In the low frequency domain, the comparison between invasively measured ABP and CPP showed good to excellent  and moderate to good reliability , respectively. Different methods for pressure measurement in the assessment of dynamic cerebral autoregulation yield different results and cannot be used interchangeably.Dynamic cerebral autoregulation to spontaneous fluctuations in cerebral perfusion pressure (CPP) is often assessed by transcranial Doppler (TCD) in the time domain, yielding primarily the mean flow index (Mx), or in the frequency domain using transfer function analysis (TFA), yielding gain and phase. For both domains, the measurement of blood pressure is critical. This study assessed the inter‐method reliability of dynamic cerebral autoregulation using three different methods of pressure measurement. In 39 patients with aneurysmal subarachnoid hemorrhage, non‐invasive arterial blood pressure (ABP), invasive ABP  and CPP were recorded simultaneously with TCD. Intraclass correlation coefficient (ICC) was used to quantify reliability. Mx was higher when calculated using invasive ABP  compared to non‐invasive ABP, and CPP. The overall ICC showed poor to good reliability  (Mxa) results in higher values than those calculated using non‐invasive ABP (nMxa) and cerebral perfusion pressure (CPP) (Mxc). The comparison between Mxa, nMxa, and Mxc showed moderate reliability at best. The gain and phase in the low‐frequency domain range for transfer function analysis (TFA) showed good reliability when comparing TFA measured using CPP and invasive ABP. We advise against using these measures interchangeably. Dynamic cerebral autoregulation dampens these changes by adjusting the cerebrovascular resistance and can be assessed in humans through several (most commonly) transcranial Doppler ultrasound (TCD)‐based methods  in patients with aneurysmal subarachnoid hemorrhage (SAH).2clinicaltrials.gov  and approved by the Regional Ethical Committee of the Capital Region of Denmark , and by The Danish Data Protection Agency . Oral and written informed consent was obtained from the next‐of‐kin. The data underlying the findings of this study can be shared upon reasonable request and only after approval from the corresponding author and relevant regulatory authorities.The present work was a prospective controlled intervention study designed to evaluate the effects of noradrenaline‐induced hypertension in patients admitted to the neurointensive care unit (neuro‐ICU) with SAH. This work comprised exploratory analyses of selected data and addressed an independent working hypothesis. The study was registered at 2.1Adults (≥18 years old) admitted to the neuro‐ICU with SAH and treated with an external ventricular drain were eligible for inclusion. The exclusion criteria were conservative treatment of the aneurysm, expected death within 48 h from admission, and acute or chronic diseases associated with impaired cerebral autoregulation . For inclusion in the present study, at least one autoregulation measurement, either baseline or induced hypertension, with simultaneous recording for more than 5 min of at least two of the three pressure measurements  was required. This study included recordings from 40 participants. Subject and recording characteristics are provided in Table 2.2For each TCD session, an insonation probe (DWL) was kept stable by a LAM rack (DWL). There were no changes to the TCD settings, and the patients did not change position during recordings. Middle cerebral artery flow velocity was measured through the ipsilateral transtemporal window using MultiDop T digital (DWL) .Raw waveform data of TCD, ICP, and ABP were extracted from LabChart into a tab‐delimited file in the original resolution of 1000 Hz. The recordings were visually inspected for artifacts. Artifacts in any recording modality resulted in the removal of a period surrounding that artifact, always starting and ending with a curve nadir for the specific recording modality. Mx was calculated by averaging waveform data into blocks, which were then grouped into epochs, where a correlation coefficient was calculated. All the correlation coefficients were then averaged into one Mx‐value for the full recording period. To ensure sufficient quality of the calculations, blocks were omitted from the analysis if more than 50% of the raw measurements were missing, and epochs were omitted if more than 50% of the blocks were missing. Mx was calculated using the ‘2.3.2TFA’‐function from the publicly available R package ‘clintools’ v. 0.8.2  range from 0.07 to 0.20 Hz . Normally distributed data are presented as mean (±SD), while non‐normally distributed data are presented as median (IQR). Reliability was calculated using the two‐way mixed‐effects, single measurement, absolute agreement ICC, and classified as poor (<0.5), moderate (0.5–0.75), good (0.75–0.9), or excellent (>0.9) with reference to both the lower and upper confidence limits , and TFA for 99 periods from 39 participants   during baseline and comparable pressures during periods of induced hypertension . The ICP was 8.6  during baseline and 9.1  during periods of induced hypertension.This study included 40 participants with SAH. We were able to calculate Mx for 95 periods from 39 participants (baseline: 5) Table . The par3.1n = 68), with similar results when comparing nMxa with Mxa , nMxa with Mxc , and Mxa with Mxc  , Mxa was 0.39 , and nMxa was 0.23 . In the Bland‐Altman plots, the smallest bias was observed between Mxc and nMxa , while the bias was higher for comparison between Mxc and Mxa  and between Mxa and nMxa  . The ove) Figure .3.2n = 96; non‐normalized gain: ICC: 0.89; 95% CI: 0.84; 0.92; n = 96). The ICC for phase when comparing TFAc with TFAa in the LF range was 0.69   and TFAa  than by nTFA   Figure .4The present study is the first to use simultaneous measurements of non‐invasive ABP, invasive ABP, and CPP to assess the reliability of the two TCD derived parameters, Mx and TFA, for assessing dynamic cerebral autoregulation in patients with SAH.We found that the Mx based on non‐invasive and invasive blood pressure measurements alone were higher than the mean flow index incorporating ICP; this is in line with previous reports ‐reactivity  showed higher reliability for the comparison of invasively measured ABP with CPP. The ICC for these comparisons ranged from good to excellent. However, comparison with non‐invasively measured ABP yielded confidence limits in the area of poor reliability. Even though TFA metrics calculated using invasively measured ABP and CPP are comparable, TFA has its limitations. Thus, so far TFA has been reported to have poor repeatability and reproducibility, has been assigned no reference values, and furthermore has limited diagnostic usefulness .Informed consent was obtained by the next‐of‐kin.Supplementary MaterialClick here for additional data file.


Systolic BP fell from 134.72 ± 17.73 to 124.58 ± 11.62 mm Hg. Diastolic BP decreased from 83.95 ± 10.20 to 80.33 ± 7.04 mm Hg. The percent of patients taking antihypertensive medications decreased from 35.9% at baseline to 4.7% at 90 days. During 90 days of the TPT Program, patients achieved low glycemic variability and significant reductions in BMI and BP. Antihypertensive medication use was eliminated in nearly all patients. Future research will focus on randomized case–control comparisons.The objective of this retrospective observational cohort study was to measure glycemic variability and reductions in body mass index (BMI), blood pressure (BP), and use of antihypertensive medications in type 2 diabetes (T2D) patients participating in the digital twin-enabled Twin Precision Treatment (TPT) Program. Study participants included 19 females and 45 males with T2D who chose to participate in the TPT Program and adhered to program protocols. Nine additional enrollees were excluded due to major program non-adherence. Enrollees were required to have adequate hepatic and renal function, no myocardial infarction, stroke, or angina ≤ 90 days before enrollment, and no history of ketoacidosis or major psychiatric disorders. The TPT program uses Digital Twin technology, machine learning algorithms, and precision nutrition to aid treatment of patients with T2D. Each study participant had ≥ 3 months of follow-up. Outcome measures included glucose percentage coefficient of variation (%CV), low blood glucose index (LBGI), high blood glucose index (HBGI), systolic and diastolic BP, number of antihypertensive medications, and BMI. Sixty-four patients participated in the program. Mean (± standard deviation) %CV, LBGI, and HBGI values were low  throughout the 90-day program. BMI decreased from 29.23 ± 5.83 at baseline to 27.43 ± 5.25 kg/m Care often focuses only on improving symptoms and slowing the progression of the disease2.Type 2 diabetes is a chronic disease that typically leads to increased medication use, health risks, complications, and health care costs5. Glucose variability promotes hypoglycemic and hyperglycemic episodes that may increase the risk of diabetes complications and impair quality of life7. Glycemic variability has also been associated with cardiovascular autonomic neuropathy in type 2 diabetes patients8. In a review of ten type 2 diabetes studies, nine studies found that glucose variability was significantly associated with the development or progression of micro- and macrovascular complications9.Glycemic variability has been shown to have a significant impact on the risk of diabetes complications. Glucose variability is responsible for the development and progression of diabetes complications by causing endothelial dysfunction through oxidative stress14.Several metrics are commonly used to measure glycemic variability. The percent coefficient of variation (%CV), standard deviation of blood glucose, continuous overall net glycemic action (CONGA), low blood glucose index (LBGI), and high blood glucose index (HBGI) have been used frequently to track glycemic variability in order to reduce hypoglycemic and hyperglycemic events16. Multiple studies have shown improvements in glycemic control from bariatric surgery, low-calorie diets, or carbohydrate restriction19. However, adverse events and high cost can limit the use of bariatric surgery2. Low-calorie diets  to manage diabetes may be difficult to maintain over the long term1. Low carbohydrate studies showed improved glycemic control, but often were only small short-term trials, excluded subjects taking insulin, or were limited to morbidly obese patients24. None of the studies so far have combined long-term continuous glucose monitoring (CGM), artificial intelligence methods, and precision nutrition for long-term management of glycemic variability.Insulin and certain oral hypoglycemic medications reduce glycemic variability25. The Twin Precision Treatment (TPT) Program uses CGM and detailed participant food intake data as inputs to a digital twin-enabled machine learning predictive model in the treatment of type 2 diabetes. The model provides precision nutrition guidance each day to the patient. Some results from the TPT Program have been reported previously26. In 64 patients with type 2 diabetes who enrolled and adhered to the TPT Program, mean (standard deviation) HbA1c decreased from 8.8% (2.2%) at baseline to 7.7% (1.6%) after 30 days and 6.9% (1.1%) after 60 and 90 days . Body weight decreased from 79.0 (16.2) kg at baseline to 74.2 (14.7) kg at 90 days (p < 0.0001). Fasting blood glucose changed from 151.2 (45.0) mg/dl at baseline to 129.1 (36.7) mg/dl at 90 days (p = 0.0001). By the first week of the program, most patients (55 of 64) had glucose time in range > 70%, and 57 of 64 had time in range > 70% at 90 days. The patients also had a significant decrease in insulin resistance and a significant increase in number of steps taken per day. Most patients were able to stop taking hypoglycemic medications26.Virtual digital twins have recently been envisioned for the management of certain metabolic conditionsGiven patients’ reductions in HbA1c, weight, fasting blood glucose, and use of hypoglycemic medications, our hypothesis was that patients in the TPT program would also have reduced glycemic variability, blood pressure, body mass index (BMI), and use of antihypertensive medications. The objective of the current study was to measure changes in glycemic variability, BMI, systolic and diastolic blood pressure, and antihypertensive medication use in patients using this novel TPT digital-twin approach to managing type 2 diabetes for 90 days.2). Patients with a history of ketoacidosis, major psychiatric disorders, or myocardial infarction, stroke, or angina within 90 days prior to enrollment were excluded. This study was approved by the Medisys Clinisearch Ethical Review Board. The study was performed in accordance with the Helsinki Declaration of 1964 and its later amendments. A written informed consent was obtained from all the subjects.This retrospective study followed 64 type 2 diabetes patients in India who chose to participate in the Twin Precision Treatment Program and adhered to program protocols. Each patient had at least 3 months of follow-up. The first patient enrolled in November 2018, and the patients completed the 3-month follow-up period by December 2019. To be included in the program, participants were required to have adequate hepatic and renal function , the platform collects data to track and analyse the body’s health signals and personalizes each patient’s treatment. The TPT platform uses artificial intelligence technologies  to construct a Digital Twin model of each patient with longitudinal biological data from sensors, bloodwork, and nutritional data reported via the TPT mobile application. The Digital Twin is a dynamic digital representation of each patient’s specific metabolism, enabling personalized prediction of future health states for different interventions and selection of the ideal intervention for each patient. This includes recommendation of the best nutrition, exercise, and sleep interventions for treating chronic conditions like T2D.During TPT Program enrollment, each patient’s vitals, clinical history, electrocardiogram and biothesiometry were assessed. Fasting blood draws were done in 30-day increments at baseline, 30 days, 60 days, and 90 days. The TPT Program was supported by assistance from health coaches. Upon receiving the initial blood test report, installation of the Twin mobile app, and activation of the sensors, patients began to receive nutritional inputs from the app and assisted by the health coach. Each patient was asked to wear a Fitbit Charge 2 sensor watch to continuously record heart rate, sleep parameters, step count, and other fitness parameters. Patients were asked to use a digital Bluetooth-enabled blood pressure meter (TAIDOC TD-3140) daily to record their blood pressure. Patients used a Powermax BCA-130 Bluetooth Smart Scale to measure their weight each morning after the first void of urine. Patients measured blood beta-hydroxybutyrate (BHB) levels with a finger prick each day. Continuous glucose monitoring (CGM) was performed to create Ambulatory Glucose Profiles throughout the study using an Abbott Libre Pro CGM Diabetes Sensor. This information was integrated into the TPT Program web-based software. All these data were transmitted to the software securely through a cellular network. The software access and biometric feedback sensor information were made available to the patients through the Twin app.27 and was further improved and expanded with additional items from certified sources28. The machine learning algorithm combined these multi-dimensional data to predict postprandial glucose response (PPGR) for each person. When the algorithm detected foods that led to high glucose area under the curve (AUC) values, it would then suggest foods with lower AUCs for that patient. Because, diet is a central determinant of blood glucose levels, it is essential to make food choices that induce normal PPGR in order to achieve normal glucose levels.Patients were asked to record their food intake on the app. To see what drove glucose response to specific foods for each participant, machine learning algorithms analysed the macronutrients, micronutrients, and biota nutrients from the database. Several types of machine learning algorithms were used, including gradient boosted decision trees, deep learning neural networks, and long short-term memory models. For each participant, factors were analysed that were found to be associated with higher glycemic response. Then participants were provided with specific food recommendations to avoid glucose spikes. Using machine learning algorithms and data fusion techniques that incorporated the continuous glucose monitor data, blood glucose values of the participants were predicted. Participants logged each food item and its quantity from every meal by selecting it from a database of more than 2000 foods together with full nutritional values. This information was based on the U.S. Department of Agriculture FoodData Central databaseThe goal of the Twin program is to provide the optimal combination of macronutrients, micronutrients and biota nutrients, while guiding each patient to eat foods that do not produce glucose spikes and to avoid foods that cause blood glucose spikes. The program placed no limit on calorie consumption, and patients were allowed to eat to satiety. Trained coaches provided nutritional assistance through telephone calls to assist in following the guidance from the app.When titrating patient medications, physicians followed medication guidelines, taking into account CGM values and patient characteristics. These medication changes were suggested by the Twin platform and were approved or altered by the physician. Patients’ insulin doses were adjusted based on their daily average blood glucose levels. Metformin and DPP-4 inhibitors were provided and titrated over time as blood sugar levels improved. Further medication management by the physician was based on customized guidelines. All patients’ symptoms were analysed and managed by the physicians.2) and systolic and diastolic blood pressure (mm Hg) were assessed at baseline (program enrollment) and at 30, 60, and 90 days after enrollment. Fasting insulin (mIU/l) and the percent of patients taking antihypertensive medications were calculated at baseline and at 90 days of program participation. Using 96 daily blood glucose readings from each patient’s continuous glucose monitor, daily glycemic variability values for percent coefficient of variation (%CV), low blood glucose index (LBGI), and high blood glucose index (HBGI) were calculated from published formulas29 and averaged over the seven days ending at day 30, day 60, and day 90 and also averaged over the entire 90-day period. Values of %CV were also available for the first day of program participation. Values of the standard deviation of blood glucose were calculated on the first day of participation and during the seven days ending at day 90. CONGA values were calculated on the first and 90th days of participation. Lipid profile values were assessed at baseline and at 30 and 90 days.Patient age, gender, and duration of diabetes were recorded at enrollment. BMI  age of 52.44 (9.96) years at enrollment. Nineteen of the patients were female (29.69%). The patients had had diabetes for 8.43 (6.52) years at enrollment, on average Table .Table 1P2) decreased significantly over the study period, from 29.23 (5.83) at baseline to 28.12 (5.50) at 30 days, 27.87 (5.35) at 60 days, and 27.43 (5.25) at 90 days  (Table The patients’ mean (SD) BMI kg/m decreaseTwenty-three patients (35.94%) were taking antihypertensive medications at baseline, but only 3 patients (4.69%) required antihypertensive medications after 90 days of the program (p < 0.0001).On the first day of program participation, the mean (SD) glucose variability (%CV) was 20.58% (10.22). Mean and median glucose variability were maintained < 18% during the study. Mean %CV (SD) was 15.75% (6.10) during days 24 to 30 (p = 0.0006 vs first day), 16.62% (5.96) during days 54 to 60 (p = 0.0025), and 17.37% (6.00) during days 84 to 90 of the program (p = 0.0276). Similarly, over all 90 days of the study the average %CV was 17.34% (4.36) (p = 0.0102)  standard deviation of blood glucose (mg/dl) on the first day of program participation was 28.59 . This decreased to 20.96  during days 84 to 90 (p < 0.0001). The mean  CONGA value (mmol/l) on the first day of program participation was 7.38 , and this decreased to 6.39  on the 90th day (p = 0.0254).15 LBGI threshold level (≤ 2.5) during the study. Mean (SD) LBGI values during 24 to 30 days, 54 to 60 days, and 84 to 90 days were 1.77 (2.59), 1.14 (1.55), and 1.21 (1.76), respectively. Over all 90 days of the program, the average LBGI value was 1.37 (1.37)  during the study: 92.2%, 89.1%, and 87.5% during days 24 to 30, 54 to 60, and 84 to 90, respectively. Over days 1 to 90 of the study period, 90.6% of patients had HBGI < 4.5  high-density lipoprotein (HDL) cholesterol values increased from 42.9 (10.5) at baseline to 44.1 (14.2) at 30 days and 48.0 (12.2) at 90 days. Low-density lipoprotein values changed from 103.7 (33.9) at baseline to 120.2 (39.9) at 30 days and 117.5 (47.9) at 90 days. Non-HDL cholesterol was 138.1 (37.5) at baseline, 154.9 (41.9) at 30 days, and 144.1 (52.0) at 90 days. Total cholesterol changed from 181.0 (39.2) at baseline to 201.0 (48.0) at 30 days and 192.1 (51.0) at 90 days. Triglycerides decreased from 186.2 (103.8) at baseline to 157.7 (92.9) at 30 days and 135.1 (77.5) at 90 days. Finally, the ratio of triglycerides/HDL changed from 4.7 (3.4) at baseline to 4.9 (7.4) at 30 days and 3.1 (2.1) at 90 days.The CGM, food intake data, Internet of Things technology, and machine learning algorithms in the Twin Precision Treatment Program optimized combinations of nutrients and provided nutritional guidance to type 2 diabetes patients that helped them consume foods that do not produce glucose spikes and avoid foods that cause blood glucose spikes.The program participants in the current study reduced mean systolic blood pressure by 7.5% (p < 0.0001) and reduced diastolic blood pressure by 4.3% (p = 0.002) from baseline over the course of the 90-day study period. The TPT Program recommended patient-specific meal plans that depended on the likes and dislikes of the patient and that were balanced across macro, micro, and biota nutrients to reduce glucotoxicity and lipotoxicity. This helped to heal inflammation and may be a reason for the improved blood pressure. Patients were also provided with supplements to ensure sufficient micronutrients were consumed. Nutritional, activity, and sleep counselling were provided by trained health coaches through the app and via telephone. Additionally, the digital twin technology enabled precise management of nutrition, activity, and sleep and helped the coach focus on the most important lifestyle variables for that patient for the improvement of blood pressure. Daily home blood pressure monitoring was done by the patient, and measurements were transmitted through Bluetooth-enabled equipment to the patient’s mobile app and to the platform and were used by the coaches to measure the impact of these interventions. Hence a feedback loop was established which enabled the efficient reduction of blood pressure.26, the 63% reduction in fasting insulin level, and the reduction in average homeostatic model assessment of insulin resistance (HOMA-IR) from 7.4 (3.5) at baseline to 3.1 (2.5) at 30 days and 3.2 (2.8) at 90 days26. Additionally, the percent of patients taking antihypertensive medications decreased from 35.9 to 4.7% (p < 0.0001). For most patients, glycemic variability was stabilized during the first week of the program, and %CV, LBGI, and HBGI were maintained within normal or low thresholds over the 90 days.Improvements over the 90 days were also seen in BMI . BMI reductions may have stemmed from the nutritional interventions, increases in physical activity (mean (SD) steps taken per day increased from 4677.4 (2804.9) at baseline to 7004.1 (3999.0) at 90 days)31. Specifically, among patients with type 2 diabetes, each 10-mm Hg reduction in blood pressure has been associated with improved mortality, reductions in cardiovascular events, coronary heart disease, stroke, albuminuria, and retinopathy32.Hypertension is found in more than half of patients with diabetes. Hypertension increases diabetes patients’ risk of micro- and macrovascular disease and chronic kidney disease and increases costs. Diabetes and hypertension both have insulin resistance in common, and both improve with lifestyle intervention. Controlling blood pressure in patients with diabetes prevents and delays micro- and macrovascular complications31. In the present study, patients reduced their mean systolic blood pressure from 134.7 to 124.6 mm Hg and reduced mean diastolic blood pressure from 83.9 to 80.3 mm Hg at 90 days, with less than 5% of patients taking antihypertensive medication by the end of the study. After 10 weeks of intensive nutrition, behavioural counselling, digital coaching, and medication management, McKenzie et al. found similar blood pressure reductions in a much more obese population (a reduction from 132 to 125 mm Hg in systolic blood pressure and a reduction from 82 to 78 mm Hg in diastolic blood pressure)1.The literature suggests that blood pressure goals of systolic/diastolic blood pressure < 130/80 mm Hg are rarely attained in patients with diabetes and that treatments employing at least two medications are needed for most patients33. Prior studies have reported some improvements in BMI after certain types of intervention. In the intensive nutritional study by McKenzie et al., BMI decreased 7.2% in a population of morbidly obese patients with type 2 diabetes1. After 12 weeks of low-carbohydrate or low-glycemic diets, type 2 diabetes patients in another study22 reduced BMI from 37.8 to 34.4 (9.0%) and from 37.9 to 36.5 (3.7%), respectively. Over a similar time period, the present study found a 6.2% reduction in the BMI of patients whose initial mean BMI was 29.Monitoring BMI in patients with type 2 diabetes is important, as increased BMI is associated with decreased life expectancy34. In patients with mean duration of diabetes of 9.0 (6.0) years, Inzucchi et al. reported an increase in %CV from 21.0 to 25.7% and a decrease in HBGI from 15.4 to 5.3 in a 24-week study of type 2 diabetes patients who received an intensification of their insulin treatment35. In patients with duration of diabetes of 8.43 (6.52) years who participated in the TPT Program, the current study found that %CV over the 90-day program was substantially lower at 17.3%.Limited interventional studies were found that reported %CV, LBGI, and HBGI results. In a study by Ohara et al. of normal treatment of type 2 diabetes patients with mean (SD) duration of diabetes of 11.6 (9.2) years, mean %CV began at 24.3% and decreased to 21.7% at 24 weeks15. In the present study, mean LBGI and HBGI over days 1 to 90 were 1.37 (low range) and 2.13 (low range), respectively, and most patients were able to eliminate hypoglycemic medication use over that time26. As reported previously, all 12 patients who had been taking insulin were able to discontinue its use, two-thirds of the patients on metformin discontinued taking metformin, and almost every patient on other oral hypoglycemic medications was able to stop taking them26. Other metrics for this population, such as HbA1c, fasting glucose, time in range, and weight, were reported previously26.In a study of 549 patients with type 2 diabetes taking insulin or oral hypoglycemic medications, McCall et al. found that mean daily LBGI and HBGI values over weeks 8 to 26 of the study were approximately 0.5  and 5.5 (moderate range), respectivelyNo cases of diabetic ketoacidosis and no episodes of symptomatic hypoglycemia were observed in the current study. Additionally, no new cases of gout were reported. The overall average patient-reported program satisfaction score was 4.4 out of 5.The strengths of this study include significant reductions in BMI and blood pressure and the maintenance of %CV, LBGI, and HBGI below low thresholds, while eliminating antihypertensive and hypoglycemic medication use in nearly all patients. The out-patient nutritional intervention employed home-cooked foods, making the intervention sustainable. Accurate assessment of nutrition was aided by the patients’ app-based logging of food.Limitations of this study include its smaller study population, retrospective nature, and the lack of a control group. Additionally, increasing the length of the program will be a goal of subsequent studies.Following 90 days of the TPT Program, patients achieved low glycemic variability and significant reductions in BMI and blood pressure. Antihypertensive medication use was eliminated in nearly all patients. Future results will examine the long-term effectiveness and sustainability of the program.


Over the last decade interest has been shown in people with symptomatic lung disease who have features both of COPD and asthma. In this review we examine how COPD and asthma are defined and examine clinical characteristics of people defined by researchers as having asthma-COPD overlap (ACO). We look at pathological and physiological features along with symptoms and consider the impact of each diagnosis upon therapeutic management. We highlight challenges in the diagnosis and management of airway disease and the various phenotypes that could be part of ACO, in so doing suggesting ways for the clinician to manage patients with features of both asthma and COPD. Chronic obstructive pulmonary disease (COPD) is now recognised to be a major cause of ill health, increased health care expenditure and premature mortality internationally . The cur1 and FVC decrease with age and this is accelerated when people smoke tobacco or are exposed to other noxious inhaled insults [1 to FVC with a value of 0.7 or less signifying that obstructed airflow is present. This simple measurement identifies the presence of emphysema on CT scanning [1/FVC of 0.7 is the best predictor of subsequent ill health [Longitudinal studies measuring lung function prospectively and cross sectionally over time ,4,5 have insults . Moreove insults . Traditiscanning  and peopscanning . Howeverscanning . This hascanning . This clscanning  and therl health .If it has proven difficult to define airflow obstruction, it has been even harder to decide what the term ‘persistent’ means. This term could imply that obstruction did not resolve when measured over time, but whether this could include significant improvements in lung function that were still below the normal predicted value, as is seen in some patients with chronic asthma, was not clear. These differences in interpretation were soon recognised as having therapeutic significance. In the 1990s an important paper from the Netherlands suggested that inhaled corticosteroids (ICS) could produce significant improvements in symptoms and lung function in COPD patients . SubsequAs a result, rather than consider in more detail what bronchodilator reversibility might signify in a patient with structural lung damage due to cigarette (or any other relevant) exposure, the tendency has been to assign patients to mutually exclusive silos—either COPD or asthma. Clinicians have always realised that this is an oversimplification and that some typical COPD patients would show larger than expected benefit from treatment of various types. What has been less clear is whether this behaviour represents a variation within an established diagnosis or is a discrete condition which consistently behaves differently from ‘true’ asthma or COPD.Over the last decade there has been renewed interest in the idea of an asthma–COPD overlap (ACO) state in part driven by the desire of the pharmaceutical industry to identify a subset of COPD patients who might respond better to the existing anti-inflammatory treatments and to explain why some asthmatic patients did not improve to the degree anticipated when given them. The most cogent rational academic exploration of this idea came from Gibson et al. in 2009 . SubsequA key issue limiting the usefulness of the ACO concept is the lack of a consistent definition. This not only hinders academic study but also confuses the clinician. This problem is not restricted to ACO but has bedeviled the field of ‘airways disease’ for the last 60 years. Indeed, the portmanteau term ‘airways disease’ to describe asthma, COPD and related conditions is itself unsatisfactory as it fails to account for airflow obstruction due to emphysema. Clearly if we have issues defining asthma and COPD, it is going to be hard to identify overlaps between them.As has been noted before, defining both asthma and COPD is like love—everyone knows what it is when it happens, but it is hard to explain to other people. By the 1980s advances in pulmonary pathology and physiology meant that definitions based only on symptoms such as chronic bronchitis were superseded by approaches using structural and/or lung function criteria. The CIBA symposium in 1959, perhaps the most famous of the meetings which attempted to re-define these conditions, proposed definitions based on variability in lung function for asthma, the presence of enlarged airspaces due to tissue loss for emphysema and symptoms of chronic cough . Helpful1, identified discrete natural histories of disease and whether this differed from that seen with patients diagnosed in life with emphysema. The famous longitudinal study of British postal workers led by Charles Fletcher provided the unexpected answer that it was lung function that identified individuals whose lung disease progressed with smoking, rather than the symptoms of bronchitis [In the 1970s and 1980s, attention was paid to whether chronic bronchitis or physiology, in the form of the FEVonchitis . Thereafonchitis  and lungonchitis  has beenThe overlap between emphysema and bronchitis  seemed to have an international dimension with workers in the USA reporting most of their patients with chronic airflow obstruction as having emphysema (based on CXR appearances) while in Britain similar patients were defined as being bronchitic . EventuaThe contrast between asthma and bronchitis was not immune from the debate between ‘lumpers and splitters’. Unlike the British who felt that chronic bronchitis was a discrete disorder of prognostic significance, the Dutch group in Groningen led by Dick Orie advocated the concept of chronic non-specific lung disease which recognised the heterogeneous nature of conditions others would describe as bronchitis, emphysema or asthma, and grouped them together . In thisLongitudinal studies in the Netherlands and New Zealand in young people who have the clinical and physiological characteristics of asthma have shown how over time they can develop fixed airflow obstruction which is often diagnosed as being COPD ,30. WhetAlthough interest in this topic subsequently declined, the 2009 article by Gibson et al. reignited old uncertainties about whether a discrete phenotype of patients with features of both asthma and COPD existed . These aIn response to these concerns, the Global Initiative in Asthma (GINA) and Global Initiative in Obstructive Lung Disease (GOLD) produced a joint consensus document highlighting practical approaches to the management of ACO . SubsequBy contrast, the ATS workshop considered a wider range of issues and raised a series of research questions which needed to be addressed before the nature of ACO could be considered finalised . The EurThese problems in definition raise several concerns about the utility of the term ACO as an aid to both academic and clinical understanding of people with objectively defined airflow obstruction. In the following sections we will examine what evidence we have for a discrete overlap of pulmonary pathology between asthma and COPD, whether patients meeting the definition of ACO behave differently from others not diagnosed in this way and whether objective physiological tests which are often the main driver of an ACO diagnosis can be relied on to distinguish these patients from others with chronic airflow obstruction.There is a dearth of evidence for a discrete pathology occurring in ACO patients. This reflects the lack of a clear definition discussed above and the fragmented nature of the data about structural and immunological features of those who do meet whatever definition is considered appropriate. The issue is not just whether the pathologies typical of asthma or COPD co-exist in the same person, but in how many people such features are present without them exhibiting the defining conditions of the overlap state.In most cases it is accepted that a prior clinical diagnosis of asthma indicates the continuing presence of that condition. However, this is not necessarily the case. Often the diagnosis is not confirmed by any objective measurement and, in the case of the overlap between asthma and obesity, an asthma diagnosis is often made in patients without any evidence of enhanced airway responsiveness or spontaneous fluctuation in lung function . The cle1 decreased in asthmatics, but the degree of air trapping, a measure of pulmonary hyperinflation, was the main driver of a low FEV1 in COPD patients. The degree of emphysema contributed to the decreased FEV1 in COPD patients but was infrequent in patients with asthma. Thus, different pathological changes contribute to the impaired physiology, but airways disease plays a role either directly or indirectly in both asthma and COPD.For many years there was a consensus based on chest X-ray studies that emphysema only rarely occurs in asthmatic patients but was a frequent finding in those presenting with COPD. It is now clear that in most COPD patients the loss of the small airways precedes the development of emphysema which becomes a more prominent feature as lung function loss worsens ,40. The 1 change of more than 12% baseline and 200mL after an unspecified bronchodilator or 4 weeks of anti-inflammatory treatment together with variable symptoms were used to define ACO. Patients exhibiting a positive response had thicker proximal airways and less evidence of emphysema than those who did not. However, the mean FEV1 in this study was relatively high at 70% predicted, so extrapolation to more severe COPD should be done with caution.These pathological issues have been more directly addressed by a Japanese group who report 3D CT imaging in COPD patients with and without a diagnosis of ACO based on the presence of a bronchodilator response and matched for their smoking history . In thisDirect study of the nature of airway inflammation in ACO subjects should help resolve matters. One of the few studies to report data on this topic came from a group in Basel who systematically collected biopsies from 129 COPD patients without features of asthma, 19 smoking asthmatics and 18 COPD patients with ACO, all of whom were undergoing diagnostic bronchoscopy and biopsy procedures. They defined ACO using a modified ERS consensus definition , but unlAn alternative approach to establishing overlap would be to look for differences in biomarkers of tissue inflammation between ACO and non-ACO COPD patients. This would be a very helpful strategy if the biomarkers concerned were both specific and sensitive in distinguishing asthma from COPD. Many inflammatory biomarkers have been linked to asthma with fractional exhaled breath nitric oxide (FeNO), being widely used as a marker of Th-2 inflammation. Unfortunately, the inflammatory process and its attendant biomarkers change as the clinical presentation of asthma evolves, with a more neutrophilic, less eosinophilic profile being seen in severe asthma, especially among patients who are relatively resistant to systemic corticosteroid treatment . Blood eAttempts to use these variables to separate ACO from COPD patients who do not meet the clinical criteria for this condition have generated conflicting results. Li et al. found that in 48 patients (42% with a history of smoking and 50% taking ICS) that an FeNO >31.5 ppb identified patients with ACO who smoked with a sensitivity of 70% and a specificity of 90% . HoweverIn many ways the most powerful argument for the existence of an overlap state between asthma and COPD comes from genetics. By combining data from several pathological studies in asthma and COPD, Christenson et al. found that genes associated with a Th2 phenotype in asthmatics were also expressed in patients with COPD and that blood eosinophil counts and airway responsiveness were increased when this was the case . They arIt could be argued that it is not important whether or not there is a clear definition of ACO if clinicians can identify a group of patients who should be managed differently. This approach runs the risk of committing the Procrustean crime of making the facts fit the prejudice of the observer—in this case that ACO must exist.In So far, data have largely focused on the overlap of COPD and asthma, i.e., in patients who look like they have COPD, how many have some features that are atypical and would fit better with a diagnosis of asthma. There are plentiful data about what happens when a young person diagnosed with asthma continues with symptoms into adulthood. Work from the Netherlands, Aberdeen, Australia and New Zealand have shown in patients followed for up to 45 years that a significant number of asthmatics go on to develop fixed airflow obstruction which is re-defined as COPD by the clinicians managing them ,65,66,67Thus far, physiological measurements made in ACO patients have been largely confined to spirometry rather than collecting data about lung volumes or gas transfer. Some studies have reported the results of non-specific bronchial challenge testing with either inhaled histamine or methacholine as the inhaled agonist ,72, but 1, the volume that a subject can expire in one second during a forced expiration from total lung capacity. Reliable standards exist for the performance [1, which means that tests repeated a few minutes apart can differ by chance by up to 160 mL. Rather surprisingly this between test variability is not much influenced by the initial FEV1 of the subject, although it is somewhat lower when the pre-test FEV1 falls below 1.5 L. By contrast the FVC is more effort dependent with a potential for more between test variation which has meant that it is less often reported during AHR and BDR tests. This is unfortunate as change in FVC gives more clinically relevant data about lung volume change in COPD and has been suggested as a better guide to AHR in asthma [In routine laboratory practice both the measurement of airway hyperresponsiveness (AHR) and BDR rely on changes in the FEVformance  which exn asthma .1 is relatively normal, but as the pre-test FEV1 falls the same dose of agonist can produce a more dramatic fall in FEV1 due to the altered airway geometry rather than a greater degree of airway smooth muscle contraction. In this context, absence of AHR is more informative than its presence, as has been seen when trying to interpret the diagnosis of asthma in obese subjects [1 over time [Although considered as being equivalent measurements of airway smooth muscle responsiveness, AHR and BDR tests are not interchangeable and often say more about the pathology of the surrounding lung than the medium sized airways where most of the inhaled stimulant is delivered. In general, AHR testing is used to diagnose asthma with a series of threshold changes identifying mild to severe degrees of airway irritability. This approach works well if the initial FEVsubjects . Relativsubjects  and accover time .1 can increase by 500 mL or more and often returns to values within the predicted normal range. This form of acute reversibility is diagnostic of bronchial asthma when it occurs but is not the kind of change commonly seen in patients diagnosed as having ACO.The situation around interpreting bronchodilator responsiveness is, if anything, even more complex. 1. These effects are not as dramatic as is the case in bronchial asthma but are more than enough to account for the variable bronchodilator responses that characterise many COPD patients. None of this requires there to be any ‘co-existing’ asthmatic pathology in the lungs of the COPD patient.As with AHR testing, the physiological basis of BDR is more complex than is commonly appreciated. Airway smooth muscle (ASM) is widely present throughout the bronchial tree down to the terminal bronchioles. In health there is a normal spontaneous variation in the degree of airway smooth muscle activation (ASM tone) which can be reduced or abolished by bronchodilator drugs; hence the enthusiasm of endurance athletes to acquire a diagnosis of asthma. This spontaneous fluctuation in ASM tone is exaggerated in bronchial asthma through a combination of airway inflammation and enhanced ASM bulk  but is p1 is relatively preserved, but a 160 mL increase in FEV1 which is within the spontaneous variability of two FEV1 measurements could be interpreted as 16% reversibility in a patient with a baseline FEV1 of 1 L. This led to the current recommended volume change which must be at least 12% of the baseline value and exceed 200 mL [These theoretical considerations aside, there are many obstacles to the easy interpretation of a bronchodilator reversibility test. The protocol adopted will influence the result. In patients with moderate–very severe airflow obstruction the number of positive tests rises with the number of bronchodilators given to the patient , a fact d 200 mL . This wad 200 mL .To use any definition of bronchodilator reversibility to make clinical decisions requires it to be stable from day to day and this is not the case in patients without a history of asthma and diagnosed as having smoking-induced COPD. This became apparent when the reversibility testing data from the ISOLDE study conducted over 20 years ago were analysed  and has It would be helpful if patients with a positive BDR on one occasion behaved differently from those who did not but this does not seem to be true, at least in studies where patients did not have a history of prior asthma. The 4-year UPLIFT trial found no relationship between health status or exacerbation rate and the initial bronchodilator response . This wa1 after a short-term bronchodilator test remains uncertain.In summary, classification of individual patients as having an asthma–COPD overlap condition based on a single bronchodilator test is unreliable and influenced by the nature of the test conducted, the severity of pre-test lung function impairment, the way in which it is interpreted and between day fluctuations in ASM tone. How much of the apparent difference in behaviour at a group level is determined by a greater than anticipated improvement in FEVOne of the main reasons to identify patients as having ACO would be to vary their treatment in order to reflect the presence of a presumed dual pathology and potential treatment approaches have been reviewed before . At pres1 and prolong life in a large clinical trial population [The crucial drug class where a clear distinction might be helpful is in the use of anti-inflammatory drugs. The most studied class has been ICS and here prior belief seems to trump evidence. For many working in this field it has been an item of faith that inhaled corticosteroids are ineffective in COPD and hence they need an explanation for the large body of data that show that ICS, usually combined with a long-acting inhaled bronchodilator, can improve health status, decrease exacerbation frequency, decrease the rate of decline in FEVpulation . The sugpulation . However1 or health status, but there are retrospective data suggesting that patients with higher blood eosinophil counts have a reduction in lung function loss over time when treated with ICS [As discussed above blood eosinophil counts have been proposed as a way to identify an ACO subtype of COPD. Airway eosinophilia has been studied in airways disease for almost 20 years mainly focusing on patients with asthma and reporting induced sputum data . Howeverwith ICS . Rather with ICS . Like inwith ICS , this drwith ICS . FurtherThe problem for the ACO concept is that the presence of a higher blood eosinophil count is not related to other proposed features of an ACO diagnosis. The distribution of blood eosinophils in COPD populations is not different from that seen in healthy patients without the disease , suggestDoctors select medical labels for a variety of reasons—to explain to patients that their problems have a rational basis with predictable outcomes that are amenable to proven treatment, to indicate the likely clinical course and prognosis of the condition and finally, on some occasions, to conceal their diagnostic uncertainty and allow them freedom to select treatment that a more restrictive diagnosis would not necessarily allow. It is our view that most cases diagnosed as ACO fall into this last category. This is not due to any ill-intent on the part of the doctor but reflects the multidimensional way in which the diagnosis of asthma and COPD have been presented over the years with a lack of clarity about which features carry most weight in reaching a diagnostic conclusion and uncertainty about how the clinical manifestations of the illness relate to the pathological changes and disease mechanisms which cause them. It is now possible using more objective measurements made in life to categorise these processes differently but the ubiquity of both asthma and COPD, coupled with the long natural history of both conditions, make implementing this a challenging undertaking. Hence, we are likely to be left with composite diagnostic categories which will inform our clinical and academic approach to these conditions. This highlights the need for long-term cohort studies to better understand both the real-life trajectories of COPD and asthma over time, and to better identify phenotypes of patients who may experience features of COPD and asthma. The question remains in this setting—is ACO a useful diagnostic subdivision? As our review of the evidence suggests, we do not believe this is the case.At the individual patient level, the lack of agreement about what a doctor might mean by the term ACO is a huge drawback. Extrapolating treatment algorithms for this condition based on what occurs in its better-defined progenitor conditions is not helpful. Reliance on a positive bronchodilator response means that the chance of the diagnosis being changed rises with the number of times the test is repeated, even when relatively strict definitions of a positive response are applied. Even if the response is positive, it does not preclude a useful response to the currently available inhaled therapies. Selection of patients based on relative blood eosinophilia has a better evidence base, at least for exacerbation prevention with some anti-inflammatory treatments. However, these beneficial effects are linked to the higher blood eosinophil count (which itself shows modest between day variation) rather than the other features of ACO and appear to be distributed across the general population rather than confined to a particular subset of patients with airways disease. In larger population studies, subjects identified as having ACO report more exacerbations than those with COPD alone. This may reflect the nature of their COPD pathology which increases their apparent AHR and leads to more between day fluctuation in airway calibre for reasons other than abnormal airway smooth muscle function.Several approaches have been proposed to deal with these issues of classification. In a thoughtful article Wise and Putcha suggest four different ‘phenotypes’ of ACO  which beThus, the conclusion reached by the person who has thought most about this topic and advocated the renaissance of the term ACO in 2009, when they revisited this topic in 2015 , seems t“A precise and useful definition of asthma–COPD overlap has not been possible, and the condition itself appears to compromise several different sub-phenotypes. It is proposed that addressing disease components via a multidimensional approach to assessment and management of obstructive airway diseases will be useful to manage the heterogeneity of these conditions.”


Patients with primary hyperparathyroidism (pHPT) and impaired kidney function (estimated glomerular filtration rate (eGFR) < 60 mL/min) are offered parathyroidectomy (PTX) to protect them from further complications. Surprisingly, two recent uncontrolled cohort studies have suggested a further decrease in kidney function following PTX. We aimed to examine the effects of PTX compared to non-surgical surveillance on kidney function in pHPT patients.n = 1977 (55%) were treated with PTX (PTX-group) whereas n = 1608 (45%) were followed without surgery (non-PTX group). Baseline was defined as time of diagnosis and kidney function was re-assessed 9–15 months after PTX (PTX group) or 9–15 months after diagnosis (non-PTX group).Historic cohort study. From the Danish National Patient Registry (NPR) and major medical biochemistry laboratories in Denmark, we identified 3585 patients with biochemically confirmed pHPT among whom p < 0.01). Stratification by baseline eGFR showed that the decrease was significant for those with a baseline eGFR value of 80–89 and > 90 mL/min, but not for those with lower eGFR values. Findings did not differ between patients with mild compared to moderate/severe hypercalcemia. However, after mutual adjustments, we identified baseline levels of calcium, PTH, and eGFR as well as age and treatment (PTX vs. no-PTX) as independent predictors for changes in kidney function.At follow-up, eGFR had decreased significantly in the PTX- compared to the non-PTX-group (median − 4% vs. − 1%, Compared to non-surgical surveillance, PTX is associated with a small but significant decrease in kidney function in pHPT patients with an initial normal kidney function. Primary hyperparathyroidism (pHPT) is an endocrine disease caused by parathyroid hormone (PTH) producing adenoma or hyperplasia in one or more of the 4 parathyroid glands . PTH levParathyroidectomy (PTX) is the only curative treatment for pHPT , 2. If sn < 300) and included only patients undergoing surgery (PTX) without studding changes in groups of patients not undergoing PTX. Accordingly, no studies have so far addressed whether a similar decrease in kidney function may occur during observation without surgery.In several studies, pHPT has been associated with an increased risk of kidney complications in terms of impaired kidney function and increased risk of kidney stones and nephrocalcinosis. Of importance, a decreased kidney function may by itself contribute to elevated PTH levels which may result in a circulus vitiosus. Accordingly, PTX is recommended by guidelines in case of kidney stones/nephrocalcinosis or if eGFR is below 60 mL/min , 5–10. RWithin a large cohort of patients with biochemically confirmed pHPT, we aimed to compare effects of PTX versus observation on kidney function measured after 1 year (9–15 months) of follow-up. Additionally, we stratified the results for baseline levels of kidney function as well as degree of hypercalcemia.In this observational study, we retrospectively identified patients with biochemically confirmed pHPT who had been treated by PTX (PTX group) or followed without surgery (non-PTX group).A flow-chart presenting selection of the study population is shown in Fig. The Danish Data Protection Agency was notified about the database (# 1–16–02-135-15), and the Danish Health and Medicines Authority granted access to retrieve data from hospital charts (# 3–3013-948/1).All Danish citizens are assigned a Civil Personal Registration (CPR) number allowing linkage between different registers. Using the CPR number, we requested results of measurements of plasma PTH, calcium and creatinine levels from major Danish medical biochemistry laboratories.A mean of two measurements of ionized or total calcium levels were above the upper limit of the reference interval.An ionized and total calcium level were both above the upper limit of the reference interval, if only one measurement of ionized or total calcium levels was available.Hypercalcemia and a high PTH level, which were normalised following PTX, if only one measurement of plasma calcium was available.We considered a diagnosis of pHPT as confirmed if blood tests on two separate occasions showed an average PTH level in the upper third- or above the upper limit of the reference interval with concomitant hypercalcemia . Since calcium levels were measured as a mixture of both ionizing and total levels at different laboratories, we accepted a diagnosis of hypercalcemia if:We used reference ranges from the local laboratories performing the analyses.In addition to excluding patients without a diagnosis of pHPT which could be confirmed by biochemistry, we restricted the population to only patient with sporadic pHPT by excluding patients who (ever) had been assigned a diagnosis of familial hypocalciuric hypercalcemia (FHH), multiple endocrine neoplasia (MEN) or parathyroid cancer. Furthermore, we excluded patients with kidney insufficiency diagnosed more than 1 year prior to the diagnosis of pHPT. From these criteria, 6884 patients with biochemically confirmed pHPT were identified.n = 3088). Furthermore, we excluded patients below 18 years of age (n = 5), as the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) Equation used to calculate eGFR values only is considered valid for patients above 18 years of age [As we aimed to study effects of PTX on kidney function from baseline to follow-up, we excluded patients without available measurements of plasma creatinine levels at baseline  and/or after 9–15 months of follow-up  (s of age . Using ts of age . Accordin = 3791), who had been assigned a procedural ICD-code of parathyroid or thyroid surgery . We included a search for thyroid surgery as it is our experience that some patients with pHPT have thyroid surgery in combination with PTX, but not always are assigned an ICD-code for both procedures. Furthermore, in order to assure correct classification (PTX vs. no surgery) of patients diagnosed with pHPT just prior to end of our initial search in June 2015, we updated our search in November 2017. Thus, we identified 1608 patients who had not been assigned a procedural code as stated above, whereas 2183 patients had been treated with PTX. As we aimed to study effects of PTX on kidney function, we excluded patients with  unsuccessful PTX (n = 206) defined as lack of normalization of plasma calcium levels or no measurements available after surgery. Accordingly, the total study population consisted of 1977 in the intervention group (PTX-treated) and 1608 in the control (non-PTX) group).We used the Danish NPR to identify patients within this group  (25 and 75% percentiles). Group differences were assessed using Chi-square test for categorical variables. For continuous variables, we compared differences between groups using Mann-Whitney U test. For changes within the group, we tested for statistical significance using Wilcoxon Signed Rank Test.The difference between baseline and follow-up levels of creatinine and eGFR was calculated in percentage to minimize differences caused by the varying measuring methods in the laboratories. Between groups differences in follow-up time, were accounted for by calculating average changes per year.In sub-analyses we stratified findings according to baseline levels of kidney function and hypercalcemia.Results were adjusted for age, sex and follow-up time in a General Linear Model using a univariate procedure. Furthermore, a multiple regression analysis was performed to assign predictors of change in kidney function.p-values < 0.05 were considered statistically significant.All statistical tests were two-sided and All calculations in the data analysis were performed using the IBM Statistical Package for Social Science (SPSS 26.0) for Mac .n = 964 (26.9%), between 60 to 90 mL/min in n = 1681 (46.9%) and below 60 mL/min in n = 940 (26.2%) of the patients. A total of n = 1977 (55%) were treated with (successful) PTX, whereas n = 1608 (45%) were followed without surgery. Characteristics of the non-PTX- vs PTX-group were significantly different in all studied aspects. The PTX group was younger, had higher men to women ratio and baseline biochemistry showed a better kidney function, and higher PTH and calcium levels.Baseline characteristics are displayed in Table At follow-up, all biochemical variables were within the normal range in the PTX-group. The follow-up time was significantly longer in the PTX group. This was due to the definition of the follow-up period in the PTX group as 9–15 months after PTX, which resulted in a mean time gap of 7 months from time of diagnosis to PTX.p < 0.001). This was not changed by accounting for differences in average follow-up time i.e., eGFR decreased by a median of 2.7% per year in the PTX group and by only 0.7% per year in the non-PTX group (p < 0.001).Compared with no surgical intervention, PTX was associated with an overall significant decrease in eGFR values Table . As showStratification by kidney function at baseline showed that the decline in kidney function following PTX was only significant in the group of patients with a baseline eGFR > 60 mL/min, whereas eGFR did not change significantly compared to the non-PTX group if baseline eGFR was < 60 mL/min Fig. b. AnalysFurther stratification of baseline eGFR values into eight categories  showed that only patients with a baseline eGFR between 80 and 89 mL/min and > 90 mL/min had a significant decline in kidney function following PTX compared to the non-PTX group  as in those with moderate to severe hypercalcemia Fig. .Table Results from our historic cohort study showed that after 9–15 months follow-up, surgical cure of pHPT is associated with a decline in kidney function compared to surveillance without surgical intervention. Subgroup analyses showed that this especially applies to those with an initial (near-) normal kidney function, whereas no decline in eGFR was observed if kidney function was impaired at baseline.Our results are in accordance with the findings from two previous retrospectives studies by Tassone et al.  and GarcPHPT is associated with an increased risk of kidney impairment through several of different mechanisms which include hypercalciuria, development of kidney calcifications and higher rate of hypertension , 22.Similar to previous studies, our study showed a high prevalence of kidney impairment as 26.2% of our included patients had an eGFR below 60 mL/min at baseline –25. HoweThus, no rapid decline in kidney function occurs shortly after diagnosis in patients managed conservatively. pHPT is known as a disease that often remains silent for several years before diagnosed . SeveralThe mechanism causing a decreased eGFR following PTX needs to be further elucidated. It may be speculated whether it is due to the well-known effect of PTH as a vasodilator  or the dOf interest, in our mutually adjusted multiple regression analyses, PTH levels at baseline were inversely associated with percentage change in eGFR. As no effect was observed in patients with impaired kidney function, it may be speculated whether PTH only causes kidney vasodilation if kidney function is well preserved. Of interest, PTH therapy of hypoparathyroidism for 8 years has been associated with a stable kidney function, whereas a decline in kidney function often occurs if patients are treated with conventional therapy in terms of active vitamin D and calcium supplements . FurtherThe strength of this study is firstly the large cohort which includes both a group that has received PTX and a control group, opposite the recent studies only investigating kidney function prior to and after PTX. However, our study design using a historic cohort makes it impossible to draw causal conclusions from our findings. As shown in Table Another strength of our study is that our data is based on the Danish NPR, which is a well-validated database . Data onBiochemistry was performed by various laboratories and we have no information on the exact measurement methods. We tried to compensate for this by using local reference ranges used by the specific laboratories in the relevant periods. In addition, to minimize differences caused by the different measurement methods, a percentage difference between baseline and follow-up levels of creatinine and eGFR was calculated, as most patients had these measurements performed in the same laboratory.Comparing our study with similar studies, other studies used additional exclusion criteria for the study population, like in the study from Tassone et al., thyroid and liver disease patients were excluded . We did Furthermore, it would have been of advantage if aldosterone levels had been included to test the hypothesis of an effect on eGFR of lowering aldosterone levels in response to PTX. However, aldosterone levels are not measured on a regular basis in patients with PHPT, and therefore aldosterone levels are not captured in our database. Nevertheless, we excluded patients with known kidney impairment > 1 year before the time of diagnosis, to eliminate other reasons of kidney impairment as well as tertiary hyperparathyroidism as a reason for the hyperparathyroid hypercalcemia.We cannot exclude that the observed effect on kidney function may be due to regression towards the mean. Prospective studies are needed to get a more profound understanding of this. Lastly, as pHPT is considered a slowly progressing disease, our follow-up time (9–15 months) was relatively short. In further studies, it could be of interest to study the long-term effects of PTX on kidney function.In conclusion, our study showed that PTX is associated with a clinically small but statistically significant decrease in kidney function after 9–15 months follow-up compared to pHPT patients followed without surgery. As it apparently only applies to patients with an initial (near-) normal kidney function, we do not think that this should be of major concern when deciding whether a patient with pHPT should be referred to PTX. Our findings are of interest in terms of the physiological effects of PTH on kidney function, which should be addressed more closely in further studies. Our findings do not exclude the possibility that long term kidney outcomes could be more favourable with PTX than with conservative treatment, but we did not find it to be the case in the short term.


Diabetes mellitus (DM) represents a major public health problem, with yearly increasing prevalence. DM is considered a progressive vascular disease that develops macro and microvascular complications, with a great impact on the quality of life of diabetic patients. Over time, DM has become one of the most studied diseases; indeed, finding new pharmacological ways to control it is the main purpose of the research involved in this issue. Sodium–glucose cotransporter 2 inhibitors (SGLT-2i) are a modern drug class of glucose-lowering agents, whose use in DM patients has increased in the past few years. Besides the positive outcomes regarding glycemic control and cardiovascular protection in DM patients, SGLT-2i have also been associated with metabolic benefits, blood pressure reduction, and improved kidney function. The recent perception and understanding of SGLT-2i pathophysiological pathways place this class of drugs towards a particularized patient-centered approach, moving away from the well-known glycemic control strategy. SGLT-2i have been shown not only to reduce death from cardiovascular causes, but also to reduce the risk of stroke and heart failure hospitalization. This article aims to review and highlight the existing literature on the effects of SGLT-2i, emphasizing their role as oral antihyperglycemic agents in type 2 DM, with important cardiovascular and metabolic benefits. Diabetes mellitus (DM) is a major public health problem, with yearly increasing prevalence. Worldwide, more than 460 million people have DM, with estimations stating that there will be over 700 million cases in the next 20 years . DM is aSodium–glucose cotransporter 2 inhibitors (SGLT-2i) are a modern drug class of glucose-lowering agents, whose use in DM patients has increased in recent years. Currently, the American Diabetes Association (ADA) recommends SGLT-2i as a second-line drug option, after metformin, for managing type 2 DM patients with established CVD . BesidesThis article aims to review and highlight the existing literature on the effects of SGLT-2i, emphasizing their role as oral antihyperglycemic agents in type 2 DM, with important cardiovascular and metabolic benefits.+/K+ ATP pump located on the membrane of the tubular cells provides the energy for glucose reabsorption, which is an active transport mechanism [In healthy persons, almost all filtered glucose is reabsorbed ≈180 g daily) and almost no glucose is found in the urine as a consequence of SGLT-2 and SGLT-1 action benefits. SGLT-2 proteins are mainly found in the proximal renal convoluted tubule segment 1, and are responsible for up to 90% of filtered glucose reabsorption, while, in humans, SGLT-1 acts on segment 3 of the proximal tubule and in the intestine, where it reabsorbs the remaining 10% of glucose ,17,18,190 g dailyechanism . The phyechanism . The mecechanism ,23. Currechanism ,24.By suppressing glucose reabsorption and increasing glucosuria , as well as promoting osmotic diuresis (≈400 mL/day), SGLT-2i reduce blood glucose and promote weight loss . The redTaking into consideration the fact that the glucose-lowering effect depends on kidney function, dysfunction of the renal system may alter this effect. Therefore, regarding the glucose-lowering efficacy, therapy with SGLT-2i is not recommended in patients with an estimated glomerular filtration rate (eGFR) <45 mL/min. On the other hand, given that SGLT-2i are associated with positive renal outcomes, therapy with this drug class may be considered in diabetic patients with renal impairment, to improve kidney function ,29,30. DDiabetes mellitus is a complex metabolic disorder frequently associated with excess weight, hypertension, dyslipidemia, and non-alcoholic fatty liver disease (NAFLD) ,34. MoreSGLT-2i have consistently proven their efficacy in improving glycemic control in patients with type 2 DM in numerous studies, reducing the levels of glycated hemoglobin (HbA1c), and improving the fasting and postprandial glycemic values .Bailey et al. assessed the efficacy and safety of dapagliflozin in patients with type 2 DM poorly controlled with metformin, in a phase 3, double-blind, placebo-controlled trial. A total of 546 patients were randomized to dapagliflozin 2.5, 5, or 10 mg, or a placebo, once daily. It was noted that treatment with dapagliflozin produced greater HbA1c reduction vs. the placebo  . A meta-p < 0.001 for both doses of canagliflozin) [p < 0.001) [In a 26-week, randomized, double-blind, placebo-controlled study, canagliflozin was assessed regarding its safety and efficacy in subjects with type 2 DM and poor glycemic control, uncontrolled with diet and exercise. Canagliflozin (100 and 300 mg) significantly reduced HbA1c compared to the placebo  . In a 24iflozin) . Empagli< 0.001) . A phase< 0.001) . After 2< 0.001) .Shyangdan et al. published a meta-analysis in 2016, which had the objective to indirectly compare SGLT-2i in diabetes treatment. Few differences between SGLT-2i were noted. In monotherapy, canagliflozin 300 mg achieved a greater HbA1c reduction vs. canagliflozin 100 mg (risk ratio (RR): 0.72%) and dapagliflozin 10 mg (RR: 0.63%), without significant differences when compared to empagliflozin . Goring p < 0.001) [According to a meta-analysis of randomized controlled trials, published in 2014, when added to other antidiabetic drugs, dapagliflozin reduced HbA1c and FPG by 0.52% and 20 mg/dL, respectively . A meta-< 0.001) .In a 24-week, randomized, controlled trial, empagliflozin 10 or 25 mg was added to pioglitazone in patients with type 2 DM, with or without metformin. Empagliflozin achieved a HbA1c reduction of −0.6% (10 mg) and −0.7% (25 mg) vs. −0.1% with a placebo (P for both doses of empagliflozin < 0.001) . FPG wasA summary of the presented studies, regarding the effects of SGLT-2i on improving glycemic control, is illustrated in SGLT-2i also have weight reduction benefits in diabetic patients, which may help in diminishing insulin resistance, reducing complications, and improving quality of life. Body weight loss was observed in patients with type 2 DM who were taking SGLT-2i as a monotherapy or in combination with other antidiabetic agents.Regarding body composition, Bolinder et al. showed, through dual-energy X-ray absorptiometry, that dapagliflozin reduced total body weight by mostly reducing fat mass . MoreoveFerrannini et al. observed that, even though glucosuria is persistent over time, body weight loss reaches a plateau, given that chronic glucosuria may induce an adaptive increase in energy intake. Therefore, SGLT-2i may induce greater weight loss if combined with reduced caloric intake . Ji et aCanagliflozin exhibits positive and dose-dependent effects on body weight, HbA1c, and systolic blood pressure reduction. Patients who achieved greater weight loss also achieved greater reductions in HbA1c and systolic blood pressure. A weight loss of 1% was associated with a 0.045% reduction in HbA1c and a 0.62 mmHg reduction in systolic blood pressure . In the Diabetic patients are prone to developing atherosclerotic cardiovascular disease (ASCVD), HF, and renal disease. The pathophysiological chain of the cardiorenal continuum illustrates a continuous progression up to the end stage of heart disease; with a focus on a diabetic subgroup, such as type 2 DM, this is the cardinal point in the cardiorenal continuum, as is shown in Referring to the effects of empagliflozin in type 2 DM patients with coronary artery disease, Bilgin et al. stated, in the SUPER GATE study, that the use of this SGLT-2i significantly reduced the anthropometric indices  associated with type 2 DM. In this subset of patients, the metabolic parameters, including low-density lipoprotein cholesterol levels, were improved, along with targeted blood pressure values and heart rate. The kidney function, assessed by serum creatinine levels and eGFR, was not significantly modified .The multicenter, double-blind, randomized controlled VERTIS-CV trial tested the effect of ertugliflozin on patients with type 2 DM and established ASCVD, and showed the non-inferiority of this SGLT-2i compared to a placebo, in terms of MACE and reduction in risk of the first hospitalization for HF, but not for known HF patients . The car2. Nonetheless, it remains to be clarified whether this beneficial effect can be attributed to the drug itself, or whether it is an SGLT-2 class effect [Chronic kidney disease (CKD) is recognized in 30% of patients with type 1 DM and 40% of patients with type 2 DM . Initials effect ,81,82. Es effect .The risk of developing HF in DM patients is at least two times higher compared to non-diabetic patients . The pot1. Decreased preload (increased osmotic diuresis and natriuresis);2. Decreased afterload ;+/H exchanger; increased myocardial energetics, systolic and diastolic function, cardiac output, heart rate, O2 consumption, and mediated coronary blood flow; reduction in myocardial Ca2+/calmodulin-dependent protein kinase II activity and left ventricular mass) [3. Strengthening of myocardial contractility (inhibition of cardiomyocyte Naar mass) ,84.SGLT-2i demonstrated positive effects on the scaling down of admission rates in HF patients, and the lowering of CV (cardiovascular) and all-cause mortality in diabetic patients ,85,86,87p < 0.001, at a 16-month follow-up. No significant differences were observed between empagliflozin-treated patients and patients treated with a placebo, in terms of hypoglycemic episodes, amputation of the lower limb, and bone fractures [The first clinical trial exploring the effectiveness of SGTL-2i on cardiovascular outcomes in HFrEF patients, EMPA-REG OUTCOME , met the primary outcome in lowering the deaths from cardiovascular causes, nonfatal myocardial infarction or stroke, and the secondary outcome for hospitalization for HF (hHF) . The 10 ractures . Empagliractures .The CANVAS study program  also confirmed the reduction in hHF in patients with type 2 DM and ASCVD, or patients at high risk for CV occurrence, and also confirmed the reduction in hospitalization of patients with no past events of HF. Canagliflozin diminished the risk of death from cardiovascular causes, nonfatal myocardial infarction, or stroke; however, an increased risk of amputation was recorded compared to a placebo .For dapagliflozin, the DAPA-HF (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure) study showed a reduction in hospitalization for HF and death from cardiovascular causes compared to a placebo, though this favored patients with NYHA II functional class compared to those with NYHA III or IV functional class . PositivA summary of the presented clinical trials in The results of the following ongoing trials will offer evidence-based data on the role of dapagliflozin in selected outcomes: Dapagliflozin Evaluation to Improve the LIVEs of Patients With Preserved Ejection Fraction Heart Failure (DELIVER), DAPA ACT HF-TIMI 68, Efficacy and Safety of Dapagliflozin in Acute Heart Failure (DICTATE-AHF), Dapagliflozin Heart Failure Readmission Study, DAPA MI Study, and Effectiveness of Dapagliflozin for Weight Loss ,96,97,98The recent understanding of the pathophysiological pathways of SGLT-2i places this class of drugs towards a particularized, patient-centered approach, moving away from the well-known glycemic control strategy. SGLT-2i exhibit beneficial outcomes regarding glycemic control in type 2 DM, while also exhibiting weight loss benefits; the latter effect is especially observed when combined with other weight-reduction agents. SGLT-2i, by promoting weight loss and positively impacting high blood pressure, may have an additional cardiorenal protective role. Moreover, SGLT-2i have been shown not only to reduce death from cardiovascular causes, but also to reduce the risk of stroke and hospitalization due to heart failure. As a result of the positive cardiovascular and renal outcomes reported by numerous studies, SGLT-2i might be considered as one of the most reliable and efficient treatment options in diabetic patients nowadays, given that one of the main goals in treating type 2 DM is to preservee and improve cardiorenal function. Relying on the results of SGLT-2i studies, with beneficial effects on cardiovascular outcomes and mortality in patients with type 2 DM, as well as in non-diabetic patients, prescribing this class of drugs in medical practice is becoming a priority in personalized medicine.


Hypertension (HTN) is a risk factor for cardiovascular disease; therefore, it is imperative to risk stratify potential kidney donors during evaluation. Clinic blood pressure (CBP) measurement is inaccurate in assessing presence or absence of HTN. There is paucity of data about utility of 24-h ambulatory blood pressure monitoring (ABPM) during kidney donor evaluation.24-h ABPM is performed on all kidney donors at Mayo Clinic Florida. We conducted retrospective review of 264 consecutive potential kidney donors from 1/1/2012 to 12/31/2017. Demographic, comorbid conditions, laboratory results and 24-h ABPM data were collected. Subjects were divided into two groups: Group1: Subjects with no prior history of HTN and new diagnosis of HTN using 24-h ABPM; Group 2: Subjects with no prior history of hypertension and normal BP on 24-h ABPM.P = 0.008). There was a trend of more non-Caucasians subjects (30.6% vs 19.9% P = 0.08) and more active smokers  in Group1 as compared to Group 2. Only 17 (27.4%) out of 62 newly diagnosed hypertensive subjects were deemed suitable for kidney donation as compared to 105 (58.0%) out of 181 normotensive subjects (P < 0.001).Baseline demographic included mean age 46.40 years, 39% males, 78.4% Caucasians, and mean BMI was 26.94. Twenty one subjects (8.0%) had prior diagnosis of HTN. Among 243 subjects without prior HTN, 62 (25.5%) were newly diagnosed with HTN using 24-h ABPM. CBP was high only in 27 out of 62 (43.6%) of newly diagnosed HTN subjects. Thirty-five subjects (14.4%) had masked HTN and 14 subjects (5.8%) had white-coat HTN. Newly diagnosed hypertensive subjects were more likely to be males as compared to Group 2 (53.2% vs 34.3% In our cohort, use of ABPM resulted in new diagnosis of HTN in 1 out of 4 potential kidney donors. Newly diagnosed HTN was more common in men, those with non-Caucasian race, and in active smokers. There was a significantly reduced acceptance rate for kidney donation among newly diagnosed HTN subjects. Further studies are needed to determine the value of 24-h ABPM among these high risk groups. Living kidney donation is critically important in renal transplantation because of the large number of end-stage renal disease patients on the kidney transplant waiting list . PotentiClinic blood pressure (CBP) measurement is the most common method of identifying hypertension; however, office based blood pressure measurement has several limitations due to measurement technique errors and inherent variability in the blood pressure . It is uIn the general, diagnosis of HTN is missed in about a quarter of the population and the prevalence of white coat HTN and masked HTN further complicate the matters . This phThe study was approved by institutional review board. Mayo Clinic Florida has integrated electronic health records (EHR) with access to kidney donor candidates’ work up. Subjects were identified from query of billing records for kidney donor evaluation between 01/01/2012 to 12/31/2017 at Mayo Clinic Florida where all kidney donor candidates undergo 24-h ABPM as part of routine pre-kidney donation evaluation. We retrospectively collected data from EHR on demographics, comorbidities, history of tobacco use, medications, office BP as well as data from 24-h ABPM, and laboratory results. Office BP was measured by clinical staff using auscultatory method with a wall aneroid sphygmomanometer  at the time of kidney donor evaluation visit at the transplant clinic. A cut-off value of systolic BP ≥140 mm (Hg) or diastolic BP ≥90 mm (Hg) was used to define elevated BP based on office BP measurement.Spacelabs ABPM monitor and software  was used for ABPM. BP was measured automatically and stored every 10 min during awake hours and every 20 min during nocturnal hours during 24-h ABPM. Subjects were determined to have new diagnosis of hypertension if they had no prior history of hypertension and/or not on antihypertensive medications at the time of donor evaluation, and if one of the following occurred during the 24-h ABPM: mean daytime systolic blood pressure > 135 mmHg, mean daytime diastolic blood pressure > 85 mmHg, mean nighttime systolic blood pressure > 120 mmHg, mean nighttime diastolic blood pressure > 75, overall 24-h mean systolic blood pressure > 130, overall 24-h mean diastolic blood pressure > 80.P values outlined above not meeting the criteria of new diagnosis of hypertension. Masked hypertension was defined as clinic systolic BP ≤ 140 mm (Hg) and clinic diastolic BP ≤ 90 mm (Hg) and ABPM exceeding the systolic or diastolic BP outlined above for the diagnosis of hypertension. Subjects were divided into two groups: Group 1: Subjects with no prior history of hypertension and new diagnosis of hypertension using 24-h ABPM during donor evaluation; Group 2: Subjects with no prior history of hypertension and normal BP on 24-h ABPM.White-coat hypertension was defined as clinic systolic BP ≥ 140 mm (Hg) or diastolic BP ≥ 90 mm (Hg) and ABPM systolic and diastolic Bp-values less than 0.05 were considered statistically significant. All analysis was performed in the R Statistical Software .Data were summarized with the mean (SD), for numeric variables and number (percent) for categorical variables. Chi-square was used to look for significant differences and relationships between categorical variables amongst groups. The Kruskal Wallis test was used to assess significant differences for continuous variables. All statistical tests were two sided and Total of 264 subjects underwent kidney donor evaluation between 01/01/2012 to 12/31/2017 at Mayo Clinic Florida. Baseline demographics included mean age 46.40 ± 13.13 years, 39.0% males, 78.4% Caucasian, mean BMI 26.93 ± 6.72, and history of tobacco use 39.8% (Table p = 0.36).Normal dipping pattern was defined as ≥10% drop in nocturnal systolic and diastolic BP as compared to awake systolic and diastolic BP readings. Non-dipping was defined as < 10% decrease in nocturnal systolic and diastolic BP as compared to awake systolic and diastolic BP. There was no statistically difference between the hypertensive and normotensive groups for abnormal dipping pattern  and Group 2  are summarized in Table P = 0.008). Trends observed consisted of more non-Caucasians race subjects (30.6% vs 19.9% P = 0.081) and more active smokers  in Group1 as compared to Group 2. There was no other statistical difference between the groups  Table There was a clinical and statistically significant difference in the percentage of subjects who were accepted for kidney donation among the newly diagnosed hypertensive and normotensive groups. Only 17 (27.4%) out of 62 newly diagnosed hypertensive subjects were deemed suitable for kidney donation as compared to 105 (58.0%) out of 181 normotensive subjects (p < 0.001), whereas there was no statistically significant difference for denial due to psychosocial issues . Furthermore, there was no statistically significant difference between the groups for other comorbid conditions . Among the normotensive group, 76 out of 181 subjects were deemed ineligible for kidney donation . There was a statistically significant difference between hypertensive and normotensive groups for denial due to medical reasons  of 243 potential kidney donors. While this number is seemingly small, this finding has important implications. By ruling out hypertension, we were able to proceed with the kidney donation in 7 out of 14 subjects (50% similar to normotensive group 58%) with all the subsequent benefits on the respective recipients. It also avoided the unnecessary use of anti-hypertensive medications, potential stress of carrying the hypertension diagnosis, and overburdening the medical health system. One important observation is that masked hypertension was 2.5 times as high in our cohort than white coat hypertension. This contradicts with previous studies  that exaOur study has important clinical implications. We acknowledge that 24-h ABPM might not be universally available in all transplant centers. In the current study, we were able to identify male gender, non-Caucasian race, and active smoking history as the population at risk in which a 24-h ABPM will be most beneficial. Even in situations where a 24-h ABPM is not available, we believe that in this at risk group relying solely on single clinic BP is not sufficient and other methods of measuring BP such as home BP monitoring or automated office BP measurement, which averages out multiple office BP readings, should be utilized. Indeed, previous studies have demonstrated that home BP and in office automated BP measurements do correlate with 24-h ABPM readings , 17.In the general population, there is limited data about the use of 24-h ABPM to screen for hypertension in the absence of abnormal office blood pressure readings. Our cohort, which represents a relatively healthy population that is volunteering to donate an organ, provides a unique opportunity to estimate the magnitude of undiagnosed hypertension in the community.The new diagnosis of hypertension may result in careful recalculation of risk benefit ratio for donor candidacy by both the transplant team and the potential donors. In our cohort, only 27.4% of subjects who had newly diagnosed hypertension were ultimately accepted as suitable candidates for organ donation as compared to 58.0% of normotensive subjects. Our study is limited by the lack of available data on whether new diagnosis of hypertension resulted in the unwillingness of donor candidates to further pursue kidney donation or the transplant team deciding not to accept as donors based upon the risk benefit ratio or the combination of the two factors. Over the last few years, there is an increasing acceptability of potential donors with controlled hypertension as suitable candidates . WhetherThe strengths of our study include large sample size, availability of data on office and ABPM, and detailed evaluation of co-morbid conditions. Our study is limited by its retrospective nature and the lack of specific reasons for donor denial. We are encouraged; however, that we included a large number of subjects that included larger proportion of non-Caucasian donors compared to previously published reports. While the definition of HTN in the general population has evolved over the period of the study, we used a unified definition over the 5-year study period for sake of simplicity and to facilitate statistical analysis. Future studies in living kidney donors using the current ACC/AHA criteria for diagnosing HTN should be performed to confirm or refute our results.In conclusion, using 24-h ABPM in a large number of living kidney donors that included 21.6% of the cohort of non-Caucasian race, we were able to demonstrate that relying on clinic BP alone did misclassify HTN in 20% of cases. We were also able to demonstrate that male gender, non-Caucasian race, and smoking history are risk factors for HTN misclassification and we recommend that scrutiny in measuring BP in these groups of potential kidney donors should be undertaken. Masked HTN was more prevalent in our cohort compared to previously published reports. Future studies should be directed to determine if the prevalence of masked HTN varies by donor race.