD include high blood pressure, acidosis, inflammation, genetics, histology, and blood and urine biomarkers identified in observational studies that classify exposures and adjust for confounders in multivariable regression models. For example, a systematic review of biomarkers (that included 15 studies and 27 biomarkers) predicting onset or progression of DKD in type 2 diabetes beyond conventional risk factors identified the following significant biomarkers: interleukin-18, asymmetric dimethyl arginine, urinary ceruloplasmin, immunoglobulin G, and transferrin for the onset of diabetic nephropathy; asymmetric dimethyl arginine, vascular cell adhesion molecule 1, interleukin-6, von Willebrand factor, and intracellular cell adhesion molecule 1 for the progression of DKD; and high-sensitivity C-reactive protein, E-selectin, tissue-type plasminogen activator, von Willebrand factor, and triglycerides for both.Risk prediction for DKD development and prognosis is important to guide clinical decision-making. This includes screening, interventions, nephrology referral, multidisciplinary CKD care, education, vascular access planning, home dialysis referrals, and kidney transplant assessments. The model that included age, body mass index, smoking, diabetic retinopathy, hemoglobin A1c, systolic blood pressure, high-density lipoprotein, triglycerides, and urine albumin to creatinine ratio (ACR) performed the best to predict DKD risk. Diabetic kidney disease prognosis is typically determined using the 2-year and 5-year kidney failure risk equation (KFRE), which incorporates age, sex, eGFR, and urine ACR to predict kidney failure and eGFR decline but other risk prediction models for eGFR < 60 mL/min/1.73 m2 at 5 years and 40% decline of eGFR at 3 years also exist.47 Kidney failure risk equation is able to effectively determine the 2-year and 5-year risks of kidney failure, but it predicts higher than observed risk for diabetic nephropathy. Machine learning algorithms have also been used to predict doubling of serum creatinine and kidney failure with area under the curve (AUC) of >0.80. Currently, no risk prediction models are perfect and inaccuracy and imprecision may lead to erroneous decisions, most likely related to factors not captured by model inputs, such as blood and/or urine multiomics, which have the potential to improve the accuracy and discrimination of risk prediction models for DKD.Risk prediction models for the development of DKD has also been developed and validated. A systematic review of 41 studies including 46 and 18 prognostic models for nephropathy  in type 2 diabetes identified 2 superior models to predict risk for DKD. glycemic control (hemoglobin A1c < 7%), statins if high cardiovascular risk. RAAS inhibition, SGLT2 inhibition, glucagon-like peptide 1 (GLP-1) receptor agonists, and mineralocorticoid receptor antagonists (MRAs). However, it remains unclear which individual patients, as opposed to populations of patients generalized from clinical trials, preferentially benefit or are at highest risk of harms of specific interventions, which may be able to be predicted by precision medicine-based approaches.The treatment of DKD includes blood pressure lowering with lifestyle modification  and medications , Treatments for patients with these conditions can currently be targeted to the specific genetic variant a patient harbors. For example, patients with neonatal diabetes mellitus and a specific methylation signature at the 6q24 chromosomal locus have been shown to respond well to sulphonylureas with regard to glycemic control, while other patients with neonatal diabetes mellitus require treatment with insulin. Furthermore, sulphonylureas have been shown to be effective treatment in patients with monogenic diabetes of the young caused by mutations in HNF4A and HNF1A genes, but not in those with mutations in GCK, in whom the development of diabetic complications is unlikely. Monogenic diabetes of the young associated with HNF1B mutation requires insulin to achieve adequate glycemic control. As good glycemic control leads to the prevention and/or delay of the secondary sequelae of diabetes, such as DKD, precision medicine in monogenic diabetes has demonstrated significant success in the individualized treatment of disease. Exome sequencing has been used to improve the diagnosis of monogenetic genetic kidney diseases in the setting of CKD of unknown etiology, such as podocytopathies, collagenopathies, tubulopathies, ciliopathies, but the prevalence of these co-existing disorders in the setting of diabetes is unknown.61One of the most significant progresses toward precision medicine in DKD has been in the treatment of monogenic diabetes. Neonatal diabetes mellitus and monogenic diabetes of the young are the 2 most prevalent diagnoses in monogenic diabetes, and both have had multiple causal genetic variants identified. Many of the loci identified help us to understand the pathophysiology of disease, pointing toward the glomerular basement membrane (COL4A3 and BMP7), or to genes implicated in renal biology (COLEC11 and DDR1). Pathogenetic variants of DKD susceptibility genes identified by whole exome sequencing, such as the COL4A3 gene also partially explained the more severe DKD phenotype  in 9 maturity-onset diabetes in young patients with biopsy-proven DKD compared with their parents with less severe DKD. However, most of these associations have not been replicated in independent diverse cohorts, and the necessary functional work-up of associated genes and specific causal mechanisms have yet to be performed. Furthermore, the associated environmental influences that contribute to disease risk in the setting of complex inheritance are still, for the most part, unknown.In contrast to monogenic disease, the translational benefits following from the genetic discoveries in the more common polygenic causes of disease, including type 1 and type 2 diabetes, have been less established. Genome-wide association studies (GWAS) in DKD, conducted in patients with both type 1 and type 2 diabetes, have revealed approximately 33 genes to be associated with disease. Polygenetic risk scores are a way to represent an individual’s risk for developing a disease by adding together all the risk loci, weighted by how risky they were found to be in the GWAS analyses. Although the polygenetic risk score provides insight into the distribution of genetic risk for individuals within a population, it does not yet provide clinically applicable results for the individual patient with DKD. Genomic studies also offer promise in identifying novel pathways in DKD pathophysiology and potential targets for drug development, which are desperately needed to improve kidney outcomes.As a first step toward translating these GWAS discoveries toward individualized patient care, a polygenetic risk score for DKD was recently developed. Related to the metabolome, the proteome is the global collection of proteins that reflect the influence of genetics, epigenetics, and the environment. The metabolome and proteome as they relate to kidney disease are influenced by variation between individuals ,69 age, comorbidities, GFR,7074 tubular secretion,76 etiology of CKD, diet,79 medications,81 and gut microbiota.8284 To study the metabolome and proteome, metabolites in bodily fluids are separated using chromatography or electrophoresis followed by high-resolution mass spectrophotometry for untargeted identification and quantification. Targeted proteomic platforms include Olink and Somalogic. Olink is a proximity extension assay in which oligonucleotide antibody-pairs contain unique DNA sequences allowing hybridization with subsequent proximity extension creating DNA reporter sequences that are amplified by real-time polymerase chain reaction allowing for scalable multiplexing. The Somalogic platform SomaScan consists of protein-capture reagents made of short single-stranded DNA sequences that incorporate hydrophobic modifications that measure native proteins in complex matrices by transforming available binding sites on individual proteins into a corresponding reagent concentration, which is then quantified by hybridization to microarrays. Metabolomics has been used to identify blood and urine metabolites that are associated with adverse clinical outcomes in nephrology, including proteinuria, incident CKD,8789 CKD progression,91 kidney failure, and cardiovascular death. Proteomic approaches have also been used to evaluate the diagnosis, treatment, and prognosis across a range of etiologies of kidney disease and platforms.9496The metabolome is the global collection of small molecules, typically <1500 Da, which includes carbohydrates, amino acids, organic acids, and lipids.98 For example, the urine proteome measured by liquid chromatography-mass spectroscopy (LC-MS) can accurately distinguish between healthy controls and patients with diabetes , normoalbuminuria and nephropathy , and non-DKD with accuracy  and may be useful in settings where a kidney biopsy is not feasible or its potential risks outweighs its potential benefits. Novel mechanisms of DKD that have been identified by metabolomics/proteomics include innate and adaptive immune responses, inflammation, angiogenesis, fibrosis, tumor necrosis factor pathways, and galactose/glycerol metabolism.Metabolomics and proteomics have been evaluated for their ability to improve the accuracy of diagnosis in DKD, to identify novel pathways involved in DKD pathogenesis, and to improve the prediction of CKD progression and kidney failure. In the PROVALID study, a prospective multinational cohort of 2560 adults with type 2 diabetes, a panel of 12 biomarkers explained 34% of variability in DKD progression but the contribution of individual biomarkers was low. These biomarkers were also unable to discriminate between stable eGFR and rapid eGFR decline beyond baseline eGFR. In another study of 3 cohorts, 12 biomarkers were associated with >20% decline in eGFR, and 2 biomarkers in particular (kidney injury molecule 1 and beta 2 microglobulin) modestly improved risk prediction in addition to eGFR and albuminuria. In another study, 13 biomarkers were individually associated with eGFR progression in DKD. In a case-control study of individuals with type 2 diabetes and an eGFR of 30 to 60 mL/min/1.73 m2, 30/207 serum biomarkers were associated with rapid progression of renal failure. Ongoing efforts, such as the Kidney Precision Medicine Project—a multicenter prospective study in adults with acute kidney injury or CKD who undergo a protocol kidney biopsy—aim to stratify patients based on molecular features of disease, such as histopathology, the transcriptome, the proteome, the metabolome, in addition to clinical characteristics to identify critical cells, pathways, and targets for novel therapies and preventive strategies.Regarding DKD prognosis and risk prediction, there have been several metabolomic/proteomic studies that have demonstrated conflicting results. In the ORIGIN trial, 15 of 239 biomarkers were independently associated with eGFR change. as well as the response to spironolactone. In addition, urinary polypeptides identified in this trial predict responsiveness to angiotensin receptor blockers. Systems biology approaches could be used in future trials of DKD to select for high-risk participants to enrich the trial population for those at the highest risk of events to reduce the sample size requirement beyond eGFR and ACR eligibility criteria.117 These novel approaches are lagging in nephrology RCTs but are promising although they require significant biostatistical expertise.Metabolomics and proteomics can also be used to predict response to therapy in DKD. For example, in the PRIORITY trial, the urine CKD273 classifier predicted progression to microalbuminuria, CKD and 30% decrease in eGFR,In summary, DKD is a heterogeneous disease with a wide range of clinical presentations, biomarker/genetic profiles, treatments, and outcomes. Improvements in understanding disease pathophysiology and individualizing treatments are needed. Though the results of the reported genetic and metabolomic/proteomic studies are representative of a model for using genomics and metabolomics/proteomics in precision medicine of DKD, we still have far to go. At present, we do not yet have the tools to truly implement precision medicine in DKD. In the future, stratifying clinical research cohorts by relevant high-risk and low-risk genotypes or metabolomic/proteomic profiles may help to make clinical trials in DKD more effective, and in turn, lead to individualized treatment protocols and improved outcomes, experiences, and quality of life for patients. Perhaps in the future, precision medicine will be used to assist patients, caregivers and clinicians  to have a better understanding of the risks of both diabetes and DKD and can better inform shared decision-making to initiate lifestyle interventions and pharmacotherapy to improve clinical outcomes. Finally, clinicians, researchers, funding agencies, and policy-makers must strive to ensure that precision medicine approaches are inclusive and equitably accessible to diverse groups of patients to maximize individual and population outcomes.


Background and Objectives: To compare autonomic and vascular responses during reactive hyperemia (RH) between healthy individuals and patients with sickle cell anemia (SCA). Materials and Methods: Eighteen healthy subjects and 24 SCA patients were subjected to arterial occlusion for 3 min at the lower right limb level. The pulse rate variability (PRV) and pulse wave amplitude were measured through photoplethysmography using the Angiodin® PD 3000 device, which was placed on the first finger of the lower right limb 2 min before  and 2 min after the occlusion. Pulse peak intervals were analyzed using time–frequency (wavelet transform) methods for high-frequency (HF: 0.15–0.4) and low-frequency (LF: 0.04–0.15) bands, and the LF/HF ratio was calculated. Results: The pulse wave amplitude was higher in healthy subjects compared to SCA patients, at both baseline and post-occlusion (p < 0.05). Time–frequency analysis showed that the LF/HF peak in response to the post-occlusion RH test was reached earlier in healthy subjects compared to SCA patients. Conclusions: Vasodilatory function, as measured by PPG, was lower in SCA patients compared to healthy subjects. Moreover, a cardiovascular autonomic imbalance was present in SCA patients with high sympathetic and low parasympathetic activity in the basal state and a poor response of the sympathetic nervous system to RH. Early cardiovascular sympathetic activation (10 s) and vasodilatory function in response to RH were impaired in SCA patients. Sickle cell anemia (SCA) is an autosomal recessive disorder characterized by a single mutation in the β-globin gene, which leads to the production of abnormal hemoglobin (Hb) called HbS. When deoxygenated, HbS polymerizes, and a mechanical distortion of red blood cells (RBCs) occurs, i.e., sickling . Sickle It has been established that blood rheological alterations , chronicMore recently, autonomic nervous system (ANS) dysfunction has been demonstrated to be implicated in the pathophysiology of SCA . A recenSeveral tests are available for the evaluation of the autonomic function, such as plasma catecholamines measurement, baroreflex sensitivity tests, and muscle sympathetic nerve activity . HoweverMany works have found that pulse rate variability (PRV), which is extracted from photoplethysmography (PPG) data, can serve as an alternative measurement of ANS activity ,21,22. PReactive hyperemia (RH) is the increase in blood flow, within a given vascular territory, in response to an occlusion time . SeveralA non-observational trial was conducted with 18 healthy subjects (HbAA genotype) and 24 patients with SCA (HbSS genotype) to study the effects of RH on vascular and cardiac activity. The sickle cell anemic patients were recruited at the Special Hematology Clinic of the “Juan Bruno Zayas Alfonso” General Teaching Hospital in Santiago de Cuba, during the 2013–2014 period. Before enrollment, all patients and control subjects had clinical examination with blood pressure measurements to check for the absence of reactive hyperemia contraindication. The participants were in a resting state for the first 10 min, under controlled ambient temperature (24–27 °C) and luminance (dim light) conditions. PPG was then used to record the pulsatile volume flow at the first finger of the lower right limb, both at baseline and during a post-occlusion hyperemia test. This research was approved by the Committee of Medical Ethics of Santiago de Cuba University of Medical Sciences and conducted in the Laboratory of Basic Sciences of the same institution. All subjects gave written informed consent and were in a clinical steady-state phase of their disease, with no painful crisis and blood transfusion within the previous three months.The exclusion criteria were as follows: patients receiving treatment with hydroxyurea, central or peripheral nervous system disorders (stroke or neuromuscular disorders), skin disorders, implanted electronic devices (pacemakers or implantable cardioverter defibrillators), upper or lower limb amputations, women who were pregnant or menstruating, and any type of heart arrhythmia.® 18 digital plethysmograph , which captures the volume variations of the pulse wave via the reflection method (at 850 nm with a 3.5-mA photodiode). The PPG signal was then passed to an analog band pass filter from 0.1 to 15 Hz (Butterworth 5th order filter) and digitized at a resolution of 8 bits (106 samples per second). The recorded data were transmitted, processed and archived using the VAPLET® auxiliary software . This software allows for the exportation of the signal in a beat-by-beat manner, such that it can then be processed by the Octave software 2019 ) ) .The onset and systolic peak of the arterial pulse wave were detected to calculate the pulse–pulse intervals (PPIs) and pulse volume amplitude (PVA) using the model proposed by Pascau-Simón . The sphTo establish the PRV, the PPIs of high-frequency (HF: 0.15–0.4) and low-frequency (LF: 0.004–0.15) bands were analyzed, as recommended by the International Consensus of Experts on HRV (1996) . Time–frt-test of independent samples was applied for the variables that presented a normal distribution and the Mann–Whitney U test for those that did not. The data are expressed as the mean ± standard deviation (SD). Mathematical analyses and dynamic graphs (https://www.gnu.org/software/octave/download.html (accessed on 15 January 2021)). The average of the LF/HF matrices for the PRV was calculated from the CWT-Morlet analysis during the 2 min period after cuff deflation and interpolated at 2 Hz (0.5 s). Statistical analyses were performed with the JASP software ). Significance was defined as p < 0.05.For the comparison of the groups, a c graphs  were perThe patients with SCA and the control healthy subjects were similar regarding age, sex, body mass index, systolic blood pressure (SBP), and heart rate at rest. The weight, height, diastolic blood pressure, and mean blood pressure levels were significantly lower in the SCA patients than in the controls .In the basal state, no statistically significant differences were found in the amplitude of the pulse wave between the healthy subjects and patients with sickle cell anemia. However, after reactive hyperemia, the post-occlusion pulse wave amplitudes were higher in healthy subjects compared to SCA patients . An incrIn the present study, an impaired sympathetic activity in response to RH was observed in SCA patients. Previous studies have demonstrated that ANS activity is impaired in SCA patients compared to healthy individuals ,31,32. NDiastolic blood pressure (DBP) and mean blood pressure (MBP) levels were significantly lower in SCA patients than healthy control groups. These findings differ from what has been reported by other authors who have not observed such differences ,32. HoweThe dynamic changes in ANS that occur during the activation maneuvers can be determined through the time–frequency methods used in the present study. The pattern of ANS activation during reactive hyperemia differs between SCA patients compared to healthy subjects. A quick sympathetic nervous system response, reflected in increments in the LF and the LF/HF ratio, was observed in healthy subjects after occlusion in this study. This has been interpreted as an early cardiovascular sympathetic reflex (10 s after occlusion) in response to RH caused by the metaboreflex . The accIn addition, the parasympathetic activity  was greater in SCA patients than in healthy controls after RH. This indicates an exaggerated parasympathetic response that modifies reflexive sympathetic activity arising in response to RH in SCA patients. However, parasympathetic activity immediately after RH was lower in SCA patients than in healthy subjects. The low baseline levels of parasympathetic activity in these subjects may explain the inability of the heart to respond sufficiently to stimuli that activate the sympathetic nervous system.Pearson et al.  speculatIn rats, chronic intermittent hypoxia causes significant cell loss in the nucleus ambiguus, a structure from which several vagal efferent axons innervate ganglionated plexuses in the dorsal surface of cardiac atria, which in turn may have functional roles in cardiac regulation . In addiThe results of the present study show that there was no significant difference between SCA patients and healthy subjects in pulse wave amplitudes in the basal state. It has previously been reported that increased peripheral blood flow occurs during the steady state with a periodic microcirculatory flow pattern, which may compensate for alterations in red blood cell rheology. The arteriolar diameter increases during the vaso-occlusive crisis compared to the intervals between the crises . HoweverThe hyperactive endothelium seen in SCA enhances red blood cell and neutrophil adhesion, resulting in a slowed blood flow and sickling in post-capillary venules, followed by vaso-occlusion and ischemia . In addiMany articles have reported an alteration of ANS activity in response to RH in patients with SCA. However, these papers did not assess dynamic changes in the ANS during the RH maneuver. The dynamics of ANS activation during RH may provide valuable information for evaluating the cardiovascular autonomic neuropathic that may be present in sickle cell disease. The results of the present study demonstrate that both ANS activity and PPG amplitude are impaired in patients with SCA; thus, the autonomic and endothelial status in SCA patients can be closely evaluated by applying the techniques detailed herein. Further studies are clearly warranted to clarify the relationship between altered ANS activity and SCA severity. A limitation of our study was the small sample size. This was, however, comparable to many papers concerning ANS activity in the literature.Vasodilatory function, as measured by PPG, was lower in SCA patients compared to healthy subjects. Moreover, a cardiovascular autonomic imbalance was present in SCA patients with high sympathetic and low parasympathetic activity in the basal state and a poor response of the sympathetic nervous system to RH. An early cardiovascular sympathetic activation (10 s) and vasodilatory function in response to RH were impaired in SCA patients.


Background: The derivatives-reactive oxygen metabolites (d-ROMs) and plasma antioxidant capacity (PAT) tests are oxidative indexes. Severe asthma has been related to oxidative stress. We aimed to investigate d-ROMs and PAT values in severely controlled asthmatics and the correlation of these values with lung function. Methods: Blood samples were collected from severely controlled asthmatics and centrifuged at 3000 rpm for 10 min. The supernatant was collected. The assays were performed within three hours of collection. The fraction of exhaled nitric oxide (FeNO), impulse oscillometry (IOS), and spirometry were determined. Symptom control was recorded using the asthma control test (ACT). Results: Approximately 40 patients with severe controlled asthma (75%: women), mean age of 62 ± 12 years, were recruited. Approximately 5% had obstructive spirometry. The IOS revealed airway abnormalities even though the spirometric results were within the normal range, with it being more sensitive than spirometry. The D-ROMs and PAT test values were higher than normal, indicating oxidative stress in severe asthmatics with controlled asthma. D-ROMs were positively correlated with R20 values, indicating central airway resistance. Conclusions: The IOS technique revealed an otherwise hidden airway obstruction with spirometry. The D-ROMs and PAT tests revealed a high level of oxidative stress in severe controlled asthmatics. D-ROMs correlate with R20, indicating central airway resistance. The role of the imbalance between oxidants and antioxidants in favor of oxidants, termed oxidative stress in the pathogenesis of asthma, arises as the chicken or the egg causality dilemma. Although airway inflammation in asthma tends to increase the production of reactive oxygen species (ROS) and reactive nitrogen species (RNS), contributed to mainly by eosinophils and neutrophils , accumulIn the pathogenesis of asthma, eosinophilic and neutrophilic airway inflammation induces symptoms and oxidative stress . Since eThe oxidative stress generated in the airway of patients with asthma causes epithelial cell injury . FurtherThe derivatives of reactive oxidative metabolites (d-ROMs) test analyzing the total amount of hydroperoxides in serum via the Fenton’s reaction  is used Severe asthma has been associated with the mechanisms of oxidative biology. The utility of these tests in assessing the overall oxidative status of patients with asthma and the correlation of the oxidative stress values with lung function needs to be better evaluated. This study aimed to investigate the d-ROMs and PAT test levels in severely controlled asthmatics and the correlation of the oxidative stress values with lung function.In this pilot study, blood samples were collected from patients with severely controlled asthma monitored at the Asthma Outpatient Clinic of the University of Thessaly from 1 November 2022 to 1 December 2022. Our sample consisted of patients between 18 and 80 years of age with severe well-controlled asthma requiring high-dose ICS/LABA combination therapy to prevent it from becoming uncontrolled. Asthmatic patients currently smoking or with a smoking pack history greater than 10 were excluded. We also excluded patients receiving systemic corticosteroids or suffering from COPD  and/or other relevant lung diseases causing alternating impairment in lung function or respiratory infection during the last month.Verbal and written informed consent were obtained from all subjects before the study, according to the Helsinki Declaration. The protocol was approved by the Larissa University Hospital Ethics Committee .Symptom control was determined using the asthma control test (ACT). Moreover, detailed lung function tests were performed in the following order: the fraction of exhaled nitric oxide (FeNO), impulse oscillometry (IOS) performance, and then spirometry.The ACT provided us with information on how well asthma had been controlled over the last four weeks, giving a score out of 25. A score of less than 20 means that asthma has not been controlled during the past four weeks .The fraction of exhaled nitric oxide (FeNO)  was performed according to American Thoracic Society/European Respiratory Society (ATS/ERS) guidelines . The cutIOS measurements were performed in triplicate according to standard guidelines with a Jaeger MasterScreen IOS system  ,18,19. VSpirometry  was performed according to ATS/ERS guidelines . The preBlood samples were collected. The samples were centrifuged at 3000 rpm for 10 min at 4 °C, and the supernatant was collected. Assays were performed within three hours of blood collection.d-ROMs FAST tests were performed on fresh serum within three hours of blood collection. No previously frozen and then defrosted samples were used for the test. In this test, hydroperoxides released from proteins in the acidic medium are converted to alkoxy and peroxyl radicals in the presence of transition metals, which are able to oxidize alkylsubstituted aromatic amines , showing increased absorbance at 505 nm. The method detects the density of the colored complex photometrically, which is directly proportional to the concentration of hydroperoxides, as previously described ,30. D-ROThe PAT test  is an automated test designed to assess the antioxidant capacity of plasma by measuring its ferric-reducing ability. Ferric to ferrous ion reduction causes a color change that can be photometrically assessed, as previously described . PAT tesThe chi-square test was used to make comparisons between frequencies. An unpaired t-test was used for comparing parametric data between two groups, while non-parametric data were analyzed with the Mann–Whitney U test. Spearman’s correlation was used for correlation analysis between oxidative markers, pulmonary function variables, and demographic, clinical, and laboratory parameters. Statistical analyses were performed with IBM SPSS Statistics for Windows, version 23.0, IBM Corp., Armonk, NY, USA. Forty asthmatics with severely controlled asthma were recruited for the study with an average age of 62 ± 12 years, 55% of whom were women. The mean asthma history, maintenance therapy, lung function parameters, d-ROMs and PAT tests values, and ACT score of the study population and according to gender are presented in p = 0.030) than the females. There was no significant difference in weight between the genders . Interestingly, the IOS results revealed airway abnormalities even though the spirometry results were within range, thus being more sensitive than spirometry. A significant negative correlation was found between FEV1 and R5 , di5-20 , and Fres .All patients received high doses of ICS/LABA and LAMA. Approximately 5% of the study population had obstructive spirometry. The mean R5 values were higher than 0.5 kPa/L/s in the studied population. The mean AX values were abnormal as they were higher than 1.0 kPa/L; Fres levels were also elevated in the population. The males had significantly higher R5 values which indicated higher total airway resistance, higher R20 values which indicated approximate central airway resistance, and Fres and AX values which revealed higher expiratory flow limitations than females. The males were significantly taller . No correlation was found between d-ROMs, FeNO, the ACT test, asthma history, and maintenance therapy. No correlation was found between the PAT test values and the several lung function parameters, neither between FeNO nor the ACT test. No correlation was found between the PAT test values, asthma history, and maintenance therapy. The D-ROMs and PAT test values indicated very high levels of oxidative stress given the reference values . We founIn this study, we investigated d-ROMs and PAT test values in severely controlled asthmatics and the correlation between oxidative stress values and lung function. The D-ROMs and PAT test values indicated a very high level of oxidative stress in severe asthmatics with controlled asthma. Interestingly, d-ROMs were positively correlated with R20 values that indicate central airway resistance. No correlation was found between the tests and the spirometric parameters. Moreover, we found that the IOS results revealed airway abnormalities even though the spirometric results were within range, thus being more sensitive than spirometry. Moreover, a significant inverse correlation was found between FEV1 and R5, di5-20, and Fres.ROS are constitutively present in cells and tissues in small but measurable concentrations ,31. They2), hydrogen peroxide (H2O2), and all peroxides (ROOR) [The most prominent ROS are the superoxide anion (Os (ROOR) . The keys (ROOR) ,34. BothThe amount of biologically active ROS might indicate individual health status, and their quantification holds potential for clinically relevant applications. Organic peroxides and lipoperoxides (d-ROMs) are intermediate metabolites generated early in the oxidative cascade , with thNotably, several studies support that in cardiovascular patients, d-ROM values above 395–482 U.Carr are associated with an increase in all cardiovascular events, major adverse cardiovascular events, heart failure, atrial fibrillation, and cardiovascular death ,41,42. Tp < 0.001) [In this study, the mean PAT values in the group of asthmatics were 2807 ± 1344 U.Cor, indicating very high values of oxidative stress. The study of Petrushevska et al. found that the PAT test values were significantly higher in patients with severe COVID-19 than non-infected individuals  . For the first time, our study showed that d-ROMs were positively correlated with R20hz values, an indicator of approximate central airway resistance, demonstrating that oxidative stress is associated with altered pulmonary mechanics. A previous study by Sunil et al. found that World Trade Center dust exposure, at 21 days, increased lung resistance, central airway resistance, tissue damping, and tissue elastance along with inflammation and oxidative stress in a murine model . No corrFurthermore, no correlation was detected between d-ROMs or PAT values and FeNO. Similarly, the study by Sone et al. found that there was no significant association between the levels of salivary NO and oxidative stress markers such as d-ROMs and biological antioxidant potential (BAP) in a sample of 250 elite university athletes in Japan . The FeNFor many years, IOS was promoted as an alternative measurement technique for airway resistance and obstruction in patients where maneuvers involved in plethysmography and spirometry prove difficult to perform, such as in the elderly, children, and obese patients ,47,48. IWe also found an inverse correlation between IOS parameters and FEV1. In support of our findings, there are many previous studies that have supported a moderate inverse correlation between IOS parameters such as R5Hz, Fres, and AX and FEV1 variables ,55,56,57p = 0.030) than the females, thus potentially confounding the detected difference in the impedance values between the genders.In this study, we found a significant difference in the impedance values between the genders. However, the differences were in the AX and Fres results which were not corrected for anthropometric parameters, and further studies are needed before safe conclusions can be drawn. According to Robinson et al., asthma is associated with abnormalities in IOS measures of peripheral airway dysfunction, which is stronger in men and in those with asthma persisting since childhood . PorojanThis study has some limitations. Firstly, the small sample size and the high mean age of the subjects reduced the power of the study and the degree to which we can apply the results of this study to a broader context. Secondly, a major limitation was that the sample size consisted only of patients with severe controlled asthma and lacked a control group of healthy individuals. Moreover, only 5% of the study population had obstructive spirometry. Moreover, in this study, we did not report Z-scores, which are believed to be more reliable indicators for interpreting the oscillometry results . HoweverThe IOS technique is increasingly employed in routine lung function testing, revealing an otherwise hidden airway obstruction with spirometry. A significant inverse correlation was confirmed between FEV1 and IOS parameters of airway obstruction such as R5, di5-20, and Fres. For the first time, the D-ROMs and PAT tests indicated a high level of oxidative stress in severe asthmatics with controlled asthma. The D-ROMs values were correlated with central airway resistance. Future studies are required to validate the scope and potential significance of oxidative status measurements and their correlations with airway mechanics in larger cohorts to establish multi-ethnic reference ranges and standardize the commercially available oxidative status tests prior to their routine incorporation into clinical practice.


Renal failure is one of the most serious vascular effects of hypertension. For better therapy and prevention of complications, early kidney disease identification in these patients is absolutely essential. However, current studies have proposed plasma Neutrophil Gelatinase Associated Lipocalin (pNGAL) to be a better biomarker comparative to serum creatinine (SCr). This study assessed the diagnostic utility of plasma neutrophil gelatinase-associated lipocalin (pNGAL) as a biomarker for early nephropathy diagnosis in hypertensive individuals.p-value < 0.05 was considered statistically significant.This hospital-based case–control study comprised 140 hypertensives and 70 healthy participants. A well-structured questionnaire and patient case notes were used to document relevant demographic and clinical information. 5 ml of venous blood sample was taken to measure fasting blood sugar levels, creatinine, and plasma NGAL levels. All data were analyzed using the Statistical Package for Social Sciences  and a In this study the plasma neutrophil gelatinase-associated lipocalin (NGAL) levels were significantly higher in cases compared to controls. Hypertensive cases also had significantly higher waist-circumference compared to the control group. The median fasting blood sugar level was significantly higher in cases compared to controls. This study established the use of Modification of Diet in Renal Disease (MDRD), Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI), and Cockcroft and Gault formula (CG) as the most accurate predictive equations for assessing renal dysfunction. The threshold for NGAL above which renal impairment can be assessed was found to be 109.4 ng/ml , 120 ng/ml  and 118.6 ng/ml  for MDRD, CKD-EPI and CG equations respectively. The prevalence of CKD was 16.4%, 13.6% and 20.7% respectively using the MDRD, CKD-EPI and CG.From this study, pNGAL is a better indicator of kidney impairment in the early stages of CKD as compared with sCr in general hypertensive population. Acute KAccording to reports by Abd EIHafeez et al. , the preCKD is known to be linked to aging, diabetes, hypertension, obesity, and other cardiovascular diseases; the presumptive pathological findings are diabetic glomerulosclerosis and hypertensive nephrosclerosis . After dAlthough blood creatinine is commonly used as an index of renal function, higher creatininemia is primarily a marker of glomerular filtration  and cannThis hospital-based case–control study was conducted at the Bono regional hospital in Sunyani Municipal. The Bono region can be found in the middle belt of Ghana which is bordered to the north by the Black Volta River and to the east by the Lake Volta, and to the south by the Ashanti, Eastern and Western regions. Its capital city is Sunyani and its Municipal Assembly covers a total land area of 506.7 km2. It lies between Latitudes 70 20’N and 70 05’N and Longitudes 20 30’W and 20 10’W. The hospital is a 300-bed capacity with a special hypertensive clinic. The Bono regional hospital is the main referral hospital in the municipality which serves all the nearby districts and villages.The necessary sample was obtained using the Kelsey’s formula:Where r is the ratio of Hypertensives to healthy controls, which is 2:1 in this study, l., 2013 . And p1-From the formula above, the minimum number of hypertensives required for this study was 40 with 20 healthy controls. However this study employed 210 participants. 140 hypertensive patients and 70 health controls.This study enrolled 210 participants consisting of one hundred and forty (70 men and 70 women) hypertensives under management at the clinic, mean age of 59.23 ± 5.8 and seventy (38 men and 32 women) study participants without hypertension condition, with mean age of 56.49 ± 7.83 as controls. This study excluded participants with chronic diseases such as liver disease, diabetes, elevated serum creatinine and urea, HIV, TB and hepatitis B and C to help minimize potential confounding factors. All participants were enrolled regardless of their educational or marital status and patients’ history was carefully recorded by interview and confirmed from their folders as well.A well-structured questionnaire and patients’ medical records were used to document relevant demographic and clinical history of the participants. Hypertensive patients were diagnosed according to the WHO criteria of systolic blood pressure ≥ 140 mmHg; diastolic blood pressure ≥ 90 mmHg and confirmed on two occasions by a physician. Height to the nearest centimeter without shoes and weight to the nearest 0.1 kg in light clothing was estimated. Weight measurement was done using a bathroom scale  and height was measured with a wall-mounted ruler. Waist circumference measurements were taken using Constant tension tape such as, Figure Finder Tape Measure and was measured in the nearest centimeter. The blood pressure of the study participants was measured by qualified health personnel using a mercury sphygmomanometer and a stethoscope in accordance with the recommendations of the American Heart Association.A fingertip capillary whole blood sample was collected from each subject after overnight fasting for determination of fasting blood sugar levels using Accu-Chek Advantage Blood Glucose Monitoring System. . Calibration of the instrument was performed at 7:00 am using the test kit glucose control solution. Vacutainer needle was used to draw all the two set of blood samples, with 3mls in the vacutainer plain tube and 2mls in a chilled vacutainer tube containing potassium ethylenediamine tetracetate (EDTA). The plain tube sample after clotting was centrifuged and the serum was stored at—80 °C until assayed and the chilled EDTA sample was promptly separated by a refrigerated centrifuge  and the plasma was stored at—80 °C until further analysis according to standard operating procedures.Creatinine levels were measured on serum samples using a BT 3000 fully automated chemistry analyzer (BT-3000) following the standard operating procedures for estimating quantitative analyte. The accepted reference range for creatinine measurement was 0.74 to 1.35 mg/dL or (65.4 to 119.3 micromoles/L) for adult men, and 0.59 to 1.04 mg/dL or (52.2 to 91.9 micromoles/L) for adult women. NGAL measurement was done using commercially available ELISA kit . According to the manufacturer's instructions, reagent was used to measure samples from both the subjects and the controls using the solid phase ELISA method. The accepted reference range in the laboratory was 0.625 ng/ml – 20 ng/ml.P-value of < 0.05 was considered to be statistically significant.The data obtained from the study was entered into Microsoft excel software and analyzed using the statistical Package for Social Sciences  Continuous variables with normal distribution were expressed as mean ± standard deviation (SD) and the median and inter quartile range (IQR) used for variables that were not normally distributed. Categorical variables were expressed in proportions and compared with chi-square test. Receiver Operating Characteristics Curve was used to evaluate an area under the curve of NGAL in the assessment of renal impairment. Bland and Altman plots were used to assess bias among the various creatinine equations . Confidence interval of 95% was used and a p < 0.0001). The median weight and waist circumference were significantly higher in cases than the controls. Similarly, the biochemical parameters including the median fasting blood sugar and plasma neutrophil gelatinase-associated lipocalin (NGAL) were significantly higher in cases compared to controls (p < 0.05). However, there was no significant difference of median creatinine levels between cases and control (p > 0.05). For the chronic kidney diseases equation, no significant differences were observed between median MDRD equation and CKD-EPI equation values of cases and controls (p > 0.05).From Table The diagnostic performance of NGAL in the assessment of renal impairment among hypertensive patients is shown in Table Table p-values were observed in all ROC analysis of NGAL for the different gold standard methods (p < 0.0001)Figure As shown in Fig. p < 0.0001). The coefficient of determination  was 0.70. This means that, each unit increase of NGAL will influence 70.0% of the increase change in the creatinine levels. NGAL was significant negatively related with MDRD equation (p < 0.0001), Cockroft-Gault equation (p < 0.0001) and CKD-EPI creatinine equation (p < 0.0001). The coefficients of determination  were 0.42, 0.55 and 0.27which means that, each unit decrease of NGAL influences 42.0%, 55.0% and 27.0% increase change in values of MDRD equation, Cockroft-Gault equation and CKD-EPI creatinine equations.Figure The search for more prognostically reliable, sensitive, and specific biomarkers to help manage patients with or at risk for renal disease has increased in recent years. The complications associated with chronic kidney disease and renal failure can be avoided or reduced with early detection and treatment . HyperteFindings of this current study revealed higher NGAL figures in cases than the controls and there was no significant difference of median creatinine levels of cases compared to controls. Similar to this current study, Gharishvandi et al.  & BolignThe results of this current study also confirm the assertion by the National Kidney Foundation that high blood pressure (BP) is a common cause of CKD and hence patients with high BP are at an increased risk of loss of kidney function and development of CKD. A research on adult patients revealed that those who later developed clinically significant Acute Kidney Injury had significantly greater urine NGAL levels at 1, 3, and 18 h following heart surgery . Also, sThe results of this current study indicated higher waist circumference in the cases compared to the controls. The increased waist circumference (WC) observed when the CKD subjects were compared to the controls is similar to the work of Levey et al. . Indeed,In this current study, the best cut-off values to predict renal impairment in hypertensive patients was assessed using all the three validated creatinine based equations and the best threshold for NGAL above which renal impairment would be diagnosed was 120.0ngml based on the CKD-EPI creatinine based equation which also had sensitivity and specificity of 100% and 72%.The findings of this study are in conformity with the work of Levey et al., (2009) and also David Bolignano et al. with cut-off level for sNGAL of 435 ng/ml  , 29. AgaOur cut-off values were slightly lower than the findings of David Bolignano et al. because most of our patients were probably at the early stages of CKD .2., although CKD-EPI was better compared to the other two, which is in direct conformity with the previous study.The practical application of GFR predictive formula is to diagnose and stratify chronic kidney disease in patients with kidney disease. According to the study of Levey et al.,  the CKD-pNGAL of 0.92 (0.87–0.98).The ROC curve showing the area under curve of NGAL in the assessment of renal impairment among hypertensive were assessed using GFR as the Gold standard. Significant asymptomatic p-value was obtained in all ROC analysis of NGAL for the different gold standard methods, but the best AUC was 0.87 (0.81–0.93) using CKD-EPI. The findings of this current study was consistent with the work of  who had 2 value) was 0.70. This means that, each unit increase of NGAL will influence 70.0% of the increase change in the creatinine levels. NGAL was significant negatively related with MDRD equation (p < 0.0001), Cockroft-Gault equation (p < 0.0001) and CKD-EPI creatinine equation (p < 0.0001). The coefficients of determination  were 0.42, 0.55 and 0.27 which means that, each unit decrease of NGAL influences 42.0%, 55.0% and 27.0% increase change in values of MDRD equation, Cockroft-Gault equation and CKD-EPI creatinine equations.In this current study scatterplot with linear regression analysis of the individual patient data points for NGAL in relation to creatinine showed a strongly significant positive relationship. The coefficient of determination (RThe findings of this current study was comparable to the work of David Bolignano et al.  in the uThe results of this current study indicate that pNGAL is a better indicator of kidney impairment in the early stages of CKD as compared with serum Creatinine in general hypertensive population. NGAL showed good cut-off point in diagnosing renal impairment with good sensitivity and specificity compared to creatinine. Also, hypertension is a common cause of CKD and hence patients with high blood pressure are at increased risk of loss of kidney function and development of CKD. Individuals with high BP should therefore be carefully evaluated for the presence of CKD especially those with decreased GFR using the NGAL biomarker. It is important to look into the significance of pNGAL as a biomarker for the early detection of kidney failure among other populations and for the differential diagnosis of renal disease etiology in other cardiometabolic illnesses.